US20220089605A1 - Novel morphinans useful for treating medical disorders - Google Patents
Novel morphinans useful for treating medical disorders Download PDFInfo
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- US20220089605A1 US20220089605A1 US17/538,197 US202117538197A US2022089605A1 US 20220089605 A1 US20220089605 A1 US 20220089605A1 US 202117538197 A US202117538197 A US 202117538197A US 2022089605 A1 US2022089605 A1 US 2022089605A1
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- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 title abstract description 29
- 108020001588 κ-opioid receptors Proteins 0.000 claims abstract description 28
- 102000048260 kappa Opioid Receptors Human genes 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 59
- -1 1-hydroxylcyclopropylmethyl Chemical group 0.000 claims description 58
- 150000002431 hydrogen Chemical group 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 20
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 11
- 208000035475 disorder Diseases 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229930194542 Keto Natural products 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000000468 ketone group Chemical group 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 206010012335 Dependence Diseases 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 230000036407 pain Effects 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000005945 imidazopyridyl group Chemical group 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 208000003251 Pruritus Diseases 0.000 claims description 2
- LFMFPKKYRXFHHZ-UHFFFAOYSA-N R24 Chemical compound C1=C(Cl)C(C)=CC=C1NC1=NC(N)=C(C=CC=C2)C2=N1 LFMFPKKYRXFHHZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 208000000094 Chronic Pain Diseases 0.000 claims 1
- 208000004550 Postoperative Pain Diseases 0.000 claims 1
- 208000004296 neuralgia Diseases 0.000 claims 1
- 208000021722 neuropathic pain Diseases 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 201000009032 substance abuse Diseases 0.000 claims 1
- 231100000736 substance abuse Toxicity 0.000 claims 1
- 208000011117 substance-related disease Diseases 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- 208000009935 visceral pain Diseases 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 38
- 239000000556 agonist Substances 0.000 abstract description 9
- 238000006243 chemical reaction Methods 0.000 description 85
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 54
- 238000002360 preparation method Methods 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 239000012074 organic phase Substances 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 239000007787 solid Substances 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 125000003342 alkenyl group Chemical group 0.000 description 18
- 239000012071 phase Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 description 13
- 125000001183 hydrocarbyl group Chemical group 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 12
- 238000004108 freeze drying Methods 0.000 description 12
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 12
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
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- 150000002148 esters Chemical group 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
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- 125000002252 acyl group Chemical group 0.000 description 9
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
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- 125000004429 atom Chemical group 0.000 description 7
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—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:
- 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
- C07D489/08—Oxygen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/08—Bridged systems
Definitions
- the present disclosure generally relates to novel morphinans useful in treating medical disorders.
- KORs Kappa opioid receptors
- MORs mu opioid receptors
- DORs delta opioid receptors
- KORs such as analgesia, anti-pruritic actives (see Irian S, Cowan A. “Kappa opioid agonists suppress chloroquine-induced scratching in mice.” Eur J. Pharmacol 2004; 502, 233-7) and diuresis (see Barber A, Gottschlich R. “Novel developments with selective non-peptidic kappa-opioid receptor agonists.” Exp Opinion Investigational drugs. 1997; 6: 1351-68; DeHaven-Hudkins D L, Dolls R.
- KORs selective agonists were designed as potential analgesics in an attempt to avoid of side effects associated with traditional opioid analgesics such as respiratory depression, dependence, addiction, and constipation. Some KORs have been tested in clinical trial but failed due to side effects like diuresis, sedation, and dysphoria, et al or lack of efficacy. Some examples include spiradoline mesylate (see Wadenberg M L, “A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist.” CNS Drug Rev. 2003, Summer, 9(2): 187-98), enadoline for potential analgesics (see Walsh S L., Strain E C, Abreu M. E. Bigelow G. E.; “Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans.” Psychopharmacology 2001, 157, 151-162), and ADL-10-0101.
- CR-845 is another KORs agonist currently in the clinical trials for analgesics and anti-pruritic agents.
- TRK-820 was originally developed as potential analgesics but achieved success as anti-pruritic reagents and received regulatory approval in Japan.
- KORs agonists are also developed for other indications such fedotozine as potential therapeutics for irritable bowel syndrome and dyspepsia, and asimadoline as potential treatment for irritable bowel syndrome and functional dyspepsia.
- FIG. 1 is a response curve of compound 5a measuring the % effect versus the log of the concentration (nM) which affords the EC 50 .
- R is hydrogen, alkyl, substituted alkyl, cycloalkyl, alkyl cycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl;
- R 1 and R 2 independently are hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl;
- R 3 is hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol;
- R 7 and R 8 independently are hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl;
- R 10 is hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine
- R 14 is hydrogen, hydroxy, or alkoxy
- R 20 , R 21 , R 22 , R 23 , and R 24 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle;
- R 25 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent;
- X is nitrogen, oxygen, or sulfur
- the dashed line represents an optional double bond.
- compositions comprising any of the compounds of Formula (I) and at least one pharmaceutically acceptable excipient.
- the present disclosure provides a method for treating a kappa opioid receptor-related disease or disorder.
- the method comprises administrating the composition comprising a compound of Formula (I) to an individual in need thereof.
- the present disclosure provides compounds comprising Formula (I), pharmaceutical compositions comprising any of the compounds of Formula (I) and at least one pharmaceutically acceptable excipient, and methods for treating a kappa opioid receptor-related disease or disorder.
- the compounds disclosed herein have been shown to be selective to the kappa opioid receptor and, as such, would provide a therapy for treating kappa opioid receptor-related diseases or disorders.
- R is hydrogen, alkyl, substituted alkyl, cycloalkyl, alkyl cycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl;
- R 1 and R 2 independently are hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl;
- R 3 is hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol
- R 7 and R 8 independently are hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl;
- R 10 is hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine
- R 14 is hydrogen, hydroxy, or alkoxy
- R 20 , R 21 , R 22 , R 23 , and R 24 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle;
- R 25 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent;
- X is nitrogen, oxygen, or sulfur
- the dashed line represents an optional double bond.
- R may be hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl.
- R may be hydrogen, methyl, allyl, cyclopropylmethyl, or cyclobutylmethyl.
- R may be cyclopropylmethyl or 1-hydroxylcycloproylmethyl.
- R 1 and R 2 independently may be hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl. In other embodiments, R 1 and R 2 independently may be hydrogen, hydroxyl, methoxy, methyl, or chloride. In specific embodiments, R 1 and R 2 may be hydrogen.
- R 3 may be hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol. In other embodiments, R 3 may be hydroxy, methoxy, ethoxy, isopropoxy, or phenoxy. In specific embodiments, R 3 may be hydroxyl.
- R 7 and R 8 independently may be hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl. In other embodiments, R 7 and R 8 independently may be hydrogen, chloro, hydroxyl, amino, methoxy, or methyl. In specific embodiments, R 7 and R 8 may be hydrogen.
- R 10 may be hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine. In other embodiments, R 10 may be hydrogen, hydroxy, methoxy, or amine. In specific embodiments, R 10 may be hydrogen.
- R 14 may be hydrogen, hydroxy, or alkoxy. In other embodiments, R 14 may be hydrogen or hydroxy. In specific embodiments, R 14 may be hydrogen.
- R 20 , R 21 , R 22 , R 23 , and R 24 independently may be hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle wherein heterocycle is chosen from furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzo
- R 20 , R 21 , R 22 , R 23 , and R 24 may be aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle wherein the heterocycle is defined above.
- one of R 20 , R 21 , R 22 , and R 23 is a heterocycle or substituted heterocycle and the rest are chosen from hydrogen or halogen, and R 24 may be hydrogen wherein heterocycle is defined above.
- R 20 , R 21 , R 23 , and R 24 may be hydrogen and R 22 may be furyl, thienyl, or 4-hydroxyphenol.
- R 25 may be hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent wherein the heterocycle is defined above.
- R 25 may be hydrogen, alkyl, or substituted alkyl.
- R 25 may be C 1 -C 4 alkyl or substituted C 1 -C 4 alkyl.
- R 25 may be methyl.
- X may be nitrogen, oxygen, or sulfur. In other embodiment, X may be nitrogen or oxygen. In specific embodiments, X may be nitrogen.
- the dashed line may represent an optional double bond. In specific embodiments, the dashed line may represent a single bond.
- R may be cyclopropylmethyl or 1-hydroxylcyclopropylmethyl;
- R 3 may be hydroxyl;
- R 1 , R 2 , R 7 , R 8 , R 10 , R 14 , R 20 , R 21 , R 23 , and R 24 may be hydrogen;
- R 22 may be furyl, thienyl, or 4-hydroxyphenyl; and
- R 25 may be methyl as shown below.
- the morphinans and normorphinans detailed herein include any compound comprising a morphinan structure as diagrammed below, wherein R is alkyl, substituted alkyl, alkylcycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl in morphinans, and R is hydrogen in normorphinans.
- R is alkyl, substituted alkyl, alkylcycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl in morphinans
- R is hydrogen in normorphinans.
- the ring atoms of the core morphinan structure are numbered as shown below:
- Morphinan compounds have asymmetric centers.
- the core morphinan compound may have at least four chiral carbons (designated by asterisks in the diagram above); namely, C-5, C-13, C-14, and C-9.
- the compound comprising Formula (I) may have a ( ⁇ ) or a (+) orientation with respect to the rotation of polarized light. More specifically, each chiral center of the morphinans or normorphinans may have an R or an S configuration.
- the compounds described herein may have at least four chiral centers, namely carbons C-5, C-9, C-13, and C-14. At each chiral center, the stereochemistry at the carbon atom is independently R or S.
- the configuration of C-5, C-9, C-13, and C-14, respectively, may be RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, or SSSS, provided that the C-15 and C-16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule.
- the group on C-6 of the compounds comprising Formula (I) exist as alpha isomers or beta isomers.
- the alpha isomer to beta isomer ratio of any of these compounds may be from about 0:100 to about 100:0.
- the carbons on the cyclopropyl ring of the compounds comprising Formula (I) exist in either an R or S configuration.
- the compound comprising Formula (I) may be a free form or a salt.
- the salt is preferably a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts may include, without limitation, hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, acetate, formate, tartaric acid, bitartrate, stearate, phthalate, hydroiodide, lactate, monohydrate, mucate, nitrate, phosphate, salicylate, phenylpropionate, isobutyrate, hypophosphite, maleic, malic, citrate, isocitrate, succinate, lactate, gluconate, glucuronate, pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate, terephthalate, and the like.
- the pharmaceutically acceptable salt includes an alkaline or alkaline earth metal ion salt.
- sodium, potassium or other pharmaceutically acceptable inorganic salts are used.
- the salt forms may be amorphous or in various polymeric forms including hydrates, or solvates with alcohols or other solvents.
- the disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound comprising Formula (I) and at least one pharmaceutically acceptable excipient.
- a pharmaceutical composition of the disclosure comprises at least one pharmaceutically acceptable excipient.
- suitable excipients may include diluents, binders, fillers, buffering agents, pH modifying agents, disintegrants, dispersing agents, stabilizers, preservatives, and coloring agents.
- the amount and types of excipients may be selected according to known principles of pharmaceutical science.
- the excipient may include at least one diluent.
- suitable diluents may include microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, and trehalose.
- MCC microcrystalline cellulose
- cellulose derivatives i.e., acetate and butyrate
- the excipient may comprise a binder.
- Suitable binders may include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
- the excipient may include a filler.
- suitable fillers may include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone.
- the filler may be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
- the excipient may comprise a buffering agent.
- Buffers may include phosphates, carbonates, citrates, and the like.
- suitable buffering agents may include, but are not limited to, MOPS, HEPES, TAPS, Bicine, Tricine, TES, PIPES, MES, Tris buffers or buffered saline salts (e.g., Tris buffered saline or phosphate buffered saline).
- the excipient may include a pH modifier.
- the pH modifying agent may be sodium carbonate or sodium bicarbonate.
- the excipient may also include a preservative.
- suitable preservatives may include antioxidants, such as alpha-tocopherol or ascorbate, or EDTA (ethylenediaminetetraacetic acid), EGTA (ethylene glycol tetraacetic acid), BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), and the like.
- the excipient may include a disintegrant.
- Suitable disintegrants may include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
- the excipient may include a dispersion enhancer.
- Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose.
- the excipient may include a lubricant.
- suitable lubricants may include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.
- Suitable color additives may include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
- the weight fraction of the excipient(s) in the composition may be about 99% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1% or less of the total weight of the composition.
- the pharmaceutical composition may be mixed with one or more excipients to form a solid, liquid, or cream dosage form.
- excipients for example, a pharmaceutically acceptable carrier, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable carrier, or a pharmaceutically acceptable carrier, or a pharmaceutically acceptable carrier.
- Methods of formulating a solid, liquid, or cream dosage form are known in the art.
- the present disclosure provides processes to prepare compounds comprising Formula (I).
- the processes commences by converting the 6-keto position on the morphinan or nor-morphinan to the corresponding amino, hydroxyl, or thiol group in either the alpha isomer or beta isomer. These processes are disclosed and known in the arts.
- the next step in the process comprises contacting the amino, hydroxyl, or thiol group with an acyl group to form an amide, an ester, or a thioester.
- These processes may utilize an acyl coupling agent, a proton acceptor, and at least one solvent. These processes may be conducted at various temperatures and pressures. Numerous processes are known by the skilled artisan and disclosed in the arts.
- the present disclosure provides a method of treating a kappa opioid receptor-related disease or disorder, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I).
- compounds comprising Formula (I) are thought to mediate the kappa opioid receptor activity primarily as an agonist.
- the binding at this site is thought to treat pain, pruritis, addiction, depression, stress, anxiety, autoimmune disorders, mycocardial infarction, inflammation, edemia, emetic, or neurological diseases.
- a compound comprising Formula (I) may be administered orally via a solid or liquid dosage form (tablet, gel cap, time release capsule powder, solution, or suspension in aqueous or non-aqueous liquid), parenterally (i.e., subcutaneously, intradermally, intravenously, (i.e., as a solution, suspension or emulsion in a carrier), intramuscularly, intracranially, or intraperitoneally), or topically (i.e., transdermally or transmucosally, including, but not limited to buccal, rectal, vaginal and sublingual).
- a solid or liquid dosage form tablet, gel cap, time release capsule powder, solution, or suspension in aqueous or non-aqueous liquid
- parenterally i.e., subcutaneously, intradermally, intravenously, (i.e., as a solution, suspension or emulsion in a carrier), intramuscularly, intracranially, or intraperitoneally
- topically i.e.
- the compounds may be administered in saline or with a pharmaceutically acceptable excipient as described above.
- the compound may be administered as primary therapy, or as adjunct therapy, either following local intervention (surgery, radiation, local chemotherapy) or in conjunction with at least one other chemotherapeutic agent.
- Suitable subjects may include, without limit, humans, as well as companion animals such as cats, dogs, rodents, and horses; research animals such as rabbits, sheep, pigs, dogs, primates, mice, rats and other rodents; agricultural animals such as cows, cattle, pigs, goats, sheep, horses, deer, chickens and other fowl; zoo animals; and primates such as chimpanzees, monkeys, and gorillas.
- the subject can be of any age without limitation. In a preferred embodiment, the subject may be a human.
- the compound comprising Formula (I) will be administered in a therapeutically effective amount which includes prophylactic amounts or lower dosages for example, when combined with another agent.
- an effective amount refers to doses of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof.
- the precise amount to be administered can be determined by the skilled practitioner in view of desired dosages, side effects, and medical history of the patient.
- the compounds comprising Formula (I) have an EC 50 of less than about 10 nM of the binding affinity of the kappa receptor. In various embodiments, the compounds comprising Formula (I) have an EC 50 of less than about 10 nM, or less than 8 nM, or less than about 4 nM, or less than about 1 nM.
- the compounds of Formula (I) have an EC 50 in the Flipr Calcium assay of less than 10 nM in whole cells.
- the compounds comprising Formula (I) have an EC 50 of less than about 10 nM, or less than 8 nM, or less than about 4 nM, or less than about 3 nM.
- acyl denotes the moiety formed by removal of the hydroxy group from the group COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R 1 , R 1 O—, R 1 R 2 N—, or R 1 S—, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
- acyloxy denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
- O oxygen linkage
- alkyl as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
- alkenyl as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
- alkynyl as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
- aromatic as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion.
- aromatic encompasses “aryl” groups defined below.
- aryl or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.
- Carbocyclo or “carbocyclic” as used herein alone or as part of another group denote optionally substituted, aromatic or non-aromatic, homocyclic ring or ring system in which all of the atoms in the ring are carbon, with preferably 5 or 6 carbon atoms in each ring.
- substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- halogen or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
- heteroatom refers to atoms other than carbon and hydrogen.
- heteroaromatic as used herein alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
- the heteroaromatic group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon.
- Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like.
- substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
- the heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom.
- Exemplary heterocyclo groups include heteroaromatics as described above.
- substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
- oxygen protecting group denotes a group capable of protecting an oxygen atom (and hence, forming a protected hydroxyl group), wherein the protecting group may be removed, subsequent to the reaction for which protection is employed, without disturbing the remainder of the molecule.
- oxygen protecting groups include ethers (e.g., allyl, triphenylmethyl (trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), ⁇ -methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (
- substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom, and moieties in which the carbon chain comprises additional substituents.
- substituents include alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- the solution was concentrated on rotary evaporator. To the residue was added ethyl acetate then followed by a saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and then concentrated in vacuo to a residue. The residue was chromatographed on silica gel with hexane/ethyl acetate as mobile phase providing 9.2 g of compound (3) as amorphous solid.
- naltrexone HCl (2) (10.g, 26.5 mmol) and THF (150 mL) was added a MeNH 2 solution (2.0 N, 15 mL, 30 mmol). The resulting mixture was stirred at room temperature under nitrogen for 30 minutes. Then, NaHB(OAc) 3 (12.3 g, 56.2 mmol) was added over two hours. Then, the reaction was quenched by slowly adding 1% HCl solution (60 mL). The solution was stirred at room temperature for 15 minutes and the pH was adjusted to 8.5 with NaHCO 3 powder. The top organic phase was separated; the aqueous phase was extracted with MeOH/CH 2 Cl 2 . The combined organic extracts were dried over anhydrous sodium sulfate.
- the combined organic extracts were filtered through diatomaceous earth; the organic filtrate was separated and dried over anhydrous sodium sulfate. After filtration, the dried organic phase was concentrated under vacuum.
- the measurement of opioid receptor binding affinity was conducted using a radioligand binding assay on the membranes prepared from HEK293 cells (human embryonic kidney cell line) that were heterologously expressed for the recombinant human mu, delta or kappa opioid receptors.
- the assay buffers used for opioid receptor binding studies were 50 mM Tris.HCl (pH 7.4) for KOR, 50 mM Tris.HCl (pH 7.4) with 5 mM MgCl 2 for MOR, and 50 mM Tris.HCl (pH 7.4) with 10 mM MgCl 2 plus 1 mM EDTA for DOR. Wash buffer was containing 50 mM Tris.HCl with pH 7.4.
- the opioid receptor binding affinity were compared to three known standards: Naltrindole, U-50488 (trans-(+)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamide, see M. Doi, T. Ishida and M, Inoue; Structure of K-agonist, U-50488 Acta Cryst. (1990). C46, 676-678), and DAMGO (D-Ala2 MePhe4, Gly(ol)5]encephalin, see Allan D. Blake, George Bot, John C.
- the radio ligands were prepared at the final concentration of 0.5 nM for [ 3 H]DAMGO, 0.5 nM for [ 3 H]diprenorphine, and 0.5 nM for [ 3 H] DADLE, which were used as the competing radioligands for mu, kappa and delta receptor respectively.
- Cell membrane of HEK293 cells transfected with opioid receptors was prepared in the amount of 20 ug of MOR, 6.7 ug of KOR and 6.7 ug of DOR per each well respectively. These membranes containing the receptor of interest were incubated with increasing concentrations of test compound in the presence of a single concentration of radioligand. The fixed concentration of the radioligand was used and serial dilutions of the test compound were prepared.
- Testing started at 10 uM of testing compound to 4-fold serial dilution for 8-points detection. Transfer 1 ⁇ l of compounds/high control/low control to the 96 well plates according to the plate map, then dispense 100 ⁇ l of membrane stock solution into the plate, add 100 ⁇ l of radio ligand solution. Incubation was carried out for 1 hour at room temperature with 300 rpm gentle agitation. Then, soaked the Unifilter-96 GF/C filter plates with 50 ⁇ l of 0.3% Poly ethyleneimine per well for at least 0.5 hour at room temperature, and filtered the reaction mixture through the plates using FilterMateTM harvester, then wash each plate for four times with cold wash buffer. The filter plates are then dried for 1 hour at 50° C. After drying, the filter was sealed in polyethylene and adds 50 ⁇ l of Perkin Elmer Microscint 20 cocktail and the radioactivity counted in a Perkin Elmer MicroBeta2 counter.
- Binding data are analyzed using GraphPad Prism 5.0 and IC 50 is generated by non-linear regression from dose response curves. Use the model “log (inhibitor) vs. response—Variable slope” to fit the data. This data is shown in Table 1.
- the compounds 5a, 5b, 7a, 7b, 18a, 19a, and 21a provided better IC 50 then U-50488.
- the FLIPR Calcium Assay is used to measure the ability of an opioid ligand to induce a functional response upon receptor binding.
- the MOR, DOR and KOR are G-protein coupled receptors (GPCRs) which play an important role in cell signaling.
- the receptor is activated by a ligand then triggering G-protein activation inside the cell.
- An activated G-protein induces various cascades of intracellular messengers including calcium flux.
- the functional cell-based assays evaluated the changes of intracellular calcium level which were detected through use of fluorescent calcium-sensitive reporter dyes.
- the basic system of performing a calcium mobilization assay includes the FLIPR Calcium Assay Kit and the FLIPR Tetra® System, which were used to observe changes in intracellular calcium levels and determine the dose-response in HEK293 cells transfected with the recombinant human mu, delta or kappa opioid receptors.
- the cells used in the assay were grown in the culture medium of 88% DMEM which contains 10% FBS, 300 ug/mL G418, 2 ug/mL Blasticidin, 1% GlutaMax and 1% Penicillin/Streptomycin (Hyclone-SV30010). Seeded 20000 cells in 20 uL medium to each well of assay plate (Greiner-781946), and the cells were maintained at 37° C. in an incubator with 5% CO 2 for 20 hours. The compound was then prepared at 5-fold serial dilution to get 10 doses and 500 nL of each concentration was transferred to compound plate.
- DMEM which contains 10% FBS, 300 ug/mL G418, 2 ug/mL Blasticidin, 1% GlutaMax and 1% Penicillin/Streptomycin
- assay buffer (20 mM HEPES and 1 ⁇ HBSS) was added to each well of compound plate; the plate was spin at 1500 rpm for 15 seconds. Then 20 uL of 2 ⁇ Fluo-4 DirectTM No-wash Loading Buffer ((Invitrogen-F10471) was gently dispensed to each well of assay plate and was spin at 1000 rpm for 15 s, incubated at 37° C. for 50 min. The assay plate was removed from the incubator and placed at room temperature for 10 min. Then, the assay plate, compound plate and tip box were placed directly into the FLIPR Tetra® System.
- compound 5a provided improved cell assays over U-69596 as well as compounds 5b, 7a, and 7b.
- the response curve for compound 5a is shown in FIG. 1 .
Abstract
The present invention related to novel morphinans, compositions comprising the novel morphinans, and their uses as agonists of the kappa opioid receptor.
Description
- This application is a continuation of U.S. application Ser. No. 16/834,449, filed Mar. 30, 2020 which claims the benefit of U.S. Provisional Application No. 62/826,188, filed Mar. 29, 2019, all of which is incorporated herein by reference in its entirety for all purposes.
- The present disclosure generally relates to novel morphinans useful in treating medical disorders.
- Kappa opioid receptors (KORs) exist in many parts of the body such as brain, spinal cord, and on central and peripheral terminals. KORs play an important role in signal transduction; like other two opioid receptors mu opioid receptors (MORs) and delta opioid receptors (DORs). Agonist-induced activation of KORs leads to the inhibition of adenylyl cyclase and calcium channel activity while stimulation of the potassium channel activities (see Law P Y, Wong Y H, Loh H H; “Molecular mechanisms and regulation of opioid receptor signaling” Annu Rev Pharmacol Toxicol 2000; 40: 389-430).
- A variety of physiological processes are related to the activation of KORs such as analgesia, anti-pruritic actives (see Irian S, Cowan A. “Kappa opioid agonists suppress chloroquine-induced scratching in mice.” Eur J. Pharmacol 2004; 502, 233-7) and diuresis (see Barber A, Gottschlich R. “Novel developments with selective non-peptidic kappa-opioid receptor agonists.” Exp Opinion Investigational drugs. 1997; 6: 1351-68; DeHaven-Hudkins D L, Dolls R. E.; “Peripherally restricted opioid agonists as novel analgesic agents.” Curr Pharm Des 2004; 10:743-57), inflammation, immune system modulation, et al. which offer great potentials for KORs to treat many medical disorder such as pain, depression, autoimmune disorders, and neurological diseases.
- Many KORs selective agonists were designed as potential analgesics in an attempt to avoid of side effects associated with traditional opioid analgesics such as respiratory depression, dependence, addiction, and constipation. Some KORs have been tested in clinical trial but failed due to side effects like diuresis, sedation, and dysphoria, et al or lack of efficacy. Some examples include spiradoline mesylate (see Wadenberg M L, “A review of the properties of spiradoline: a potent and selective kappa-opioid receptor agonist.” CNS Drug Rev. 2003, Summer, 9(2): 187-98), enadoline for potential analgesics (see Walsh S L., Strain E C, Abreu M. E. Bigelow G. E.; “Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans.” Psychopharmacology 2001, 157, 151-162), and ADL-10-0101.
- CR-845 is another KORs agonist currently in the clinical trials for analgesics and anti-pruritic agents. TRK-820 was originally developed as potential analgesics but achieved success as anti-pruritic reagents and received regulatory approval in Japan.
- KORs agonists are also developed for other indications such fedotozine as potential therapeutics for irritable bowel syndrome and dyspepsia, and asimadoline as potential treatment for irritable bowel syndrome and functional dyspepsia.
- What is needed is a novel opioid kappa agonists which has potential therapeutic value to treat various KORs-related medical disorder without side effects.
-
FIG. 1 is a response curve of compound 5a measuring the % effect versus the log of the concentration (nM) which affords the EC50. - Among the various aspects of the present disclosure is compound comprising Formula (I):
- wherein:
- R is hydrogen, alkyl, substituted alkyl, cycloalkyl, alkyl cycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl;
- R1 and R2 independently are hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl;
- R3 is hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol; R7 and R8 independently are hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl;
- R10 is hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine;
- R14 is hydrogen, hydroxy, or alkoxy;
- R20, R21, R22, R23, and R24 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle;
- R25 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent;
- X is nitrogen, oxygen, or sulfur; and
- the dashed line represents an optional double bond.
- In another aspect, the present disclosure provides pharmaceutical compositions comprising any of the compounds of Formula (I) and at least one pharmaceutically acceptable excipient.
- In still another aspect, the present disclosure provides a method for treating a kappa opioid receptor-related disease or disorder. The method comprises administrating the composition comprising a compound of Formula (I) to an individual in need thereof.
- Other features and iterations of the invention are described in more detail below.
- The present disclosure provides compounds comprising Formula (I), pharmaceutical compositions comprising any of the compounds of Formula (I) and at least one pharmaceutically acceptable excipient, and methods for treating a kappa opioid receptor-related disease or disorder. The compounds disclosed herein have been shown to be selective to the kappa opioid receptor and, as such, would provide a therapy for treating kappa opioid receptor-related diseases or disorders.
- (I) Compounds Comprising Formula (I)
- One aspect of the present disclosure provides compounds comprising Formula (I):
- wherein:
- R is hydrogen, alkyl, substituted alkyl, cycloalkyl, alkyl cycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl;
- R1 and R2 independently are hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl;
- R3 is hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol;
- R7 and R8 independently are hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl;
- R10 is hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine;
- R14 is hydrogen, hydroxy, or alkoxy;
- R20, R21, R22, R23, and R24 independently are hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle;
- R25 is hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent;
- X is nitrogen, oxygen, or sulfur; and
- the dashed line represents an optional double bond.
- In some embodiments, R may be hydrogen, alkyl, substituted alkyl, alkylcycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl. In other embodiments, R may be hydrogen, methyl, allyl, cyclopropylmethyl, or cyclobutylmethyl. In specific embodiments, R may be cyclopropylmethyl or 1-hydroxylcycloproylmethyl.
- In some embodiments, R1 and R2 independently may be hydrogen, halogen, hydroxy, alkoxy, aryloxy, amino, amine, nitro, alkyl, or substituted alkyl. In other embodiments, R1 and R2 independently may be hydrogen, hydroxyl, methoxy, methyl, or chloride. In specific embodiments, R1 and R2 may be hydrogen.
- In some embodiments, R3 may be hydrogen, hydroxy, alkyoxy, aryloxy, halogen, amino, or thiol. In other embodiments, R3 may be hydroxy, methoxy, ethoxy, isopropoxy, or phenoxy. In specific embodiments, R3 may be hydroxyl.
- In some embodiments, R7 and R8 independently may be hydrogen, halogen, hydroxy, alkoxy, amino, amine, thiol, alkyl, or substituted alkyl. In other embodiments, R7 and R8 independently may be hydrogen, chloro, hydroxyl, amino, methoxy, or methyl. In specific embodiments, R7 and R8 may be hydrogen.
- In some embodiments, R10 may be hydrogen, hydroxy, alkyoxy, keto, ether, ester, amino, or amine. In other embodiments, R10 may be hydrogen, hydroxy, methoxy, or amine. In specific embodiments, R10 may be hydrogen.
- In some embodiments, R14 may be hydrogen, hydroxy, or alkoxy. In other embodiments, R14 may be hydrogen or hydroxy. In specific embodiments, R14 may be hydrogen.
- In some embodiments, R20, R21, R22, R23, and R24 independently may be hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle wherein heterocycle is chosen from furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, thienyl, phenol, or imidazopyridyl. In other embodiments, at least one of R20, R21, R22, R23, and R24 may be aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, or substituted alkylheterocycle wherein the heterocycle is defined above. In another embodiment, one of R20, R21, R22, and R23 is a heterocycle or substituted heterocycle and the rest are chosen from hydrogen or halogen, and R24 may be hydrogen wherein heterocycle is defined above. In specific embodiments, R20, R21, R23, and R24 may be hydrogen and R22 may be furyl, thienyl, or 4-hydroxyphenol.
- In another embodiment, R25 may be hydrogen, halogen, alkyl, substituted alkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, substituted heterocycle, alkylheterocycle, substituted alkylheterocycle, or absent wherein the heterocycle is defined above. In some embodiments, R25 may be hydrogen, alkyl, or substituted alkyl. In an alternate embodiment, R25 may be C1-C4 alkyl or substituted C1-C4 alkyl. In specific embodiments, R25 may be methyl.
- In one embodiment, X may be nitrogen, oxygen, or sulfur. In other embodiment, X may be nitrogen or oxygen. In specific embodiments, X may be nitrogen.
- In other embodiments, the dashed line may represent an optional double bond. In specific embodiments, the dashed line may represent a single bond.
- In exemplary embodiments, R may be cyclopropylmethyl or 1-hydroxylcyclopropylmethyl; R3 may be hydroxyl; R1, R2, R7, R8, R10, R14, R20, R21, R23, and R24 may be hydrogen; R22 may be furyl, thienyl, or 4-hydroxyphenyl; and R25 may be methyl as shown below.
- In general, the morphinans and normorphinans detailed herein include any compound comprising a morphinan structure as diagrammed below, wherein R is alkyl, substituted alkyl, alkylcycloalkyl, alkenyl, substituted alkenyl, aryl, substitute aryl, alkylaryl, or substituted alkylaryl in morphinans, and R is hydrogen in normorphinans. For the purposes of illustration, the ring atoms of the core morphinan structure are numbered as shown below:
- Morphinan compounds have asymmetric centers. In particular, the core morphinan compound may have at least four chiral carbons (designated by asterisks in the diagram above); namely, C-5, C-13, C-14, and C-9.
- The compound comprising Formula (I) may have a (−) or a (+) orientation with respect to the rotation of polarized light. More specifically, each chiral center of the morphinans or normorphinans may have an R or an S configuration. The compounds described herein may have at least four chiral centers, namely carbons C-5, C-9, C-13, and C-14. At each chiral center, the stereochemistry at the carbon atom is independently R or S. The configuration of C-5, C-9, C-13, and C-14, respectively, may be RRRR, RRRS, RRSR, RSRR, SRRR, RRSS, RSSR, SSRR, SRRS, SRSR, RSRS, RSSS, SRSS, SSRS, SSSR, or SSSS, provided that the C-15 and C-16 atoms are both on the alpha face of the molecule or both on the beta face of the molecule.
- The group on C-6 of the compounds comprising Formula (I) exist as alpha isomers or beta isomers. The alpha isomer to beta isomer ratio of any of these compounds may be from about 0:100 to about 100:0.
- The carbons on the cyclopropyl ring of the compounds comprising Formula (I) exist in either an R or S configuration.
- The compound comprising Formula (I) may be a free form or a salt. When the compound is in a salt form, the salt is preferably a pharmaceutically acceptable salt. Pharmaceutically acceptable salts may include, without limitation, hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, acetate, formate, tartaric acid, bitartrate, stearate, phthalate, hydroiodide, lactate, monohydrate, mucate, nitrate, phosphate, salicylate, phenylpropionate, isobutyrate, hypophosphite, maleic, malic, citrate, isocitrate, succinate, lactate, gluconate, glucuronate, pyruvate, oxalate, fumarate, propionate, aspartate, glutamate, benzoate, terephthalate, and the like. In other embodiments, the pharmaceutically acceptable salt includes an alkaline or alkaline earth metal ion salt. In particular, sodium, potassium or other pharmaceutically acceptable inorganic salts are used. The salt forms may be amorphous or in various polymeric forms including hydrates, or solvates with alcohols or other solvents.
- (II) Pharmaceutical Compositions
- The disclosure also provides a pharmaceutical composition comprising a compound comprising Formula (I) and at least one pharmaceutically acceptable excipient.
- (a) Compounds Comprising Formula (I)
- The compounds comprising Formula (I) are described in more detail in Section (I).
- (b) Excipient
- A pharmaceutical composition of the disclosure comprises at least one pharmaceutically acceptable excipient. Non-limiting examples of suitable excipients may include diluents, binders, fillers, buffering agents, pH modifying agents, disintegrants, dispersing agents, stabilizers, preservatives, and coloring agents. The amount and types of excipients may be selected according to known principles of pharmaceutical science.
- In one embodiment, the excipient may include at least one diluent. Non-limiting examples of suitable diluents may include microcrystalline cellulose (MCC), cellulose derivatives, cellulose powder, cellulose esters (i.e., acetate and butyrate mixed esters), ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, corn starch, phosphated corn starch, pregelatinized corn starch, rice starch, potato starch, tapioca starch, starch-lactose, starch-calcium carbonate, sodium starch glycolate, glucose, fructose, lactose, lactose monohydrate, sucrose, xylose, lactitol, mannitol, malitol, sorbitol, xylitol, maltodextrin, and trehalose.
- In another embodiment, the excipient may comprise a binder. Suitable binders may include, but are not limited to, starches, pregelatinized starches, gelatin, polyvinylpyrrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, polypeptides, oligopeptides, and combinations thereof.
- In another embodiment, the excipient may include a filler. Suitable fillers may include, but are not limited to, carbohydrates, inorganic compounds, and polyvinylpyrrolidone. By way of non-limiting example, the filler may be calcium sulfate, both di- and tri-basic, starch, calcium carbonate, magnesium carbonate, microcrystalline cellulose, dibasic calcium phosphate, magnesium carbonate, magnesium oxide, calcium silicate, talc, modified starches, lactose, sucrose, mannitol, or sorbitol.
- In still another embodiment, the excipient may comprise a buffering agent. Buffers may include phosphates, carbonates, citrates, and the like. Representative examples of suitable buffering agents may include, but are not limited to, MOPS, HEPES, TAPS, Bicine, Tricine, TES, PIPES, MES, Tris buffers or buffered saline salts (e.g., Tris buffered saline or phosphate buffered saline).
- In various embodiments, the excipient may include a pH modifier. By way of non-limiting example, the pH modifying agent may be sodium carbonate or sodium bicarbonate.
- In another alternate embodiment, the excipient may also include a preservative. Non-limiting examples of suitable preservatives may include antioxidants, such as alpha-tocopherol or ascorbate, or EDTA (ethylenediaminetetraacetic acid), EGTA (ethylene glycol tetraacetic acid), BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), and the like.
- In a further embodiment, the excipient may include a disintegrant. Suitable disintegrants may include, but are not limited to, starches such as corn starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pecitin, and tragacanth.
- In yet another embodiment, the excipient may include a dispersion enhancer. Suitable dispersants may include, but are not limited to, starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose.
- In a further embodiment, the excipient may include a lubricant. Non-limiting examples of suitable lubricants may include minerals such as talc or silica; and fats such as vegetable stearin, magnesium stearate, or stearic acid.
- In still another embodiment, it may be desirable to provide a coloring agent. Suitable color additives may include, but are not limited to, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C).
- The weight fraction of the excipient(s) in the composition may be about 99% or less, about 95% or less, about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, about 65% or less, about 60% or less, about 55% or less, about 50% or less, about 45% or less, about 40% or less, about 35% or less, about 30% or less, about 25% or less, about 20% or less, about 15% or less, about 10% or less, about 5% or less, about 2%, or about 1% or less of the total weight of the composition.
- The pharmaceutical composition may be mixed with one or more excipients to form a solid, liquid, or cream dosage form. Methods of formulating a solid, liquid, or cream dosage form are known in the art.
- (III) Processes to Prepare Compounds Comprising Formula (I)
- In yet another aspect, the present disclosure provides processes to prepare compounds comprising Formula (I). The processes commences by converting the 6-keto position on the morphinan or nor-morphinan to the corresponding amino, hydroxyl, or thiol group in either the alpha isomer or beta isomer. These processes are disclosed and known in the arts.
- The next step in the process comprises contacting the amino, hydroxyl, or thiol group with an acyl group to form an amide, an ester, or a thioester. These processes may utilize an acyl coupling agent, a proton acceptor, and at least one solvent. These processes may be conducted at various temperatures and pressures. Numerous processes are known by the skilled artisan and disclosed in the arts.
- (IV) Methods of Treating Kappa Opioid Receptor-Related Disease or Disorder
- In still another aspect, the present disclosure provides a method of treating a kappa opioid receptor-related disease or disorder, wherein the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a compound of Formula (I).
- Without being bound to any theory, compounds comprising Formula (I) are thought to mediate the kappa opioid receptor activity primarily as an agonist. The binding at this site is thought to treat pain, pruritis, addiction, depression, stress, anxiety, autoimmune disorders, mycocardial infarction, inflammation, edemia, emetic, or neurological diseases.
- The compounds may be administered to the subject by a variety of routes. For example, a compound comprising Formula (I) may be administered orally via a solid or liquid dosage form (tablet, gel cap, time release capsule powder, solution, or suspension in aqueous or non-aqueous liquid), parenterally (i.e., subcutaneously, intradermally, intravenously, (i.e., as a solution, suspension or emulsion in a carrier), intramuscularly, intracranially, or intraperitoneally), or topically (i.e., transdermally or transmucosally, including, but not limited to buccal, rectal, vaginal and sublingual). In one embodiment, the compounds may be administered in saline or with a pharmaceutically acceptable excipient as described above. The compound may be administered as primary therapy, or as adjunct therapy, either following local intervention (surgery, radiation, local chemotherapy) or in conjunction with at least one other chemotherapeutic agent.
- Suitable subjects may include, without limit, humans, as well as companion animals such as cats, dogs, rodents, and horses; research animals such as rabbits, sheep, pigs, dogs, primates, mice, rats and other rodents; agricultural animals such as cows, cattle, pigs, goats, sheep, horses, deer, chickens and other fowl; zoo animals; and primates such as chimpanzees, monkeys, and gorillas. The subject can be of any age without limitation. In a preferred embodiment, the subject may be a human.
- Generally, the compound comprising Formula (I) will be administered in a therapeutically effective amount which includes prophylactic amounts or lower dosages for example, when combined with another agent. As used herein, “an effective amount” refers to doses of compound sufficient to provide circulating concentrations high enough to impart a beneficial effect on the recipient thereof. The precise amount to be administered can be determined by the skilled practitioner in view of desired dosages, side effects, and medical history of the patient.
- Generally, the compounds comprising Formula (I) have an EC50 of less than about 10 nM of the binding affinity of the kappa receptor. In various embodiments, the compounds comprising Formula (I) have an EC50 of less than about 10 nM, or less than 8 nM, or less than about 4 nM, or less than about 1 nM. I
- In general, the compounds of Formula (I) have an EC50 in the Flipr Calcium assay of less than 10 nM in whole cells. In various embodiments, the compounds comprising Formula (I) have an EC50 of less than about 10 nM, or less than 8 nM, or less than about 4 nM, or less than about 3 nM.
- The compounds described herein have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic form. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
- The term “acyl,” as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxy group from the group COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R is R1, R1O—, R1R2N—, or R1S—, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
- The term “acyloxy,” as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(O)O— wherein R is as defined in connection with the term “acyl.”
- The term “alkyl” as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.
- The term “alkenyl” as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
- The term “alkynyl” as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
- The term “aromatic” as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons. These aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion. The term “aromatic” encompasses “aryl” groups defined below.
- The terms “aryl” or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.
- The terms “carbocyclo” or “carbocyclic” as used herein alone or as part of another group denote optionally substituted, aromatic or non-aromatic, homocyclic ring or ring system in which all of the atoms in the ring are carbon, with preferably 5 or 6 carbon atoms in each ring. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- The terms “halogen” or “halo” as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
- The term “heteroatom” refers to atoms other than carbon and hydrogen.
- The term “heteroaromatic” as used herein alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon. Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- The terms “heterocyclo” or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo groups include heteroaromatics as described above. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- The terms “hydrocarbon” and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
- The term “oxygen protecting group” as used herein denotes a group capable of protecting an oxygen atom (and hence, forming a protected hydroxyl group), wherein the protecting group may be removed, subsequent to the reaction for which protection is employed, without disturbing the remainder of the molecule. Exemplary oxygen protecting groups include ethers (e.g., allyl, triphenylmethyl (trityl or Tr), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals (e.g., methoxymethyl (MOM), β-methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM), 2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters (e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate), silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), triphenylsilyl (TPS), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS) and the like. A variety of oxygen protecting groups and the synthesis thereof may be found in “Greene's Protective Groups in Organic Synthesis,” 4th Ed. by P.G.M. Wuts and T.W. Greene, John Wiley & Sons, Inc., 2007.
- The “substituted hydrocarbyl” moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom, and moieties in which the carbon chain comprises additional substituents. These substituents include alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxy, keto, ketal, phospho, nitro, and thio.
- When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements.
- Having described the invention in detail, it will be apparent that modifications and variations are possible without departing from the scope of the invention defined in the appended claims.
- The following examples are included to demonstrate certain embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples represent techniques discovered by the inventors to function well in the practice of the invention. Those of skill in the art should, however, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention, therefore all matter set forth is to be interpreted as illustrative and not in a limiting sense.
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- To a stirred solution of naltrexone (2) (9.15 g, 26.8 mmol) in 250 ml of toluene were added N-benzylmethylamine (3.6 ml, 28 mmol) and p-toluenesulfonic acid monohydride (51 mg, 0.268 mmol). The reaction flask was equipped with a Dean-Stark trap and was refluxed for 17 hours. The toluene was removed and the crude products were dissolved in 75 ml of methanol. NaBH3CN (2.1 g, 32.7 mmol) was then added to the resulting solution and the mixture was stirred at 0° C. After stirring for 2 h, LC-MS indicated the reaction was completed. The solution was concentrated on rotary evaporator. To the residue was added ethyl acetate then followed by a saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate twice. The combined organic layer was washed successively with saturated aqueous sodium bicarbonate solution, saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and then concentrated in vacuo to a residue. The residue was chromatographed on silica gel with hexane/ethyl acetate as mobile phase providing 9.2 g of compound (3) as amorphous solid.
- To a Parr bottle were added 6β-N-benzyl-N-methylnaltrexamine (3) (4.3 mmol), 10% Palladium on Carbon (wetted with ca. 50% water, 190 mg), and glacial acetic acid (30 mL). The Parr bottle was attached to the Parr Hydrogenation Apparatus and flushed three times with nitrogen and then with three times with hydrogen. The mixture was reacted for 24 hours at room temperature under a pressure of 35 psi of hydrogen. A reaction aliquot was taken and LC-MS indicated the reaction was complete. The Parr bottle was removed from the Parr Hydrogenation Apparatus and the reaction mixture was filtered through celite. The filtrate was concentrated. To the residue was added water (15 mL) and the pH was then adjusted to 9 using 29% ammonia. The resulting mixture was extracted with 1:9 methanol/chloroform, the organic extracts were combined, and dried over anhydrous sodium sulfate. The dried organic solution was concentrated in vacuo, the residue was purified on silica gel column with methanol/DCM/Et3N mixture as mobile phase, concentrating the collected fractions, and dried under vacuo, providing 1.2 g of product. M+H+=357.47 on LC-MS; 1H NMR (CDCl3) δ ppm 6.65 (1H, d, J=8.0 Hz), 6.54 (1H, d, J=8.0 Hz), 4.53 (1H, d, J=8.0 Hz), 3.05-2.97 (2H, m), 2.64-2.54 (3H, m), 2.49 (s, 3H), 2.36 (d, 2H, J=4 Hz), 2.22-2.13 (m, 2H), 1.95-1.92 (1H, m), 1.67-1.60 (2H, m), 1.45-1.40 (2H, m), 0.84-0.81 (1H, m), 0.52 (2H, d, J=8 Hz), 0.12-0.11 (2H, m)
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- To the mixture of 6β-N-methylnaltrexamine (4) (0.5 g, 1.4 mmol), (1S,2S)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen for two hours where LC-MS indicated the reaction was done. To the reaction solution was added ethyl acetate (70 mL). The resulting solution was washed with brine then dried over anhydrous sodium sulfate. The dried organic phase was concentrated on a rotary evaporator. The residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and this solution was cooled in ice bath. To the cooled solution was added an equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.4 g off-white solid. M+H+=491.37 on LC-MS.
- To the mixture of 6β-N-methylnaltrexamine (4) (0.5 g, 1.4 mmol), (1R, 2R)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen for two hours where LC-MS indicated the reaction was complete. To the reaction solution was added ethyl acetate (70 mL) and the resulting solution was washed with brine. The organic phase was dried over anhydrous sodium sulfate. The dried organic phase was concentrated on a rotary evaporator to a residue. The residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and the resulting solution was cooled in ice bath. To this solution was added an equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.5 g compound (3) as off-white solid. M+H+=491.36 on LC-MS.
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- To the mixture of naltrexone HCl (2) (10.g, 26.5 mmol) and THF (150 mL) was added a MeNH2 solution (2.0 N, 15 mL, 30 mmol). The resulting mixture was stirred at room temperature under nitrogen for 30 minutes. Then, NaHB(OAc)3 (12.3 g, 56.2 mmol) was added over two hours. Then, the reaction was quenched by slowly adding 1% HCl solution (60 mL). The solution was stirred at room temperature for 15 minutes and the pH was adjusted to 8.5 with NaHCO3 powder. The top organic phase was separated; the aqueous phase was extracted with MeOH/CH2Cl2. The combined organic extracts were dried over anhydrous sodium sulfate. The dried organic solution was concentrated under vacuum. The residue was further purified on silica gel column eluting with MeOH/CH2Cl2/Et3N. The product was obtained as off-white solid, M+H+=357.20 on LC-MS.
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- To the mixture of 6α-N-methylnaltrexamine (6) (0.5 g, 1.4 mmol), (1S,2S)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen for two hours where LC-MS indicated the reaction was complete. To the reaction solution was added ethyl acetate (70 mL). The resulting solution was washed with brine and the organic phase was dried over anhydrous sodium sulfate. The dried organic phase was concentrated under vacuum and the residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and cooled in ice bath. To the cooled solution was added equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.3 g off-white solid. M+H=491.24 on LC-MS.
- To the mixture of 6α-N-methylnaltrexamine (6) (0.5 g, 1.4 mmol), (1R,2R)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen for two hours where LC-MS indicated the reaction was complete. To the reaction solution was added ethyl acetate (70 mL). The resulting solution was washed with brine and the organic phase was dried over anhydrous sodium sulfate. The dried organic phase was concentrated on a rotary evaporator and the residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and cooled in ice bath. To the cooled solution was added equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.35 g off-white solid. M+H+=491.38 on LC-MS.
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- To a three-neck reaction flask under nitrogen was placed starting material (8) (14.0 g, 37.1 mmol), followed by adding dichloromethane (150 mL), and triethylamine (22.40 g, 221 mmol); the resulting mixture was cooled in ice bath, to the cold reaction was added acyl chloride (17.6 g, 122.1 mmol). After finishing addition, ice bath was removed; the reaction was stirred at room temperature for 4 hours; LC-MS analysis indicated the reaction was completed; the reaction was placed in ice bath, then water (200 mL) was added slowly to quench the reaction; the pH of the reaction mixture was adjusted to 4-5 with dilute hydrogen chloride. The organic phase was separated, the aqueous phase was extracted with dichloromethane (250 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate. After filtration, the dried organic phase was concentrated under vacuum; it provided a dark yellow solid, 10.18 g, [M+H]+=504.6 on LC-MS.
- To a three-neck reaction flask was placed the intermediate (9) (5.0 g, 9.9 mmol) and benzene (100 mL); to the resulting solution was added benzoic acid (1.21 g, 9.9 mmol) and benzylmethylamine (2.41 g, 19.8 mmol). The resulting mixture was heated to refluxing with azeotropic distillation for 24 hours. Then, the reaction was cooled to room temperature. To the reaction was added methanol (20 mL), followed by adding sodium cyano borohydride (0.94 g, 15.0 mmol). The reaction was stirred at room temperature for 2 hours. LC-MS analysis indicated the reaction was complete. To the reaction was added water (20 mL) and saturated sodium hydrogen carbonate solution (100 mL). The product was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (200 mL) and dried over anhydrous sodium sulfate. After filtration, the dried organic solution was concentrated under vacuum; the crude material was further purified on silica gel column with a mixture of ethyl acetate/hexane/methanol/triethylamine. Concentration of the collected fractions under vacuum provided an oil material, 6.0 g, [M+H]+=609.7 on LC-MS.
- In a three-neck reaction flask under nitrogen was placed intermediate (10) (6.0 g, 9.86 mmol) and THF. To the resulting solution was added LiAlH4 (1.50 g, 39.5 mmol), the reaction was heated to reflux for 2-4 hours; LC-MS analysis indicated the reaction was completed. The reaction was cooled to room temperature, then reaction was dumped into an ice/water mixture (150 mL); to the mixture was then added 20% sodium hydroxide solution (2 mL), followed by added ethyl acetate (150 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×150 mL). The combined organic extracts were filtered through diatomaceous earth; the organic filtrate was separated and dried over anhydrous sodium sulfate. After filtration, the dried organic phase was concentrated under vacuum. The crude material was further purified on silica gel column with a mixture of ethyl acetate/hexane/methanol/triethylamine, concentration of the collected fractions under vacuum provided an oil material, 3.16 g; [M+H]+=553.7 on LC-MS. 1H NMR (400 MHz, CDCl3): 0.43-0.48 (2H, m), 0.82-0.87 (2H, m), 1.30-1.70 (4H, m), 1.95-2.8 (1H, m), 2.15-2.32 (2H, m), 2.35 (3H, s), 2.53 (1H, d, J=12.8 Hz), 2.60-2.70 (2H, m), 2.75 (1H, d, J=12.8 Hz), 2.72-2.82 (1H, m), 2.97-3.8 (2H, m), 3.72 (1H, d, J=13.6 Hz), 3.81 (1H, d, J=13.6 Hz), 4.77 (1H, d, J=7.6 Hz), 5.22 (2H, s), 6.53 (1H, d, J=8.0 Hz), 6.73 (1H, d, J=8.0 Hz), 7.15-7.51 (10H).
- To the hydrogenation reaction flask was added intermediate (11) (3.16.0 g, 5.72 mmol and methanol (30 mL), followed by adding phthalic acid (1.9 g, 11.4 mmol) and 10% Pd/C (2.36 g). The reaction was carried out under hydrogen atmosphere at room temperature for 24 hours. LC-MS analysis indicated the reaction was complete. The reaction was filtered through diatomaceous earth and the filtrate was concentrated under vacuum to provide a grey solid, 3.38 g. [M+H]+=373.5 on LC-MS.
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- To a three-neck round bottom flask were added intermediate (9) (3.0 g, 5.96 mmol) and methanol (10 mL), followed by adding 30% methylamine in methanol (2.4 g, 23.1 mmol), and acetic acid (0.1 mL). The resulting mixture was stirred at room temperature for 2 hours and then the reaction was placed in ice bath. Sodium cyanoborohydride (1.5 g, 23.9 mmol) was added. The ice bath was removed and the reaction was stirred at room temperature for 24 hours. LC-MS analysis indicated the reaction was complete. To the reaction was added water (50 mL) and followed by adding ethyl acetate (150 mL). The mixture's pH was adjusted to ˜8 with saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (150 mL×2). The combined organic extracts were dried over anhydrous sodium sulfate. Concentrating the dried organic extracts under vacuum provided a solid, 3.15 g. [M+H]+=519.6 on LC-MS.
- In a three-neck reaction flask under nitrogen was placed intermediate (13) (3.15 g, 6.07 mmol) and THF (30 mL). To the resulting solution was added LiAlH4 (0.69 g, 18.2 mmol); the reaction was heated to reflux for 2-4 hours; LC-MS analysis indicated the reaction was completed. The reaction was cooled to room temperature and then poured into an ice/water mixture (100 mL). To the mixture was then added 20% sodium hydroxide solution (1.5 mL) followed by added ethyl acetate (100 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic extracts were filtered through diatomaceous earth, the organic filtrate was separated, and dried over anhydrous sodium sulfate. After filtration, the dried organic phase was concentrated under vacuum to provide an oil. 1.98 g; [M+H]+=463.6 on LC-MS.
- To the hydrogenation reaction flask under nitrogen was placed intermediate (14) (3.16.0 g, 5.72 mmol) and methanol (30 mL), followed by adding phthalic acid (1.42 g, 8.54 mmol) and 10% Pd/C (1.78 g). The reaction was then carried out under hydrogen atmosphere at room temperature for 24 hours. LC-MS analysis indicated the reaction was complete. The reaction was filtered through diatomaceous earth and was concentrated under vacuum to provide a grey solid, 2.72 g. [M+H]+=373.5 on LC-MS.
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- To the three-neck reaction flask under nitrogen at room temperature were added (1S,2S)-2-(3-furyl)cyclopropane-1-carboxylic acid (20 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL). The resulting solution was washed with 5% NaHSO4 aqueous solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 mL×3), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum. The residue was further purified on reverse phase LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined and the product was obtained as white powder after lyophilization, 10 mg, yield=14.7%. [M+H]+=507.6 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature were added (1R,2R)-2-(3-furyl)cyclopropane-1-carboxylic acid (20 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete and the solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL). The resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 m×3 L), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum, the residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization: 14 mg, yield=20.6%. M+H+=507.6 on LC-MS.
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- To the three-neck reaction flask under nitrogen at room temperature was added (1S,2S)-2-(3-furyl)cyclopropane-1-carboxylic acid (20 mg, 0.134 mmol), intermediate (12) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 mL×3), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate. The filtrate was then concentrated under vacuum and the residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% AC). The collected fractions were combined; the product was obtained as white powder after lyophilization, 14 mg, yield=20.6%. [M+H]+=507.6 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature were added (1R,2R)-2-(3-furyl)cyclopropane-1-carboxylic acid (20 mg, 0.134 mmol), intermediate (12) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 mL×3), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum and the residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization yielding a white powder, 21 mg, yield=30.9%. [M+H]+=507.6 on LC-MS.
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- To the three-neck reaction flask under nitrogen at room temperature were added (1S,2S)-2-(3-thienyl)cyclopropane-1-carboxylic acid (22.5 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete and the solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL) and the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL), 5% aqueous NaHCO3 solution (2.0 mL), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under vacuum and the residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 15 mg, yield=21.4%. [M+H]+=523.7 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature were added (1R,2R)-2-(3-thienyl)cyclopropane-1-carboxylic acid (22.5 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was done. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL), 5% aqueous NaHCO3 solution (2.0 mL), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtered organic phase was then evaporated under vacuum. The residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 6.5 mg, yield=9.3%. [M+H]+=523.7 on LC-MS.
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- To the three-neck reaction flask under nitrogen at room temperature were added (1S,2S)-2-(3-thienyl)cyclopropane-1-carboxylic acid (22.5 mg, 0.134 mmol), intermediate 12 (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL). The resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL), 5% aqueous NaHCO3 solution (2.0 mL), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum. The residue was further purified on reverse phase LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 13 mg, yield=18.5%. [M+H]+=523.7 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature were added (1R,2R)-2-(3-thienyl)cyclopropane-1-carboxylic acid (22.5 mg, 0.134 mmol), intermediate 12 (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 mL×3), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under vacuum. The residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 14 mg, yield=20.0%. [M+H]+=523.7 on LC-MS.
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- To the three-neck reaction flask under nitrogen at room temperature were added (1S,2S)-2-(3-thienyl)cyclopropane-1-carboxylic acid (23.9 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL), 5% aqueous NaHCO3 solution (2.0 mL), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum and the obtained residue was further purified on preparation LC with mobile phase (A:0.01% TFA/H2O, B:100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 16 mg, yield=22.4%. [M+H]+=533.6 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature were added (1R,2R)-2-(3-(4-hydroxylphenyl)cyclopropane-1-carboxylic acid (23.9 mg, 0.134 mmol), intermediate (15) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×2), 5% aqueous NaHCO3 solution (2.0 mL×2), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under vacuum. The residue was further purified on reverse phase LC with mobile phase (A: 0.01% TFA/H2O, B: 100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 13 mg, yield=18.2%. [M+H]+=533.6 on LC-MS.
-
- To the three-neck reaction flask under nitrogen at room temperature were added (1S,2S)-2-(3-(4-hydroxylphenyl)cyclopropane-1-carboxylic acid (23.9 mg, 0.134 mmol), intermediate (12) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solid was dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL), 5% aqueous NaHCO3 aqueous solution (2.0 mL), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under vacuum, the residue was further purified on preparation LC with mobile phase (A: 0.01% TFA/H2O, B: 100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 11 mg, yield=15.4%. [M+H]+=533.6 on LC-MS.
- To the three-neck reaction flask under nitrogen at room temperature was added (1R,2R)-2-(3-(4-hydroxylphenyl)cyclopropane-1-carboxylic acid (23.9 mg, 0.134 mmol), intermediate (12) (50 mg, 0.134 mmol) and THF (1.0 mL); after the solids were dissolved under stirring, DEPBT (80 mg, 0.268 mmol) and triethylamine (27 mg, 0.268 mmol) were added. The reaction was stirred at room temperature overnight. LC-MS analysis indicated the reaction was complete. The solvent was removed under vacuum. To the residue was added dichloromethane (2.0 mL), the resulting solution was washed with 5% aqueous NaHSO4 solution (2.0 mL×3), 5% aqueous NaHCO3 solution (2.0 mL×3), and brine (2.0 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then evaporated under vacuum. The residue was further purified on preparation LC with mobile phase (A: 0.01% TFA/H2O, B: 100% ACN). The collected fractions were combined; the product was obtained as white powder after lyophilization, 10 mg, yield=14.0%. [M+H]+=533.6 on LC-MS.
-
- To the mixture of intermediate (22) (prepared based on literature method (Chem. Pharm. Bull. 2004, 52(6), 664-669) (0.5 g, 1.4 mmol), (1S,2S)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen until LC-MS analysis indicated the reaction was complete. To the reaction solution was added ethyl acetate (70 mL). The resulting solution was washed with brine, dried over anhydrous sodium sulfate, and then filtered. The dried organic phase was concentrated under vacuum. The residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and this solution was cooled in ice bath. To the cooled solution was added an equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.14 g off-white solid. [M+H]+=505.37 on LC-MS.
- To the mixture of intermediate (22) (prepared based on literature method (Chem. Pharm. Bull. 2004, 52(6) 664-669)(0.5 g, 1.4 mmol), (1R,2R)-2-(3-furyl)cyclopropane-1-carboxylic acid (0.22 g, 1.4 mmol), DMF (5.0 mL) was added HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (0.53 g, 1.4 mmol) and triethylamine (0.39 mL, 2.8 mmol). The resulting yellow solution was stirred at room temperature under nitrogen until LC-MS analysis indicated the reaction was complete. To the reaction solution was added ethyl acetate (70 mL). The resulting solution was washed with brine, dried over anhydrous sodium sulfate, and then filtered. The dried organic phase was concentrated under vacuum. The residue was purified on silica gel eluting with a mixture of Et3N/MeOH/CH2Cl2. The collected desired fractions were concentrated under vacuum. The obtained oil product was dissolved in ethyl acetate and this solution was cooled in ice bath. To the cooled solution was added an equivalent of 1.0 N HCl in ether. The resulting mixture was concentrated under vacuum to provide 0.25 g off-white solid. [M+H]+=505.38 on LC-MS.
- The measurement of opioid receptor binding affinity was conducted using a radioligand binding assay on the membranes prepared from HEK293 cells (human embryonic kidney cell line) that were heterologously expressed for the recombinant human mu, delta or kappa opioid receptors.
- The assay buffers used for opioid receptor binding studies were 50 mM Tris.HCl (pH 7.4) for KOR, 50 mM Tris.HCl (pH 7.4) with 5 mM MgCl2 for MOR, and 50 mM Tris.HCl (pH 7.4) with 10 mM MgCl2 plus 1 mM EDTA for DOR. Wash buffer was containing 50 mM Tris.HCl with pH 7.4.
- The opioid receptor binding affinity were compared to three known standards: Naltrindole, U-50488 (trans-(+)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]phenylacetamide, see M. Doi, T. Ishida and M, Inoue; Structure of K-agonist, U-50488 Acta Cryst. (1990). C46, 676-678), and DAMGO (D-Ala2 MePhe4, Gly(ol)5]encephalin, see Allan D. Blake, George Bot, John C. Freeman, and Terry Reisine‡ Differential Opioid Agonist Regulation of the Mouse m Opioid Receptor* THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 272, No. 2, Issue of January 10, pp. 782-790, 1997).
- The radio ligands were prepared at the final concentration of 0.5 nM for [3H]DAMGO, 0.5 nM for [3H]diprenorphine, and 0.5 nM for [3H] DADLE, which were used as the competing radioligands for mu, kappa and delta receptor respectively.
- Cell membrane of HEK293 cells transfected with opioid receptors was prepared in the amount of 20 ug of MOR, 6.7 ug of KOR and 6.7 ug of DOR per each well respectively. These membranes containing the receptor of interest were incubated with increasing concentrations of test compound in the presence of a single concentration of radioligand. The fixed concentration of the radioligand was used and serial dilutions of the test compound were prepared.
- Testing started at 10 uM of testing compound to 4-fold serial dilution for 8-points detection. Transfer 1 μl of compounds/high control/low control to the 96 well plates according to the plate map, then dispense 100 μl of membrane stock solution into the plate, add 100 μl of radio ligand solution. Incubation was carried out for 1 hour at room temperature with 300 rpm gentle agitation. Then, soaked the Unifilter-96 GF/C filter plates with 50 μl of 0.3% Poly ethyleneimine per well for at least 0.5 hour at room temperature, and filtered the reaction mixture through the plates using FilterMate™ harvester, then wash each plate for four times with cold wash buffer. The filter plates are then dried for 1 hour at 50° C. After drying, the filter was sealed in polyethylene and adds 50 μl of Perkin Elmer Microscint 20 cocktail and the radioactivity counted in a Perkin Elmer MicroBeta2 counter.
- Specific binding is determined by subtraction of the Bound CPM values in the presence of 50-100× excess of cold ligand. Data is fitted using the saturation analysis non-linear curve fitting routines in Prism®. Calculate the inhibition using following equation:
-
% Inhibition=(1-(Assay well-Average_LC)/(Average_HC-Average_LC))*100% - Binding data are analyzed using GraphPad Prism 5.0 and IC50 is generated by non-linear regression from dose response curves. Use the model “log (inhibitor) vs. response—Variable slope” to fit the data. This data is shown in Table 1.
-
TABLE 1 Binding Affinity Kappa Mu Delta IC50 IC50 IC50 Selectivity # Compounds (nM) (nM) (nM) μ/k δ/k 1 U-50488 14.59 — — — — 2 DAMGO — 0.68 — — — 3 Naltrindole — — 0.18 — — 4 5a 0.42 10.73 86.46 1.76 207.59 5 5b 7.76 3.47 69.01 0.45 8.90 6 7a 0.05 0.3 0.66 5.85 12.6 7 7b 0.24 0.52 0.68 2.16 2.82 8 16a 0.94 1.55 5.46 1.65 5.80 9 16b 6.74 7.18 34.05 1.07 5.05 10 17a 1.22 4.96 43.07 4.07 35.3 11 17b 6.49 45.37 71.58 6.99 11.0 12 18a 0.97 1.58 10.93 1.63 11.3 13 18b 6.15 76.83 118.0 12.5 19.2 14 19a 0.17 1.37 16.34 8.05 96.1 15 19b 0.46 5.98 146.8 13.0 319 16 20a 102.3 119.3 160.9 1.12 1.57 17 20b 16.02 8.08 11.76 0.50 0.73 18 21a 0.85 1.25 30.23 1.47 35.6 19 21b >200 114.2 385 <0.57 <1.93 20 23a 0.070 12.2 261.2 174.3 3731 21 23b 0.62 73.71 528.2 118.9 1331 - As the data in the above table indicated, the compounds 5a, 5b, 7a, 7b, 18a, 19a, and 21a provided better IC50 then U-50488.
- The FLIPR Calcium Assay is used to measure the ability of an opioid ligand to induce a functional response upon receptor binding.
- The MOR, DOR and KOR are G-protein coupled receptors (GPCRs) which play an important role in cell signaling. The receptor is activated by a ligand then triggering G-protein activation inside the cell. An activated G-protein induces various cascades of intracellular messengers including calcium flux. The functional cell-based assays evaluated the changes of intracellular calcium level which were detected through use of fluorescent calcium-sensitive reporter dyes. The basic system of performing a calcium mobilization assay includes the FLIPR Calcium Assay Kit and the FLIPR Tetra® System, which were used to observe changes in intracellular calcium levels and determine the dose-response in HEK293 cells transfected with the recombinant human mu, delta or kappa opioid receptors.
- The cells used in the assay were grown in the culture medium of 88% DMEM which contains 10% FBS, 300 ug/mL G418, 2 ug/mL Blasticidin, 1% GlutaMax and 1% Penicillin/Streptomycin (Hyclone-SV30010). Seeded 20000 cells in 20 uL medium to each well of assay plate (Greiner-781946), and the cells were maintained at 37° C. in an incubator with 5% CO2 for 20 hours. The compound was then prepared at 5-fold serial dilution to get 10 doses and 500 nL of each concentration was transferred to compound plate. Then 30 uL assay buffer (20 mM HEPES and 1×HBSS) was added to each well of compound plate; the plate was spin at 1500 rpm for 15 seconds. Then 20 uL of 2×Fluo-4 Direct™ No-wash Loading Buffer ((Invitrogen-F10471) was gently dispensed to each well of assay plate and was spin at 1000 rpm for 15 s, incubated at 37° C. for 50 min. The assay plate was removed from the incubator and placed at room temperature for 10 min. Then, the assay plate, compound plate and tip box were placed directly into the FLIPR Tetra® System. 10 uL compound was transferred from compound plate to the assay plate in FLIPR Tetra Fluorometric Imaging Plate Reader and plate was for 140 times; then alculated the “Max-Min” starting from Read 1 to 140 to generate the final signal for % Effect calculation; The data was analyzed using Prism, curve fitting equation “log(agonist) vs. response—Variable slope.” Table 2 shows the results of these assays.
-
TABLE 2 Cell Assay (FLIPR Calcium) Kappa # Compounds EC50 (nM) 1 U-69593 46.93 2 5a 2.64 3 5b 9.7 4 7a 6.86 5 7b 3.76 - As can be seen in Table 2, compound 5a provided improved cell assays over U-69596 as well as compounds 5b, 7a, and 7b. The response curve for compound 5a is shown in
FIG. 1 .
Claims (14)
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
R is hydrogen, methyl, allyl, cyclopropylmethyl, 1-hydroxylcyclopropylmethyl, or cyclobutylmethyl;
R1 and R2 independently are hydrogen, halogen, hydroxy, alkoxy, or aryloxy;
R3 is hydrogen, hydroxy, alkoxy, or alkanoate;
R7 and R8 independently are hydrogen, alkyl, or substituted alkyl;
R10 is hydrogen, hydroxy, alkyoxy, or keto;
R14 is hydrogen, hydroxy, or alkoxy;
one of R20, R21, R22, and R23 is represented by the compound of Formula (II) and the rest are chosen from hydrogen or halogen, and R24 is hydrogen;
R25 is hydrogen, alkyl, substituted aryl, alkylaryl, substituted alkylaryl, heterocycle, or substituted heterocycle;
R26 and R27 independently are H, Cl, Br, F, CF3, CN, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, substituted aryl, or heterocycle;
R28 is hydrogen or halogen;
R29 is absent, hydrogen, or C1-C6 alkyl;
X is nitrogen;
Y is selected from a group consisting of O, S, and N;
and
the dashed line represents an optional double bond;
wherein the substitution on R26 and R27 independently are Cl, Br, F, CF3, CN, C1-C6 alkyl, or C3-C6 cycloalkyl.
2. The compound of claim 1 , wherein the carbons attached to R20-R24 on the cyclopropyl ring independently have an R or S configuration.
3. The compound of claim 1 , wherein heterocycle is chosen from a group consisting of furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, thienyl, phenol, and imidazopyridyl.
4. The compound of claim 1 , wherein; R3 is hydroxy, C1-C4 alkyoxy, or alkanoate; R7 and R8 are each hydrogen, R14 is hydrogen or hydroxy; R20, R21, R23, and R24 are hydrogen, R22 is furyl, substituted furyl, thienyl, substituted thienyl, pyrrole or substituted pyrrole; and R25 is C1-C4 alkyl.
5. The compound of claim 1 , wherein R is cyclopropylmethyl; R3 is hydroxy; R14 is hydroxy; and R25 is methyl; R26 is hydrogen; R27 is Cl; and Y is O.
6. The compound of claim 1 , wherein R is cyclopropylmethyl; R3 is hydroxy; R14 is hydroxy; and R25 is methyl; R26 and R27 are Cl; and Y is O.
7. The compound of claim 1 , wherein R is cyclopropylmethyl; R3 is hydroxy; R14 is hydroxy; and R25 is methyl; R26 is hydrogen; R27 is CF3; and Y is O.
8. The compound of claim 1 , which has an optical activity of (−) or (+); and carbons C-5, C-13, C-14, and C-9, respectively, have a configuration chosen from RRRR, RRSR, RRRS, RRSS, RSRR, RSSR, RSRS, RSSS, SRRR, SRSR, SRRS, SRSS, SSRR, SSSR, SSRS, or SSSS, provided that the C-15 and the C-16 carbons are both either on the alpha face of the molecule or the beta face of the molecule.
9. The compound of claim 1 , wherein carbon C-6 has an alpha configuration or a beta configuration.
10. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
11. A method for treating a kappa opioid receptor-related disease or disorder, the method comprising administering a pharmaceutically effective amount of the pharmaceutical composition of claim 10 to an individual in need thereof;
wherein the wherein the kappa opioid receptor-related disease or disorder is pain, pruritis, or an addiction.
12. The method of claim 10 , wherein addiction is substance abuse addiction.
13. The method of claim 10 , wherein pain is chronic pain, visceral pain, neuropathic pain, and post-surgical pain.
14. The method of claim 10 , wherein the individual is a human.
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