US20210023043A1

US20210023043A1 - Methods of Treating Hyperalgesia

Info

Publication number: US20210023043A1
Application number: US16/801,567
Authority: US
Inventors: Conrad Cowan; Michael Koblish; Michael W. Lark
Original assignee: Trevena Inc
Current assignee: Trevena Inc
Priority date: 2015-12-14
Filing date: 2020-02-26
Publication date: 2021-01-28
Also published as: US20170333385A1; CA3007020A1; WO2017106306A1; AU2016372028B2; IL259992B; JP6991993B2; HK1251472A1; JP2019504113A; IL259992A; US10588889B2; KR20180093930A; CN108366997A; AU2016372028A1; EP3389657A4; IL281293A; JP2021169521A; HK1254672A1; EP3389657A1

Abstract

This application describes compounds and methods that can be used to treat, reverse, or avoid hyperalgesia.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/267,144, filed Dec. 14, 2015, which is incorporated by reference in its entirety. The present application is also related to U.S. Non-Provisional application Ser. No. 13/428,849, filed Mar. 23, 2012, Provisional Application No. 61/596,808 filed Feb. 9, 2012, and U.S. Provisional Application No. 61/466,809 filed Mar. 23, 2011, each of which is incorporated herein by reference in its entirety.

FIELD

This application relates to a family of compounds acting as opioid receptor ligands and methods of using such compounds for treating or reversing hyperalgesia, induced hyperalgesia, decreasing nociceptive sensitization, and the like.

BACKGROUND

Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct opioid receptor types have been described: δ, κ and μ. Furthermore, each type is believed to have sub-types. All three of these opioid receptor types appear to share the same functional mechanisms at a cellular level. For example, activation of the opioid receptors causes inhibition of adenylate cyclase, and recruits β-arrestin.
When therapeutic doses of morphine are given to patients with pain, the patients report that the pain is less intense, less discomforting, or entirely gone. In addition to experiencing relief of distress, some patients experience euphoria. However, when morphine in a selected pain-relieving dose is given to a pain-free individual, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mentation, apathy, lessened physical activity, reduced visual acuity, and lethargy may ensue. Additionally, those administered morphine and similar non-biased ligands can suffer from hyperalgesia. If the cause is due to an opioid therapeutic, it can be referred to as Opioid Induced Hyperalgesia (OIH).
There is a continuing need for new OR modulators to be used as therapeutics that do not cause hyperalgesia or that can be used to treat people that suffer from hyperalgesia, induced by opioids or otherwise. The present embodiments satisfy these needs as well as other.

SUMMARY

This application describes opioid receptor (OR) ligands. It also describes methods of treating or reversing hyperalgesia, such as but not limited to, opioid induced hyperalgesia. Accordingly, in some embodiments, methods of treating hyperalgesia in a subject are provided. In some embodiments, methods of reversing hyperalgesia, including but not limited to, opioid induced hyperalgesia, in a subject are provided. In some embodiments, the methods comprise administering to the subject a compound of any formula described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, methods of decreasing nociceptive sensitization in a subject are provided. In some embodiments, the methods comprise administering to the subject a compound of any formula described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, methods of treating pain in a subject are provided. In some embodiments, the methods comprise administering an opioid agonist to the subject until the first opioid increases nociceptive sensitization in the subject; and administering to the subject with increased nociceptive sensitization a compound of any formula described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, methods of treating pain in an opioid exposed subject are provided. In some embodiments, the methods comprise administering an opioid agonist to the subject; and administering to the subject of step a compound of any formula described herein, or a pharmaceutically acceptable salt thereof in the absence of the opioid.
In some embodiments, the compound of any formula or described herein, or a pharmaceutically acceptable salt thereof has a formula of Formula I:
In the structure above, variables A₁, A_z, A₃, A₄, A₅, B₁, B₂, B₃, B₄, B₅, and D₁can be selected from the respective groups of chemical moieties later described. OR ligand derivatives and mimetics are also provided.
In some embodiments, the compound has a formula of
or a pharmaceutically acceptable salt thereof, wherein D₁is an optionally substituted aryl; and B₅is an optionally substituted pyridyl.
This application also describes pharmaceutical compositions comprising one or more compounds as described in this application a pharmaceutically acceptable carrier. Naturally, the compounds described herein can be employed in any form, such as a solid or solution (e.g., aqueous solution) as is described further below. The compounds described herein, for example, can be obtained and employed in a lyophilized form alone or with suitable additives.
In some embodiments, uses of the compounds, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment or reversal of hyperalgesia, opioid induced hyperalgesia, and the like are provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates that biased ligands described herein do not induce hyperalgesia.

FIG. 2 illustrates that biased ligands can reverse opioid induce hyperalgesia.

DETAILED DESCRIPTION

This application describes a family of compounds, OR ligands, with a unique profile.
The compounds described herein act as agonists or antagonists of opioid receptor (OR)-mediated signal transduction. The ligands of these receptors can be used to treat pathologies associated with ORs including pain and pain related disorders, such as, but not limited to, opioid induced hyperalgesia and nociceptive sensitization.
In some embodiments, compounds also comprise Formula I:
wherein: A₁is null, CH₂, CHR₁, CR₁R₂, CH, CR₁, O, S, SO, SO₂, NH or NR₁; A₂is null, CH₂, CHR₅, CR₅R₆, CH, CR₅, O, S, SO, SO₂, NH or NR_S; A₃is null, CH₂, CHR₇, CR₇R₈, O, S, SO, SO₂, NH, NR₇, CH or CR₇; A₄is null, CH₂, cycle of the formula C(CH₂)₁₆where n=2-5, CHR₉, CR₉R₁₀, O, S, SO, SO₂, NH, NR₉, CH or CR₉; and A₅is null, CH₂, CHR₁₁, CR₁₁R₁₂, CH₂CH₂, CHR₁₁CH₂, CH₂CHR₁₁, CHR₁₁CHR₁₂, O, S, SO, SO₂, NH, NR₁₁, CH or CR₁₁.
No more than 2 out of 5 A_a(specifically A₁, A₂, A₃, A₄, A₅) can be null at the same time. The number of heteroatoms from A₁to A₅cannot exceed 2 at the same time, and O—O, S—O; S—S; S—N fragments in the ring structure are excluded from this composition.
The ring containing A₁, A₂, A₃, A₄, A₅and the carbon connected to D₁can be fused with another ring, such as benzene, pyridine, pyrimidine, furan, thiophene or pyridazine, but not limited to these examples, where the resulting bicycle is chemically stable and synthetically accessible. It is also understood that the above-mentioned fused rings could be multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, formyl, acetyl, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, and other small substitution groups. The bonds between A₁and A₂, A₂and A₃, A₃and A₄, A₄and A₅can independently be a single bond or a double bond. The bonds between A₁and A₂, A₂and A₃, A₃and A₄, A₄and A₅cannot be a double bond at the same time.
A₂and A₄can be connected by a carbon bridge. Examples of such a bridge include —CH₂—, and —CH₂CH₂—.
B₁is CH₂, CHR₁₃, CR₁₃R₁₄, O, S, SO, SO₂, NH, NR₁₃, CR₁₃or CO. B₂1 S CH₂, CHR₁₅, CR₁₅R₁₆, CR₁₅or CO. B₃is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or alkyl sulfonyl. B₄is null, C₁-C₆alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀or CO. In some embodiments, when B₄is an alkyl one or more of the hydrogens can be replaced with a deuterium. B₅is alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle or arylalkyl.
Aryl, carbocycle (non-aromatic)/heterocycle (non-aromatic with 1-3 heteroatoms, including O, N, S) are either unsubstituted, or substituted with small substitution groups. Small substitution groups can be cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkyl sulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle or carbocycle-alkyl. In some embodiments, the small substitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesuflonyl, Ph, benzyl, MeSO₂, formyl, and acetyl.
Carbocycle may contain double bonds, but they should not be aromatic.
D₁is an aryl group or a carbocycle.
An aryl group is either a monocyclic aromatic group or a bicyclic aromatic group, which may contain heteroatoms in the aromatic group (e.g. heteroaryl). The following structures are some examples of representative aryl groups, but the aryl groups are not limited to those examples:
Carbocycle is either a monocyclic or a bicyclic non-aromatic ring system. The following structures are some examples of representative carbocycle, but the carbocycle is not limited to those examples:
wherein X₁, and X₂in the carbocycle examples are independently O, S, N, NH or NR₁₈.
The aryl groups can be independently mono or multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkyloxy, amino, alkylamino, dialkylamino, mercaptanyl, alkylmercaptanyl, alkyl sulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, and/or other small substitution groups. In some embodiments, the small substitution groups are selected from F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, methanesulfonyl, Ph, benzyl, formyl, and acetyl.
In some embodiments, D₁is an aryl, or a carbocycle.
In some embodiments, R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, and R₂₀are independently: cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl or alkoxycarbonyl. In some embodiments, R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₈, R₁₉, and R₂₀are independently F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr, methoxycarbonyl, phenyl, benzyl, formyl or acetyl, whenever the resulting structure is stable.
In some embodiments, R₁and R₂, R₅and R₆, R₇and R₈, R₉and R₁₀, R₁₁and R₁₂, R₁₃and R₁₄, R₁₅and R₁₆, R₁₉and R₂₀, or R₁₅and R₁₉can form a monocycle.
In some embodiments, Me is methyl; Et is ethyl; i-Pr is i-propyl; t-Bu is t-butyl; Ph is phenyl.
In some embodiments, the following compounds can be excluded from the genus of compounds:2-[({2-[2-Ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol; 2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol; {2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; {2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1R)-1-phenylethyl]amine; {2-[(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1 S)-1-phenylethyl]amine; Benzyl({2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl})amine; 2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol; Benzyl[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine; {2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; [(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; {2-[4-(4-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}(1-phenylethyl)amine; [(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; Benzyl({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine; [(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine; 4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline; Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}(1-phenylethyl)amine; {2-(2,2-Dimethyl-4-phenyloxan-4-yl)ethyl}[(4-methoxyphenyl)methyl]amine; {2-[4-(4-Fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; [(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine
This application also describes compounds having the formula of Formula II-1 and 11-2:

wherein A₂is CH₂, CHR₅, CR₅R₆; A₄is CH₂, CHR₉, CR₉R₁₀or a cycle of the formula C(CH₂)_n, where n=2-5.

Further, in some embodiments, R₅R₆, R₉, and R₁₀are independently CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. Further, R₅and R₆, or R₉and R₁₀can form a monocyclic carbocycle.
In some embodiments, A₂and A₄can be connected by a carbon bridge. This bridge can be —CH₂— or —CH₂CH₂—.
Further, in some embodiments, B₃is selected from the following: H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl. In some embodiments, B₃is C₁-C₅alkyl. In some embodiments, B₃is H.
Further, in some embodiments, B₄is null, C₁-C₆alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀or CO. Further, R₁₉and R₂₀can form a monocycle of the formula (CH₂)_n, where n=2-4. B₅is alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl or arylalkyl.
In some embodiments, Further D₁is an aryl. Examples of the aryl groups are shown above.
Each aryl group can be independently mono or multiply substituted with F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, Ph, benzyl, formyl, or acetyl. That is, each aryl group may be multiply substituted with the same substituent (i.e., 2 chloro groups) or just be multiply substituted, albeit with different groups (e.g. an aryl group with 1 chloro and 1 methyl group would be considered multiply substituted).
This application also provides compounds having the structure of Formula III:

wherein A₂is CH₂, CHR₅or CR₅R₆; A₄is CH₂, CHR₉, CR₉R₁₀or a cycle of the formula C(CH₂)_n, where n=2-5.

Further R₅, R₆, R₉, and R₁₀are independently CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. R₅and R₆, or R₉and R₁₀can form a monocyclic carbocycle.
A₂and A₄can be connected by a carbon bridge. The bridge can be —CH₂— or —CH₂CH₂—.
Further B₃is selected from H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or alkyl sulfonyl.
Further B₄is null, C₁-C₆alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀or CO. Further, R₁₉and R₂₀can form a monocycle of the formula (CH₂)_n, where n=2-4. B₅is alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl or arylalkyl.
Further D₁is an aryl. Examples of the aryl groups are shown above.
The aryl groups can be mono or multiply substituted with F, Cl, Br, CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF₃, NH₂, NHMe, NMe₂, methoxycarbonyl, Ph, benzyl, formyl, or acetyl.
This application also provides compounds having the formula of Formula IV-1, IV-2, or IV-3, V, or VI:
wherein R₂₁and R₂₂are, independently, H or CH₃; A₄is CH₂, CR₉R₁₀or a cycle of the formula C(CH₂), where n=2-5.
Further R₉and R₁₀are independently CH₃or CH₂CH₃.
Further B₃is H, C₁-C₆alkyl or branched alkyl.
Further B₄is null, C₁-C₆alkyl, CH₂, CH₂CH₂, or —CHCH₃.
B₅is —(CH₂)_nCH₃, where n=2-3, —C(CH₃)₃, cyclohexyl, cyclopentyl, aryl or arylalkyl.
In some embodiments, the aryl group is selected from the list below:
Each aryl groups can be mono or multiply substituted with, for example, F, I, Cl, Br, CH₃, CN, OH, OMe, OEt, OCF₃, CF₃, or methanesulfonyl.
Further, in some embodiments, D₁is a phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl which can be independently mono or multiply substituted with F, Cl, Br, OCF₃, CF₃, or CH₃.
This application also provides compounds having the structure of Formula V-1, V-2, V-3, VI-1, VI-2, or VI-3:
wherein D₁is an aryl; B₅is an aryl or carbocycle.
In some embodiments, each aryl group is independently selected from the list below:
In some embodiments, each aryl group is independently mono or multiply substituted. In some embodiments, each aryl group can be independently mono or multiply substituted with I, F, Cl, Br, CH₃, CN, OH, OMe, OEt, OCF₃, CF₃, or methane sulfonyl. Further, in some embodiments, the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.
In some embodiments, D₁is an optionally mono or multiply substituted aryl. In some embodiments, B₅is an optionally mono or multiply substituted aryl or carbocycle. In some embodiments, D₁or B₅is independently selected from the group consisting of:
wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.
In some embodiments, D₁is optionally mono or multiply substituted phenyl, 2-pyridil, 3-pyridyl, or 4-pyridyl. In some embodiments, D₁is optionally substituted with one or more of F, Cl, Br, I, OCF₃, CH₃, and CF₃. In some embodiments, D₁is not substituted.
In some embodiments, B₅is optionally mono or multiply substituted
In some embodiments, B₅is substituted with one or more of Cl, Br, F, I, OMe, CN, CH₃, methanesulfonyl, and CF₃. In some embodiments, B₅is substituted with two or more of Cl, Br, F, I, OMe, CN, CH₃, CF₃, and methanesulfonyl, or a combination thereof. That is B₅can have two or more substituents but not all of the plurality of substituents needs to be the same.
In some embodiments, compounds having structures of Formula VII-1, VII-2, or VII-3
are provided, wherein D₁is an optionally substituted heteroaryl or aryl, B₃is H or alkyl, B₅is an optionally substituted aryl or heteroaryl, and R₂₆and R₂₇are each hydrogen or an isotope thereof. In some embodiments, R₂₆and R₂₇are deuterium. In some embodiments, R₂₆or R₂₇are independently alkyl. In some embodiments, B₃is C₁-C₅alkyl.
In some embodiments, the compound has a structure of Formula VIII or an enantiomer thereof.
wherein D1 is an optionally substituted heteroaryl or aryl, B3 is H or alkyl, B5 is an optionally substituted aryl or heteroaryl, and R26 and R27 are each hydrogen or an isotope thereof. In some embodiments, R26 and R27 are deuterium. In some embodiments, R26 or R27 are independently alkyl. A4 is as described herein. In some embodiments, B3 is Cl-05 alkyl. In some embodiments, the enantiomer is the R or S enantiomer at the carbon that is connected to D1.
In some embodiments, a compound has the structure of Formula IX or an enantiomer thereof.
In some embodiments, the enantiomer is the R or S enantiomer at the carbon that is connected to D₁.
In some embodiments, a compound has the structure of Formula X or an enantiomer thereof.
In some embodiments, the enantiomer is the R or S enantiomer at the carbon that is connected to D1.
In some embodiments of the structures described herein, D1 is an optionally substituted pyridyl group or phenyl group. In some embodiments, D1 is an optionally substituted 2-pyridyl, 3-pyridyl, or 4-pyridyl group or phenyl group. In some embodiments, D1 is optionally substituted with one or more of, H, OH, alkyl alcohol, halo, alkyl, amine, amide, cyano, alkoxy, haloalkyl, or aklylsulfonyl. In some embodiments, D1 is optionally substituted with one or more of H, OH, Cl, Br, F, I, OMe, CN, CH₃, CF₃.
In some embodiments of the structures described herein, B₅is an optionally substituted thiophene group. In some embodiments, B₅is substituted with an alkoxy group. In some embodiments, B₅is substituted with a C₁-C₅alkoxy group. In some embodiments, B₅is substituted with a methoxy group. In some embodiments, B₅is
In some embodiments, B₅is
wherein R₂₃, R₂₄, and R₃₀are each independently null, H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amine, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, alkylsulfanyl, and R₂₅is H or alkyl. In some embodiments, R₂₃and R₂₄together form a aryl or cycle that is attached to one or more of the atoms of B₅. R₂₃R₂₄, and R₃₀can also be further substituted. In some embodiments, R₂₃, R₂₄, and R₃₀are each independently H, NH₂, OH, Cl, Br, F, L, OMe, CN, CH₃, phenyl, C₃-C₆carbocycle, methanesulfonyl, CF₃,
wherein R₂₉is H or an alkyl. In some embodiments, R₂₉is a C₁-C₆alkyl. In some embodiments, one of R₂₃, R₂₄, and R₃₀is H. In some embodiments, at least one of R₂₃, R₂₄, and R₃₀is H. In some embodiments, two of R₂₃, R₂₄, and R₃₀are H.
The following compounds and others described herein have agonist activity for OR mediated signal transduction:[(4-chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; [(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine; 2-[({2-[2-ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol; [2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl][(2-fluorophenyl)methyl]amine; 4-[({2-[4-(2-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline; 2-[({2-[2-ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenoll; [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine. Other examples include the compounds, and pharmaceutically acceptable salts thereof, described herein.
In some embodiments, compounds, such as the ones described herein are provided. In some embodiments, a compound selected from the compounds described in the Examples is provided. The compounds can be used in any of the methods described herein, including, but not limited to, treating pain. For example, the compounds can be used for treating or reversing hyperalgesia, induced hyperalgesia, decreasing nociceptive sensitization, and the like. The compounds can be also be used in the preparation of a medicament for the same. In some embodiments, uses of the compounds for treating pain, treating or reversing hyperalgesia, induced hyperalgesia, decreasing nociceptive sensitization, and the like, are provided.
Thus, the application provides methods of generating agonist activity in OR mediated signal transduction through administration of one or more of the above recited compounds to a subject or subject in need thereof.
Various atoms in the compositions described herein can be isotopes that occur at lower frequency. Hydrogen can be replaced at any position in the compositions described herein with deuterium. Optionally, hydrogen can also be replaced with tritium. Carbon (¹²C) can be replaced at any position in the compositions described herein with ¹³C or ¹⁴C. Nitrogen (¹⁴N) can be replaced with ¹⁵N. Oxygen (¹⁶O) can be replaced at any position in the compositions described herein with ¹⁷O or ¹⁸O. Sulfur (³²S) can be replaced at any position in the compositions described herein with ³³S, ³⁴S or ³⁶S. Chlorine (³⁵Cl) can be replaced at any position in the compositions described herein with ³⁷Cl. Bromine (⁷⁹Br) can be replaced at any position in the compositions described herein with ⁸¹Br.
Selected compounds described herein are agonists and antagonists of Opioid Receptors (ORs). The ability of the compounds to stimulate OR mediated signaling may be measured using any assay known in the art to detect OR mediated signaling or OR activity, or the absence of such signaling/activity. “OR activity” refers to the ability of an OR to transduce a signal. Such activity can be measured, e.g., in a heterologous cell, by coupling an OR (or a chimeric OR) to a downstream effector such as adenylate cyclase.
A “natural ligand-induced activity” as used herein, refers to activation of the OR by a natural ligand of the OR. Activity can be assessed using any number of endpoints to measure OR activity.
Generally, assays for testing compounds that modulate OR-mediated signal transduction include the determination of any parameter that is indirectly or directly under the influence of a OR, e.g., a functional, physical, or chemical effect.
Samples or assays comprising ORs that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples (untreated with inhibitors) are assigned a relative OR activity value of 100%. Inhibition of an OR is achieved when the OR activity value relative to the control is about 80%, 50%, or 25%. Activation of an OR is achieved when the OR activity value relative to the control (untreated with activators) is 110%, 150%, 200-500% (i.e., two to five fold higher relative to the control) or, 1000-3000% or higher.
The effects of the compounds upon the function of an OR can be measured by examining any of the parameters described above. Any suitable physiological change that affects OR activity can be used to assess the influence of a compound on the ORs and natural ligand-mediated OR activity. When the functional consequences are determined using intact cells or animals, one can also measure a variety of effects such as changes in intracellular second messengers such as cAMP.
Modulators of OR activity are tested using OR polypeptides as described above, either recombinant or naturally occurring. The protein can be isolated, expressed in a cell, expressed in a membrane derived from a cell, expressed in tissue or in an animal. For example, neuronal cells, cells of the immune system, transformed cells, or membranes can be used to test the GPCR polypeptides described above. Modulation is tested using one of the in vitro or in vivo assays described herein. Signal transduction can also be examined in vitro with soluble or solid state reactions, using a chimeric molecule such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to the transmembrane and or cytoplasmic domain of a receptor. Furthermore, ligand-binding domains of the protein of interest can be used in vitro in soluble or solid state reactions to assay for ligand binding.
Ligand binding to an OR, a domain, or chimeric protein can be tested in a number of formats. Binding can be performed in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer, or in vesicles. Typically, in an assay described herein, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of the candidate modulator may be measured in the presence of the natural ligand. Often, competitive assays that measure the ability of a compound to compete with binding of the natural ligand to the receptor are used. Binding can be tested by measuring, e.g., changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic (e.g., shape) changes, or changes in chromatographic or solubility properties.
Modulators may also be identified using assays involving β-arrestin recruitment. β-arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in unactivated cells. Ligand binding to an appropriate OR is associated with redistribution of β-arrestin from the cytoplasm to the cell surface, where it associates with the OR. Thus, receptor activation and the effect of candidate modulators on ligand-induced receptor activation, can be assessed by monitoring β-arrestin recruitment to the cell surface. This is frequently performed by transfecting a labeled β-arrestin fusion protein (e.g., β-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution using confocal microscopy (see, e.g., Groarke et al., J. Biol. Chem. 274(33):23263 69 (1999)).
Another technology that can be used to evaluate OR-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion regarding BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):12736 43 (2001).
Other assays can involve determining the activity of receptors which, when activated by ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g., cAMP, by activating or inhibiting downstream effectors such as adenylate cyclase. Changes in intracellular cAMP can be measured using immunoassays. The method described in Offermanns & Simon, J. Biol. Chem. 270:15175 15180 (1995) may be used to determine the level of cAMP. Also, the method described in Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11:159 164 (1994) may be used to determine the level of cGMP. Further, an assay kit for measuring cAMP a is described in U.S. Pat. No. 4,115,538, herein incorporated by reference.
Transcription levels can be measured to assess the effects of a test compound on ligand-induced signal transduction. A host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a sufficient time to effect any interactions, and then the level of gene expression is measured. The amount of time to effect such interactions may be empirically determined, such as by running a time course and measuring the level of transcription as a function of time. The amount of transcription may be measured by using any method known to those of skill in the art to be suitable. For example, mRNA expression of the protein of interest may be detected using northern blots or their polypeptide products may be identified using immunoassays. Alternatively, transcription based assays using reporter genes may be used as described in U.S. Pat. No. 5,436,128, herein incorporated by reference. The reporter genes can be, e.g., chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, β-galactosidase and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter via attachment to a second reporter such as green fluorescent protein (see, e.g., Mistili & Spector, Nature Biotechnology 15:961 964 (1997)).
The amount of transcription is then compared to the amount of transcription in either the same cell in the absence of the test compound, or it may be compared with the amount of transcription in a substantially identical cell that lacks the protein of interest. A substantially identical cell may be derived from the same cells from which the recombinant cell was prepared but which had not been modified by introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has in some manner altered the activity of the protein of interest.
Pharmaceutical Compositions/Formulations
Pharmaceutical compositions can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. The formulations may contain a buffer and/or a preservative. The compounds and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including via inhalation, topically, nasally, orally, parenterally (e.g., intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard biological practice.
Pharmaceutical compositions can include effective amounts of one or more compound(s) described herein together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such compositions may include diluents of various buffer content (e.g., TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-glycylglycine, sodium or potassium phosphate (dibasic, tribasic), etc. or TRIS-HCl or acetate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., surfactants such as Pluronics, Tween 20, Tween 80 (Polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimersol, benzyl alcohol, parabens, etc.) and bulking substances (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidones or dextran, etc.); and/or incorporation of the material into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hyaluronic acid may also be used. Such compositions can be employed to influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of a compound described herein. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference. The compositions can, for example, be prepared in liquid form, or can be in dried powder, such as lyophilized form. Particular methods of administering such compositions are described infra.
Where a buffer is to be included in the formulations described herein, the buffer can be selected from sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris(hydroxymethyl)-aminomethane, or mixtures thereof. The buffer can also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate or mixtures thereof.
Where a pharmaceutically acceptable preservative is to be included in a formulation of one of the compounds described herein, the preservative can be selected from phenol, m-cresol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, 2-phenoxyethanol, butyl p-hydroxybenzoate, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thiomerosal, or mixtures thereof. The preservative can also be phenol or m-cresol.
The preservative is present in a concentration from about 0.1 mg/ml to about 50 mg/ml, in a concentration from about 0.1 mg/ml to about 25 mg/ml, or in a concentration from about 0.1 mg/ml to about 10 mg/ml.
The use of a preservative in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
The formulation may further comprise a chelating agent where the chelating agent may be selected from salts of ethlenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.
The chelating agent can be present in a concentration from 0.1 mg/ml to 5 mg/ml, from 0.1 mg/ml to 2 mg/ml or from 2 mg/ml to 5 mg/ml.
The use of a chelating agent in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
The formulation of the compounds described herein may further comprise a stabilizer selected from high molecular weight polymers and low molecular compounds where such stabilizers include, but are not limited to, polyethylene glycol (e.g. PEG 3350), polyvinylalcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, different salts (e.g. sodium chloride), L-glycine, L-histidine, imidazole, arginine, lysine, isoleucine, aspartic acid, tryptophan, and threonine or any mixture thereof. The stabilizer can also be L-histidine, imidazole or arginine.
The high molecular weight polymer can be present in a concentration from 0.1 mg/ml to 50 mg/m, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
The low molecular weight compound can be present in a concentration from 0.1 mg/ml to 50 mg/ml, from 0.1 mg/ml to 5 mg/ml, from 5 mg/ml to 10 mg/ml, from 10 mg/ml to 20 mg/ml, from 20 mg/ml to 30 mg/ml or from 30 mg/ml to 50 mg/ml.
The use of a stabilizer in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
The formulation of the compounds described herein may further include a surfactant. IN some embodiments, the surfactant may be selected from a detergent, ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, such as 188 and 407, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives such as alkylated and alkoxylated derivatives (tweens, e.g. Tween-20, or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate, bile acids and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. 1-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)-derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N,N-dimethylammonio-1-propanesulfonates, 3-cholamido-1-propyldimethylammonio-1-propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases) (e.g. cetyl-trimethylammonium bromide, cetylpyridinium chloride), non-ionic surfactants, polyethyleneoxide/polypropyleneoxide block copolymers (Pluronics/Tetronics, Triton X-100, Dodecyl β-D-glucopyranoside) or polymeric surfactants (Tween-40, Tween-80, Brij-35), fusidic acid derivatives—(e.g. sodium tauro-dihydrofusidate etc.), long-chain fatty acids and salts thereof C6-C12 (e.g. oleic acid and caprylic acid), acylcarnitines and derivatives, N_a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N_a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N_a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof.
The use of a surfactant in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.
Pharmaceutically acceptable sweeteners can be part of the formulation of the compounds described herein. Pharmaceutically acceptable sweeteners include at least one intense sweetener such as saccharin, sodium or calcium saccharin, aspartame, acesulfame potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener, monellin, stevioside or sucralose (4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose), saccharin, sodium or calcium saccharin, and optionally a bulk sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.
Intense sweeteners are conveniently employed in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 0.04% to 0.1% (w/v) based on the total volume of the final formulation, or is about 0.06% in the low-dosage formulations and about 0.08% in the high-dosage ones. The bulk sweetener can effectively be used in larger quantities ranging from about 10% to about 35%, or from about 10% to 15% (w/v).
The formulations of the compounds described herein may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19th edition, 1995, where such conventional techniques of the pharmaceutical industry involve dissolving and mixing the ingredients as appropriate to give the desired end product.
The phrase “pharmaceutically acceptable” or “therapeutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and preferably do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. As used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a State government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia (e.g., Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985)) for use in animals, and more particularly in humans.
Administration of the compounds described herein may be carried out using any method known in the art. For example, administration may be transdermal, parenteral, intravenous, intra-arterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppositories, or oral administration. A pharmaceutical composition of the compounds described herein can be for administration for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.
For oral administration, the pharmaceutical composition of the compounds described herein can be formulated in unit dosage forms such as capsules or tablets. The tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients, including binding agents, for example, pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose; fillers, for example, lactose, microcrystalline cellulose, or calcium hydrogen phosphate; lubricants, for example, magnesium stearate, talc, or silica; disintegrants, for example, potato starch or sodium starch glycolate; or wetting agents, for example, sodium lauryl sulphate. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, and/or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound.
For topical administration, the pharmaceutical composition of the compounds described herein can be formulated in a pharmaceutically acceptable vehicle containing 0.1 to 10 percent, or 0.5 to 5 percent, of the active compound(s). Such formulations can be in the form of a cream, lotion, sublingual tablet, aerosols and/or emulsions and can be included in a transdermal or buccal patch of the matrix or reservoir type as are conventional in the art for this purpose.
For parenteral administration, the compounds described herein are administered by either intravenous, subcutaneous, or intramuscular injection, in compositions with pharmaceutically acceptable vehicles or carriers. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents, for example, suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
For administration by injection, the compound(s) can be used in solution in a sterile aqueous vehicle which may also contain other solutes such as buffers or preservatives as well as sufficient quantities of pharmaceutically acceptable salts or of glucose to make the solution isotonic. The pharmaceutical compositions of the compounds described herein may be formulated with a pharmaceutically acceptable carrier to provide sterile solutions or suspensions for injectable administration. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspensions in liquid prior to injection or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, or the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. If desired, absorption enhancing preparations (e.g., liposomes) may be utilized. Suitable pharmaceutical carriers are described in “Remington's pharmaceutical Sciences” by E. W. Martin.
For administration by inhalation, the compounds may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, for example, lactose or starch. For intranasal administration the compounds described herein may be used, for example, as a liquid spray, as a powder or in the form of drops.
The compounds can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.
Furthermore, the compounds can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack can, for example, comprise metal or plastic foil, for example, a blister pack. The pack or dispenser device can be accompanied by instructions for administration.
The compounds described herein also include derivatives referred to as prodrugs, which can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Examples of prodrugs include compounds of the invention as described herein that contain one or more molecular moieties appended to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, and that when administered to a patient, cleaves in vivo to form the free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention. Preparation and use of prodrugs is discussed in T. Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entireties.
Dosages
The compounds described herein may be administered to a patient at therapeutically effective doses to prevent, treat, or control one or more diseases and disorders mediated, in whole or in part, by an OR-ligand interaction. Pharmaceutical compositions comprising one or more of compounds described herein may be administered to a patient in an amount sufficient to elicit an effective protective or therapeutic response in the patient. An amount adequate to accomplish this is defined as “therapeutically effective dose.” The dose will be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse effects that accompany the administration of a particular compound or vector in a particular subject.
Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio, LD50/ED50. In some embodiments, compounds that exhibit large therapeutic indices are used. While compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue to minimize potential damage to normal cells and, thereby, reduce side effects.
The data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. In some embodiments, the dosage of such compounds lies within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration. For any compound described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography (HPLC). In general, the dose equivalent of a modulator is from about 1 ng/kg to 10 mg/kg for a typical subject.
The amount and frequency of administration of the compounds described herein and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In general it is contemplated that an effective amount would be from 0.001 mg/kg to 10 mg/kg body weight, and in particular from 0.01 mg/kg to 1 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.01 to 500 mg, and in particular 0.1 mg to 200 mg of active ingredient per unit dosage form.
In some embodiments, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 500 mg, or from about 0.01 mg to about 250 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.
In some embodiments, one or more compounds described herein are administered with another compound. The administration may be sequentially or concurrently. The combination may be in the same dosage form or administered as separate doses. In some embodiments, the another compound is another analgesic or pain reliever. In some embodiments, the another compound is a non-opioid analgesic. Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include the following, non-limiting, chemical classes of analgesic, antipyretic, nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicyl salicylic acid, sulfasalazine, and olsalazin; para-aminophenol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Anti-inflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9.sup.th ed 1996); and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R. Gennaro ed. 19.sup.th ed. 1995), which are hereby incorporated by reference in their entireties.
The compounds described herein can also be administered Cox-II inhibitors. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, as well as combinations thereof, are described in U.S. Pat. No. 6,136,839, which is hereby incorporated by reference in its entirety. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.
The compounds described herein can also be administered with antimigraine agents. Examples of useful antimigraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.
The compounds described herein can also be administered with anti-constipation agents. Examples of anti-constipation agents include, but are not limited to, laxatives or stool softners. Examples of anti-constipation agents include, but are not limited to, be docusate, poloxamer 188, psyllium, methylcellulose, carboxymethyl cellulose, polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, dibasic sodium phosphate, monobasic sodium phosphate, sodium biphosphate or any combination thereof.
Medical Use
The compositions described herein may be useful for treating pain or pain associated disorders. The compositions described herein may be useful for treating immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urological and reproductive conditions, medicaments for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents and agents for the treatment of respiratory diseases and cough.
In some embodiments, methods of treating pain are provided. In some embodiments, one or more compound described herein are administered to a subject to treat the pain. In some embodiments, the pain can be post-operative pain. In some embodiments, the pain is caused by cancer. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is caused by trauma, such as but not limited to, blunt force trauma. In some embodiments, the pain is caused by inflammation.
In some embodiments, the one or more compounds can used for treating or reversing hyperalgesia. Accordingly, in some embodiments, methods of treating or reversing hyperalgesia are provided. In some embodiments, the methods comprise administering to a subject one or more compounds described herein, or pharmaceutically acceptable salts thereof. In some embodiments, a pharmaceutical composition comprising the one or more compounds, or pharmaceutically acceptable salts thereof are administered. As used herein, hyprealgesia refers to a condition where a subject has an increased sensitivity to pain. The increase sensitivity can occur at the site of a previous injury or pain sensation or can be at a different site. In some embodiments, the hyperalgesia is diffuse hyperlagesia (i.e. in more than one site on the subject) or is focal, (i.e. at a discrete site on the subject). In some embodiments, the subject has been administered a first opioid prior to being administered the one or more compounds described herein, or a pharmaceutically acceptable salt thereof.
In some embodiments, the hyperalgesia is opioid induced hyperalgesia, which can also be referred to as opioid-induced abnormal pain sensitivity or paradoxical hyperalgesia, which is described as a condition that results from the use of opioids. For example, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). This is a result of the subject being exposed to opioids. Opioid induced hyperalgesia (“OIH”) is distinct and different from what is known as “tolerance.” Without being bound to any particular theory, tolerance is due to desensitization of antinociceptive mechanisms whereas OIH is due to sensitization of pronociceptive mechanisms. Therefore, where opioid tolerance is identified as a condition in a subject the tolerance can be minimized by increasing the dose of the opioid. In contrast, increasing the dose of an opioid in a subject suffering from OIH will only worsen the condition. In some embodiments, the compounds described herein are used for the preparation of a medicament for treating hyperalgesia or opioid induced hyperalgesia.
In some embodiments, the opioid induced hyperalgesia is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin induced hyperalgesia. In some embodiments, the OIH is induced by a combination of more than one opioid. In some embodiments, the OIH is morphine induced OIH. In some embodiments, the OIH is oxycodone induced OIH. In some embodiments, the OIH is hydrocodone induced OIH. In some embodiments, the OIH is hydromorphone induced OIH. In some embodiments, the OIH is fentanyl induced OIH. In some embodiments, the OIH is buprenorphine induced OIH. In some embodiments, the OIH is heroin induced OIH.
In some embodiments, methods of decreasing nociceptive sensitization in a subject are provided. In some embodiments, the methods comprise administering to a subject one or more compounds described herein, or pharmaceutically acceptable salts thereof. In some embodiments, a pharmaceutical composition comprising the one or more compounds, or pharmaceutically acceptable salts thereof are administered. In some embodiments, the the subject has increased nociceptive sensitization. In some embodiments, the nociceptive sensitization is induced by another therapeutic. In some embodiments, the nociceptive sensitization is opioid induced nociceptive sensitization. In some embodiments, the opioid induced nociceptive sensitization is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or a pharmaceutically acceptable salt thereof, induced nociceptive sensitization.
In some embodiments, methods of treating pain in a subject are provided, wherein the method comprises administering an opioid agonist to the subject until the opioid increases nociceptive sensitization in the subject; and then administering to the subject with increased nociceptive sensitization one or more compounds described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or pharmaceutically acceptable salts thereof. In some embodiments, a pharmaceutical composition comprising the one or more compounds, or pharmaceutically acceptable salts thereof are administered.
In some embodiments, methods of treating pain are provided, wherein the methods comprising administering an opioid agonist to the subject; and then administering to the subject in the absence of the opioid and then administering to the subject one or more compounds described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and/or heroin, or pharmaceutically acceptable salts thereof. In some embodiments, a pharmaceutical composition comprising the one or more compounds, or pharmaceutically acceptable salts thereof are administered.
In some embodiments, the compounds are used in the preparation of a medicament for treating or reversing OIH, such as opioid induced OIH. In some embodiments, uses of a compound, or pharmaceutically acceptable salt thereof, for treating or reversing OIH are provided. Non-limiting examples of opioid induced OIH are described above. In some embodiments, the compounds are used in the preparation of a medicament for treating nociceptive sensitization. In some embodiments, uses of a compound, or pharmaceutically acceptable salt thereof, for treating nociceptive sensitization are provided. In some embodiments, the nociceptive sensitization is opioid induced. Non-limiting examples of opioid that can induce nociceptive sensitization are provided herein.
In some embodiments, the compound that is used in the methods, uses, or preparation of a medicament is
or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound as described in Examples 1-4, or a pharmaceutically acceptable salt thereof.
In some embodiments, 2-[({2-[2-Ethyl-2-methyl-4-(4-methylphenyl)oxan-4-yl]ethyl}amino)methyl]phenol; 2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol; {2-[2,2-Dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; {2-[(4S*, 4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1R)-1-phenylethyl]amine; {2-[(4S*, 4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1 S)-1-phenylethyl]amine; Benzyl({2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl})amine; 2-[({2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}amino)methyl]phenol; Benzyl[2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine; {2-[2-Ethyl-4-(4-fluorophenyl)-2-methyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; [(3,4-Dimethoxyphenyl)methyl]({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; {2-[4-(4-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}(1-phenylethyl)amine; [(4-Chlorophenyl)methyl]({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; Benzyl({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine; [(3,4-dimethoxyphenyl)methyl]({2-[2-ethyl-4-(2-methoxyphenyl)-2-methyloxan-4-yl]ethyl})amine; 4-[({2-[4-(2-Methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl}amino)methyl]-N,N-dimethylaniline; Benzyl({2-[4-(4-fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl})amine; {2-[2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}(1-phenylethyl)amine; [2-(2,2-Dimethyl-4-phenyloxan-4-yl)ethyl][(4-methoxyphenyl)methyl]amine; {2-[4-(4-Fluorophenyl)-2,2-dimethyloxan-4-yl]ethyl}[(4-methoxyphenyl)methyl]amine; [(3,4-Dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine, or any combination thereof is not administered.
In some embodiments, a compound of formula N-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine; N-((5-fluoropyridin-3-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine, or any stereoisomer thereof. For example, in some embodiments, the compound is Compound 54, 135, 140, 150, 155, 215, 265, 270, 500, or any combination thereof.
In some embodiments, the one or more compounds described herein can be administered by any suitable route, including, but not limited to, via inhalation, topically, nasally, orally, parenterally (e.g., intravenously, intraperitoneally, intravesically or intrathecally) or rectally in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard practice.

Definitions

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the compositions and compounds described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only not intended to be limiting. Other features and advantages of the compositions and compounds described herein will be apparent from the following detailed description and claims.
As used herein, the phrase “in need thereof” means that the subject, animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject, animal or mammal can be in need thereof. In some embodiments, the subject has been identified has having hyperalgesia, such as but not limited to, opioid induced hyperalgesia. In some embodiments, the subject has been identified as having increased nociceptive sensitization. In some embodiments, the increased nociceptive sensitization is opioid induced nociceptive sensitization.
The general chemical terms used throughout have their usual meanings. For example, the term alkyl refers to a branched or unbranched saturated hydrocarbon group. The term “n-alkyl” refers to an unbranched alkyl group. The term “C_x-C_yalkyl” refers to an alkyl group having from x to y carbon atoms, inclusively, in the branched or unbranched hydrocarbon group. By way of illustration, but without limitation, the term “C₁-C₄alkyl” refers to a straight chain or branched hydrocarbon moiety having from 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term “C₁-C₄n-alkyl” refers to straight chain hydrocarbon moieties having from 1 to 4 carbon atoms including methyl, ethyl, n-propyl, and n-butyl. C_x-C_yx can be from 1 to 10 and y is from 2 to 20. The term “C—C₆cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “C—C₇cycloalkyl” also includes cycloheptyl. Cycloalkylalkyl refers to cycloalkyl moieties linked through an alkyl linker chain, as for example, but without limitation, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted, such as, but not limited to, as specified herein. In some embodiments, the alkyl is a C₁-C₃, C₁-C₄, C₁-C₆, C₄-C₆, or C₁-C₁₀alkyl.
The terms “alkoxy”, “phenyloxy”, “benzoxy” and “pyrimidinyloxy” refer to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, that is bonded through an oxygen atom. Each of these groups may be optionally substituted.
The terms “alkylthio”, “phenylthio”, and “benzylthio” refer to an alkyl group, phenyl group, or benzyl group, respectively, that is bonded through a sulfur atom. Each of these groups may be optionally substituted.
The term “C₁-C₄acyl” refers to a formyl group or a C₁-C₃alkyl group bonded through a carbonyl moiety. The term “C₁-C₄alkoxycarbonyl” refers to a C₁-C₄alkoxy group bonded through a carbonyl moiety.
The term “halo” refers to fluoro, chloro, bromo, or iodo. In some embodiments, the halo groups are fluoro, chloro, and bromo. In some embodiments, the halo groups are fluoro and chloro.
As used herein, “carbocycle” or “carbocyclic ring” is intended to mean, unless otherwise specified, any stable 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic, bicyclic or tricyclic ring, any of which can be saturated, unsaturated (including partially and fully unsaturated), or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. In some embodiments, the bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring can also be present on the bridge. Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also included.
The term “heterocycle” is taken to mean a saturated or unsaturated 5- or 6-membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring optionally being benzofused. Exemplary heterocycles include furanyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl, pyridinyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and the like. Benzofused heterocyclic rings include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl, benzothiophenyl, indolyl, and the like, all of which may be optionally substituted, which also of course includes optionally substituted on the benzo ring when the heterocycle is benzofused.
The term “cycle” group is taken to mean a carbocylic ring, a carbocycle or a heterocarbocyle.
As used herein, the phrase a “cycle of the formula” refers to a ring that can be formed with the variable referred to. For example, in the structure
wherein A can be a cycle of the formula C(CH₂)_n, where n=2-5, it means that A is a carbon and forms a ring with itself with 2-5 CH₂groups, which could also be represented structurally as
The variable “A” is not limited to carbon and can be another atom, such as, but not limited to, a heteroatom, but the context in which the variable is used will indicate the type of atom “A” could be. This is just a non-limiting example. Additionally, the ring that is formed with “A” can also be substituted. Exemplary substituents are described herein.
In some embodiments, heterocycles include, but are not limited to, pyridinyl, indolyl, furanyl, benzofuranyl, thiophenyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally substituted.
As used herein, the term “aromatic heterocycle” or “heteroaryl” is intended to mean a stable 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic aromatic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both can be (e.g., quinoline). The second ring can also be fused or bridged as defined above for heterocycles. The nitrogen atom can be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)_p, wherein p=1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio, means an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group, respectively, substituted one or more times independently with a substituent selected from the group consisting of halo, hydroxy, and C₁-C₃alkoxy. By way of illustration, but without limitation, examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3-hydroxypropyloxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropyloxy, 3-ethoxy-4-chlorocyclohexyl, and the like. In some embodiments, substitutions include substitution 1-5 times with halo, each independently selected, or substituted 1-3 times with halo and 1-2 times independently with a group selected from hydroxy and C₁-C₃alkoxy, or substituted 1-3 times independently with a group selected from hydroxy and C₁-C₃alkoxy, provided that no more than one hydroxy and/or alkoxy substituent may be attached through the same carbon.
The terms “substituted phenyl” and “substituted heterocycle” are taken to mean that the cyclic moiety in either case is substituted. They can be substituted independently with one or more substituents. They can be substituted independently with 1, 2, 3, 4, 5, 1-3, 1-4, or 1-5 substituents. The substitution can be, independently, halo, alkyl, such as, but not limited to, C₁-C₄alkyl, alkoxy, such as but not limited to, C₁-C₄alkoxy, and alkylthio, such as but not limited to, C₁-C₄alkylthio, wherein each alkyl, alkoxy and alkylthio substituent can be further substituted independently with C alkoxy or with one to five halo groups; or substituted with one substituent selected from the group consisting of phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy, wherein the phenyloxy, benzyloxy, phenylthio, benzylthio, and pyrimidinyloxy moiety can be further substituted with one to two substituents selected from the group consisting of halo, C₁-C₂alkyl, and C₁-C₂alkoxy; or substituted with one substituent selected from the group consisting of C acyl and C₁-C₄alkoxycarbonyl, and further substituted with zero to one substituent selected from the group consisting of halo, C₁-C₄alkyl, C₁-C₄alkoxy, and C₁-C₄alkylthio. When a substituent is halo, in some embodiments, the halo groups are fluoro, chloro, and bromo. The halo can also be iodo.
DMF means N,N-dimethylformamide.
As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
By “pharmaceutical formulation” it is further meant that the carrier, solvent, excipients and salt must be compatible with the active ingredient of the formulation (e.g. a compound described herein). It is understood by those of ordinary skill in this art that the terms “pharmaceutical formulation” and “pharmaceutical composition” are generally interchangeable, and they are so used for the purposes of this application.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, and toluene sulfonic. The present disclosure includes pharmaceutically acceptable salts of any compound(s) described herein. In some embodiments, the pharmaceutically acceptable salt is a hydrochloric salt.
Pharmaceutically acceptable salts can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., USA, p. 1445 (1990).
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds described herein can be delivered in prodrug form and can be administered in this form for the treatment of disease. “Prodrugs” are intended to include any covalently bonded carriers that release an active parent drug of described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds described herein.
“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, “treating” or “treatment” includes any effect e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc. “Treating” or “treatment” of a disease state means the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting an existing disease-state, i.e., arresting its development or its clinical symptoms; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
As used herein, “preventing” means causing the clinical symptoms of the disease state not to develop i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
As used herein, “mammal” refers to human and non-human patients.
As used herein, the term “therapeutically effective amount” refers to a compound, or a combination of compounds, described herein present in or on a recipient in an amount sufficient to elicit biological activity, e.g. pain relief. In some embodiments, the combination of compounds is a synergistic combination. Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased decrease in pain, or some other beneficial effect of the combination compared with the individual components.
All percentages and ratios used herein, unless otherwise indicated, are by weight.
Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions described herein also consist essentially of, or consist of, the recited components, and that the processes described herein also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the process remains operable. Moreover, two or more steps or actions can be conducted simultaneously.
All enantiomers, diastereomers, and mixtures thereof, are included within the scope of compounds described herein. In some embodiments, a composition comprising the R enantiomer is free or substantially free of the S enantiomer. In some embodiments, a composition comprising the S enantiomer is free or substantially free of the R enantiomer. In some embodiments, a composition comprises an enantiomeric excess of at least, or about, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of either the R or the S enantiomer.
As used throughout this disclosure, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a composition” includes a plurality of such compositions, as well as a single composition, and a reference to “a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. Thus, for example, a reference to “a host cell” includes a plurality of such host cells, and a reference to “an antibody” is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
The compounds described herein and used in various embodiments described herein can be prepared according to any method, and for example, as described in U.S. Pat. No. 8,835,488, which is hereby incorporated by reference in its entirety.
The following compounds, or pharmaceutically acceptable salts thereof, can be used in any of the methods and embodiments described herein. These compounds are also described, for example, in U.S. Pat. No. 8,835,488, which is hereby incorporated by reference in its entirety.


Compound.	Name	Compound	Name

1	2-[9-(pyridin-2-yl)-6-	11	2-[({2-[4-(4-methylphenyl)oxan-4-
	oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]
	yl]ethan-1-amine		phenol
2	2-[(9R)-9-(pyridin-2-yl)-	12	2-[({2-[4-(4-fluorophenyl)oxan-4-
	6-oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]
	yl]ethan-1-amine		phenol
3	2-[9-(2-aminoethyl)-6-	13	benzyl({2-[3-(pyridin-2-
	oxaspiro[4.5]decan-9-		yl)-1-oxaspiro[4.4]nonan-3-
	yl]pyridin-4-ol		yl]ethyl})amine
4	6-[9-(2-aminoethyl)-6-	14	benzyl({2-[2,2-dimethyl-4-(4-
	oxaspiro[4.5]decan-9-		methylphenyl)oxan-4-
	yl]pyridin-3-ol		yl]ethyl})amine
5	6-[9-(2-aminoethyl)-6-	15	{2-[2,2-dimethyl-4-(4-
	oxaspiro[4.5]decan-9-		methylphenyl)oxan-4-
	yl]pyridin-2-ol		yl]ethyl}(pyridin-2-ylmethyl)amine
6	2-[(9R)-9-(2-	16	{2-[2,2-dimethyl-4-(4-
	aminoethyl)-6-		methylphenyl)oxan-4-
	oxaspiro[4.5]decan-9-		yl]ethyl}(pyridin-3-
	yl]-1-oxidopyridin-1-ium		ylmethyl)amine
7	benzyl({2-[1-(4-	17	[(2-methoxyphenyl)meth-
	fluorophenyl)cyclohex-		yl]({2-[4-(4-methylphenyl)oxan-4-
	yl]ethyl})amine		yl]ethyl})amine
8	benzyl({2-[4-(4-	18	(furan-3-ylmethyl)({2-[(9R)-9-
	fluorophenyl)oxan-4-		(pyridin-2-yl)-6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]ethyl})amine
9	[(2-methylphenyl)meth-	19	(1H-imidazol-2-
	yl]({2-[4-(4-		ylmethyl)({2-[(9R)-9-
	methylphenyl)oxan-4-		(pyridin-2-yl)-6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]ethyl})amine
10	N-{2-[2,2-dimethyl-4-	20	(1,3-oxazol-4-ylmethyl)({2-[(9R)-9-
	(4-methylphenyl)oxan-		(pyridin-2-yl)-6-oxaspiro[4.5]decan-
	4-yl]ethyl}aniline		9-yl]ethyl})amine
21	{2-[3-(pyridin-2-yl)-1-	31	{2-[2,2-dimethyl-4-(4-
	oxaspiro[4.4]nonan-3-		methylphenyl)oxan-4-yl]ethyl}[(2-
	yl]ethyl}(thiophen-2-		methylphenyl)methyl]
	ylmethyl)amine		amine
22	{2-[3-(pyridin-2-yl)-1-	32	{2-[2,2-dimethyl-4-(4-
	oxaspiro[4.4]nonan-3-		methylphenyl)oxan-4-yl]ethyl}[(3-
	yl]ethyl}(thiophen-3-		methylphenyl)methyl]
	ylmethyl)amine		amine
23	(cyclopentylmethyl)({2-	33	{2-[2,2-dimethyl-4-(4-
	[(9R)-9-(pyridin-2-yl)-6-		methylphenyl)oxan-4-yl]ethyl}[(4-
	oxaspiro[4.5]decan-9-		methylphenyl)methyl]
	yl]ethyl})amine		amine
24	{2-[2,2-dimethyl-4-(4-	34	{2-[2,2-dimethyl-4-(4-
	methylphenyl)oxan-4-		methylphenyl)oxan-4-
	yl]ethyl}(thiophen-2-		yl]ethyl}[(1R)-1-
	ylmethyl)amine		phenylethyl]amine
25	{2-[4-(4-fluorophenyl)oxan-4-	35	{2-[2,2-dimethyl-4-(4-
	yl]ethyl}[(2-		methylphenyl)oxan-4-
	methoxyphenyl)meth-		yl]ethyl}[(1S)-1-
	yl]amine		phenylethyl]amine
26	{2-[9-(1H-pyrazol-1-yl)-	36	benzyl({2-[2,2-
	6-oxaspiro[4.5]decan-9-		dimethyl-4-(4-
	yl]ethyl}(thiophen-2-		methylphenyl)oxan-4-
	ylmethyl)amine		yl]ethyl})methylamine
27	benzyl({2-[(9S)-9-	37	{2-[2,2-dimethyl-4-(4-
	(pyridin-2-yl)-6-		methylphenyl)oxan-4-
	oxaspiro[4.5]decan-9-		yl]ethyl}(2-
	yl]ethyl})amine		phenylethyl)amine
28	benzyl({2-[(9R)-9-	38	(pyrazin-2-ylmethyl)({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
29	benzyl({2-[3-(pyridin-2-yl)-1-	39	benzyl({2-[2,2-diethyl-
	oxaspiro[4.5]decan-3-		4-(pyridin-2-yl)oxan-4-
	yl]ethyl})amine		yl]ethyl})amine
30	benzyl({2-[9-(pyridin-2-	40	benzyl({2-[2,2,6,6-
	yl)-6-		tetramethyl-4-(pyridin-
	oxaspiro[4.5]decan-9-		2-yl)oxan-4-
	yl]ethyl})amine		yl]ethyl})amine
41	4-[({2-[2,2-dimethyl-4-	50	benzyl(2-{9-
	(4-methylphenyl)oxan-4-		cyclohexyl-6-
	yl]ethyl}amino)methyl]		oxaspiro[4.5]decan-9-
	phenol		yl}ethyl)amine
42	2-[({2-[2,2-dimethyl-4-	51	{2-[3-(pyridin-2-yl)-1-
	(4-methylphenyl)oxan-4-		oxaspiro[4.5]decan-3-
	yl]ethyl}amino)methyl]		yl]ethyl}(thiophen-2-
	phenol		ylmethyl)amine
43	3-[({2-[2,2-dimethyl-4-	52	{2-[3-(pyridin-2-yl)-1-
	(4-methylphenyl)oxan-4-		oxaspiro[4.5]decan-3-
	yl]ethyl}amino)methyl]		yl]ethyl}(thiophen-3-
	phenol		ylmethyl)amine
44	[(5-methylfuran-2-	53	{2-[9-(pyridin-
	yl)methyl]({2-[(9R)-9-		2-yl)-6-
	(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}(thiophen-2-
	yl]ethyl})amine		ylmethyl)amine
45	[(5-methylfuran-2-	54	{2-[(9R)-9-(pyridin-2-
	yl)methyl]({2-[9-		yl)-6-
	(pyrazin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}(thiophen-2-
	yl]ethyl})amine		ylmethyl)amine
46	benzyl({2-[9-(thiophen-	55	{2-[(9R)-9-(pyridin-2-yl)-6-
	2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}(thiophen-3-
	yl]ethyl})amine		ylmethyl)amine
47	{2-[2,2-dimethyl-4-(4-	56	{2-[(9R)-9-(pyridin-2-
	methylphenyl)oxan-4-		yl)-6-
	yl]ethyl}[(2-		oxaspiro[4.5]decan-9-
	fluorophenyl)meth-		yl]ethyl}(1,3-thiazol-2-
	yl]amine		ylmethyl)amine
48	{2-[2,2-dimethyl-4-(4-	57	{2-[(9R)-9-(pyridin-2-
	methylphenyl)oxan-4-		yl)-6-
	yl]ethyl}[(3-		oxaspiro[4.5]decan-9-
	fluorophenyl)meth-		yl]ethyl}(1,3-thiazol-5-
	yl]amine		ylmethyl)amine
49	{2-[2,2-dimethyl-4-(4-	58	{2-[9-(pyrazin-2-yl)-6-
	methylphenyl)oxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl}[(4-		yl]ethyl}(thiophen-2-
	fluorophenyl)methyl]amine		ylmethyl)amine
59	{2-[2,2-diethyl-4-	69	2-{2-[(9R)-9-(pyridin-2-yl)-6-
	(pyridin-2-yl)oxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl}(thiophen-3-		yl]ethyl}-2,3-dihydro-
	ylmethyl)amine		1H-isoindole
60	{2-[2,2-diethyl-4-	70	{2-[2,2-diethyl-4-(4-
	(pyridin-2-yl)oxan-4-		fluorophenyl)oxan-4-
	yl]ethyl}(thiophen-2-		yl]ethyl}dipropyl-
	ylmethyl)amine		amine
61	{2-[2,2,6,6-tetramethyl-	71	(2-phenylethyl)({2-
	4-(pyridin-2-yl)oxan-4-		[(9R)-9-(pyridin-2-yl)-6-
	yl]ethyl}(thiophen-2-		oxaspiro[4.5]decan-9-
	ylmethyl)amine		yl]ethyl})amine
62	{2-[2,2,6,6-tetramethyl-	72	(2-phenylethyl)({2-[9-
	4-(pyridin-2-yl)oxan-4-		(pyridin-2-yl)-6-
	yl]ethyl}(thiophen-3-		oxaspiro[4.5]decan-9-
	ylmethyl)amine		yl]ethyl})amine
63	{2-[9-(thiophen-2-yl)-6-	73	benzyl({2-[9-(6-
	oxaspiro[4.5]decan-9-		methylpyridin-2-yl)-6-
	yl]ethyl}(thiophen-2-		oxaspiro[4.5]decan-9-
	ylmethyl)amine		yl]ethyl})amine
64	{2-[9-(thiophen-2-yl)-6-	74	{2-[2,2-dimethyl-4-(4-
	oxaspiro[4.5]decan-9-		methylphenyl)oxan-4-
	yl]ethyl}(thiophen-3-		yl]ethyl}(2-
	ylmethyl)amine		phenylpropan-2-yl)amine
65	(cyclopentylmethyl)({2-	75	{2-[(9R)-9-(pyridin-2-yl)-6-
	[2,2-diethyl-4-(4-		oxaspiro[4.5]decan-9-
	fluorophenyl)oxan-4-		yl]ethyl}[2-(pyridin-3-
	yl]ethyl})amine		yl)ethyl]amine
66	(cyclopentylmethyl)({2-	76	[(2-methylpyrimidin-5-
	[4-(4-fluorophenyl)-		yl)methyl]({2-[(9R)-9-
	2,2,6,6-		(pyridin-2-yl)-6-
	tetramethyloxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
67	(2-{9-cyclohexyl-6-	77	{2-[2,2-dimethyl-4-(4-
	oxaspiro[4.5]decan-9-		methylphenyl)oxan-4-
	yl}ethyl)(thiophen-2-		yl]ethyl}[(2-
	ylmethyl)amine		methoxyphenyl)methyl]amine
68	(2-{9-cyclohexyl-6-
	oxaspiro[4.5]decan-9-
	yl}ethyl)(thiophen-3-
	ylmethyl)amine
78	{2-[2,2-dimethyl-4-(4-	87	benzyl({2-[4-(4-
	methylphenyl)oxan-4-		fluorophenyl)-2,2,6,6-
	yl]ethyl}[(3-		tetramethyloxan-4-
	methoxyphenyl)methyl]amine		yl]ethyl})amine
79	benzyl({2-[9-(4-	88	[(2,3-dimethoxyphenyl)meth-
	fluorophenyl)-6-		yl]({2-[4-(4-
	oxaspiro[4.5]decan-9-		methylphenyl)oxan-4-
	yl]ethyl})amine		yl]ethyl})amine
80	benzyl({2-[(9S)-9-(4-	89	[(3-methylthiophen-2-
	fluorophenyl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]ethyl})amine
81	benzyl({2-[(9R)-9-(4-	90	{2-[(9R)-9-(pyridin-2-yl)-6-
	fluorophenyl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}[2-(thiophen-
	yl]ethyl})amine		2-yl)ethyl]amine
82	2-[(9R)-9-(2-	91	[(2-methylthiophen-3-
	{4H,5H,6H-thieno[2,3-		yl)methyl]({2-[(9R)-9-
	c]pyrrol-5-yl}ethyl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]pyridine		yl]ethyl})amine
83	[(4,5-dimethylfuran-2-	92	[(5-methylthiophen-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
84	{2-[(9R)-9-(4-	93	{2-[9-(6-methylpyridin-
	fluorophenyl)-6-		2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl}(pyridin-4-		yl]ethyl}(thiophen-3-
	ylmethyl)amine		ylmethyl)amine
85	2-[({2-[4-(4-methoxyphenyl)-	94	{2-[4-(4-fluorophenyl)-
	2,2-dimethyloxan-4-		1-oxaspiro[5.5]undecan-
	yl]ethyl}amino)methyl]		4-yl]ethyl}(1H-pyrrol-2-
	phenol		ylmethyl)amine
86	benzyl({2-[2,2-	95	{2-[9-(6-methylpyridin-
	diethyl-		2-yl)-6-
	4-(4-		oxaspiro[4.5]decan-9-
	fluorophenyl)oxan-4-		yl]ethyl}(thiophen-2-
	yl]ethyl})amine		ylmethyl)amine
96	[(4-methylthiophen-2-	105	6-[9-{2-
	yl)methyl]({2-[(9R)-9-		[(thiophen-2-
	(pyridin-2-yl)-6-		ylmethyl)amino]ethyl}-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]pyridin-2-ol
97	{2-[(9R)-9-(4-	106	[(5-methylthiophen-2-
	fluorophenyl)-6-		yl)methyl]({2-
	oxaspiro[4.5]decan-9-		[2,2,6,6-
	yl]ethyl}[(5-		tetramethyl-4-(pyridin-
	methylfuran-2-		2-yl)oxan-4-
	yl)methyl]amine		yl]ethyl})amine
98	[(4-methyl-1,3-thiazol-	107	2-(9-{2-
	2-yl)methyl]({2-[(9R)-9-		[(thiophen-2-
	(pyridin-2-yl)-6-		ylmethyl)amino]ethyl}-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl)pyridin-4-ol
99	[(2-methyl-1,3-thiazol-	108	[(4-methylthiophen-2-
	5-yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[2,2,6,6-
	(pyridin-2-yl)-6-		tetramethyl-4-(pyridin-
	oxaspiro[4.5]decan-9-		2-yl)oxan-4-
	yl]ethyl})amine		yl]ethyl})amine
100	[(4-methyl-1,3-thiazol-	109	dibutyl({2-[(9R)-
	5-yl)methyl]({2-[(9R)-9-		9-(pyridin-
	(pyridin-2-yl)-6-		2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
101	[(2-chlorophenyl)meth-	110	{2-[(9R)-9-(4-
	yl]({2-[2,2-		fluorophenyl)-6-
	dimethyl-4-(4-		oxaspiro[4.5]decan-9-
	methylphenyl)oxan-		yl]ethyl}(thiophen-3-
	4-yl]ethyl})amine		ylmethyl)amine
102	[(3-chlorophenyl)meth-	111	{2-[(9R)-9-(4-
	yl]({2-[2,2-		fluorophenyl)-6-
	dimethyl-4-(4-		oxaspiro[4.5]decan-9-
	methylphenyl)oxan-		yl]ethyl}(thiophen-2-
	4-yl]ethyl})amine		ylmethyl)amine
103	[(4-chlorophenyl)meth-	112	(cyclopentylmethyl)({2-
	yl]({2-[2,2-dimethyl-		[4-(4-fluorophenyl)-1-
	4-(4-methylphenyl)oxan-		oxaspiro[5.5]undecan-
	4-yl]ethyl})amine		4-yl]ethyl})amine
104	6-[9-{2-[(thiophen-2-	113	{2-[2,2-diethyl-4-(4-
	ylmethyl)amino]ethyl}-		fluorophenyl)oxan-4-
	6-oxaspiro[4.5]decan-9-		yl]ethyl}(thiophen-3-
	yl]pyridin-3-ol		ylmethyl)amine
114	{2-[2,2-diethyl-4-(4-	123	benzyl({2-[4-(4-
	fluorophenyl)oxan-4-		fluorophenyl)-1-
	yl]ethyl}(thiophen-2-		oxaspiro[5.5]undecan-
	ylmethyl)amine		4-yl]ethyl})amine
115	{2-[4-(4-fluorophenyl)-	124	{2-[(9R)-9-(4-
	2,2,6,6-		fluorophenyl)-6-
	tetramethyloxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl}(thiophen-3-		yl]ethyl}[(1R)-1-
	ylmethyl)amine		phenylethyl]amine
116	{2-[4-(4-fluorophenyl)-	125	{2-[(9R)-9-(4-
	2,2,6,6-		fluorophenyl)-6-
	tetramethyloxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl}(thiophen-2-		yl]ethyl}[(1S)-1-
	ylmethyl)amine		phenylethyl]amine
117	benzyl({2-[9-(2-	126	{2-[2,2-dimethyl-4-(4-
	methoxyphenyl)-6-		methylphenyl)oxan-4-
	oxaspiro[4.5]decan-9-		yl]ethyl}[(2-
	yl]ethyl})amine		nitrophenyl)methyl]amine
118	benzyl({2-[9-(6-	127	{2-[2,2-dimethyl-4-(4-
	methoxypyridin-2-yl)-		methylphenyl)oxan-4-
	6-oxaspiro[4.5]decan-9-		yl]ethyl}[(3-
	yl]ethyl})amine		nitrophenyl)methyl]amine
119	{2-[2,2-dimethyl-4-(4-	128	2-[({2-[9-(4-
	methylphenyl)oxan-4-		fluorophenyl)-6-
	yl]ethyl}[(2-		oxaspiro[4.5]decan-9-
	methoxyphenyl)meth-		yl]ethyl}amino)methyl]
	yl]methylamine		phenol
120	{2-[9-(4-fluorophenyl)-	129	{2-[4-(4-
	6-oxaspiro[4.5]decan-		methoxyphenyl)-2,2-
	9-yl]ethyl}[(3-		dimethyloxan-4-
	methylphenyl)methyl]		yl]ethyl}[(2-
	amine		methoxyphenyl)methyl]amine
121	{2-[(9S)-9-(4-fluorophenyl)-	130	[(5-ethylthiophen-2-
	6-oxaspiro[4.5]decan-9-		yl)methyl]({2-[(9R)-9-
	yl]ethyl}[(3-		(pyridin-2-yl)-6-
	methylphenyl)methyl]		oxaspiro[4.5]decan-9-
	amine		yl]ethyl})amine
122	{2-[(9R)-9-(4-fluorophenyl)-	131	[(3,5-dimethylthiophen-2-
	6-oxaspiro[4.5]decan-9-		yl)methyl]({2-[(9R)-9-
	yl]ethyl}[(3-		(pyridin-2-yl)-6-
	methylphenyl)methyl]		oxaspiro[4.5]decan-9-
	amine		yl]ethyl})amine
132	{2-[2,2-diethyl-4-(4-	140	[(3-methoxythiophen-
	fluorophenyl)oxan-4-		2-yl)methyl]({2-[(9R)-9-
	yl]ethyl}[(6-		(pyridin-2-yl)-6-
	methylpyridin-3-		oxaspiro[4.5]decan-9-
	yl)methyl]amine		yl]ethyl})amine
133	{2-[4-(4-fluorophenyl)-	141	[(3-methoxythiophen-
	2,2,6,6-tetramethyloxan-4-		2-yl)methyl]({2-[9-
	yl]ethyl}[(6-		(pyridin-2-yl)-6-
	methylpyridin-3-		oxaspiro[4.5]decan-9-
	yl)methyl]amine		yl]ethyl})amine
134	[(4,5-dimethylthiophen-2-	142	{2-[9-(6-
	yl)methyl]({2-[(9R)-9-		methoxypyridin-2-yl)-
	(pyridin-2-yl)-6-		6-oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-9-		9-yl]ethyl}(thiophen-2-
	yl]ethyl})amine		ylmethyl)amine
135	[(2,4-dimethyl-1,3-	143	{2-[9-(6-
	thiazol-5-yl)methyl]({2-		methoxypyridin-2-yl)-
	[(9R)-9-(pyridin-2-yl)-6-		6-oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-9-		9-yl]ethyl}(thiophen-3-
	yl]ethyl})amine		ylmethyl)amine
136	{2-[9-(pyrazin-2-yl)-6-	144	{2-[4-(4-chlorophenyl)-
	oxaspiro[4.5]decan-9-		2,2-dimethyloxan-4-
	yl]ethyl}(thiophen-2-		yl]ethyl}[(2-
	ylmethyl)amine		methoxyphenyl)methyl]amine
137	[(4,5-dimethylfuran-2-	145	{2-[(9R)-9-(4-fluorophenyl)-
	yl)methyl]({2-[(9R)-9-		6-oxaspiro[4.5]decan-9-
	(4-fluorophenyl)-6-		yl]ethyl}[(5-
	oxaspiro[4.5]decan-9-		methylthiophen-2-
	yl]ethyl})amine		yl)methyl]amine
138	{2-[9-(2-methoxyphenyl)-6-	146	{2-[4-(4-fluorophenyl)-
	oxaspiro[4.5]decan-9-		1-oxaspiro[5.5]undecan-
	yl]ethyl}(thiophen-2-		4-yl]ethyl}(thiophen-3-
	ylmethyl)amine		ylmethyl)amine
139	{2-[9-(2-methoxyphenyl)-6-	147	{2-[(9R)-9-(4-fluorophenyl)-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-9-
	yl]ethyl}(thiophen-3-		yl]ethyl}[(3-methylthiophen-2-
	ylmethyl)amine		yl)methyl]amine
148	{2-[(9R)-9-(4-fluorophenyl)-	156	{2-[4-(4-fluorophenyl)-
	6-oxaspiro[4.5]decan-9-		1-oxaspiro[5.5]undecan-
	yl]ethyl}[(4-methylthiophen-2-		4-yl]ethyl}[(6-methylpyridin-3-
	yl)methyl]amine		yl)methyl]amine
149	{2-[4-(4-fluorophenyl)-	157	[(2,3-dimethoxyphenyl)meth-
	1-oxaspiro[5.5]undecan-		yl]({2-[2,2-dimethyl-
	4-yl]ethyl}(thiophen-2-		4-(4-methylphenyl)oxan-
	ylmethyl)amine		4-yl]ethyl})amine
150	{2-[(9R)-9-(4-	158	[(2,4-
	fluorophenyl)-6-		dimethoxyphenyl)meth-
	oxaspiro[4.5]decan-9-		yl]({2-[2,2-dimethyl-
	yl]ethyl}[(4-methyl-1,3-		4-(4-methylphenyl)oxan-
	thiazol-2-yl)methyl]amine		4-yl]ethyl})amine
151	{2-[2,2-diethyl-4-(4-	159	{2-[9-(4-fluorophenyl)-
	fluorophenyl)oxan-4-		6-oxaspiro[4.5]decan-
	yl]ethyl}[(5-		9-yl]ethyl}[(4-
	methylthiophen-2-		methoxyphenyl)meth-
	yl)methyl]amine		yl]amine
152	[(5-chlorothiophen-2-	160	[(5-propylthiophen-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
153	dibutyl({2-[4-(4-	161	1-{5-[({2-[(9R)-9-(pyridin-2-yl)-
	fluorophenyl)-2,2,6,6-		6-oxaspiro[4.5]decan-9-
	tetramethyloxan-4-		yl]ethyl}amino)methyl]thiophen-
	yl]ethyl})amine		2-yl}ethan-1-ol
154	{2-[(9R)-9-(4-	162	6-[9-(2-{[(4,5-
	fluorophenyl)-6-		dimethylthiophen-2-
	oxaspiro[4.5]decan-9-		yl)methyl]amino}ethyl)-
	yl]ethyl}(2-		6-oxaspiro[4.5]decan-
	phenylpropan-2-yl)amine		9-yl] pyridin-3-ol
155	{4H,5H,6H-	163	6-[9-(2-{[(4,5-
	cyclopenta[b]thiophen-2-		dimethylthiophen-2-
	ylmethyl}({2-[(9R)-9-(pyridin-		yl)methyl]amino}ethyl)-
	2-yl)-6-oxaspiro[4.5]decan-		6-oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]pyridin-2-ol
164	2-[9-(2-{[(4,5-	171	6-[9-(2-{[(3-
	dimethylthiophen-2-		methoxythiophen-2-
	yl)methyl]amino}ethyl)-		yl)methyl]amino}ethyl)-
	6-oxaspiro[4.5]decan-		6-oxaspiro[4.5]decan-
	9-yl]pyridin-4-ol		9-yl]pyridin-3-ol
165	[(5-nitrothiophen-2-	172	6-[9-(2-{[(3-
	yl)methyl]({2-[(9R)-9-		methoxythiophen-2-
	(pyridin-2-yl)-6-		yl)methyl]amino}ethyl)-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]pyridin-2-ol
166	[(3,5-	173	2-[(9R)-9-(2-{[(3-
	dimethylthiophen-2-		methoxythiophen-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]amino}ethyl)-
	(4-fluorophenyl)-6-		6-oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-9-		9-yl]-1-
	yl]ethyl})amine		oxidopyridin-1-ium
167	[(5-ethylthiophen-2-	174	2-[9-(2-{[(3-
	yl)methyl]({2-[(9R)-9-		methoxythiophen-2-
	(4-fluorophenyl)-6-		yl)methyl]amino}ethyl)-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-
	yl]ethyl})amine		9-yl]pyridin-4-ol
168	{2-[4-(4-fluorophenyl)-	175	{2-[(9R)-9-(4-fluorophenyl)-
	1-oxaspiro[5.5]undecan-4-		6-oxaspiro[4.5]decan-9-
	yl]ethyl}[(5-methylthiophen-2-		yl]ethyl}[(3-methoxythiophen-2-
	yl)methyl]amine		yl)methyl]amine
169	[(4,5-dimethylthiophen-2-	176	{2-[2,2-dimethyl-4-(4-
	yl)methyl]({2-[(9R)-9-		methylphenyl)oxan-4-
	(4-fluorophenyl)-6-		yl]ethyl}({[3-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)phe-
	yl]ethyl})amine		nyl]methyl})amine
170	{[5-(methylsulfanyl)thiophen-	177	(1-benzothiophen-2-
	2-yl]methyl}({2-		ylmethyl)({2-[(9R)-9-
	[(9R)-9-(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
178	(1-benzothiophen-3-	185	{2-[(9R)-9-(pyridin-2-yl)-6-
	ylmethyl)({2-[(9R)-9-		oxaspiro[4.5]decan-9-
	(pyridin-2-yl)-6-		yl]ethyl}({2H,3H-
	oxaspiro[4.5]decan-9-		thieno[3,4-b][1,4]dioxin-
	yl]ethyl})amine		5-ylmethyl})amine
179	[(5-chlorothiophen-2-	186	{2-[2,2-dimethyl-4-(4-
	yl)methyl]({2-[(9R)-9-		methylphenyl)oxan-4-
	(4-fluorophenyl)-6-		yl]ethyl}[(2-
	oxaspiro[4.5]decan-9-		methanesulfonylphe-
	yl]ethyl})amine		nyl)methyl]amine
180	2-{[(2-{2,2-dimethyl-4-	187	[(4-bromofuran-2-
	[4-(trifluoromethyl)phe-		yl)methyl]({2-[(9R)-9-
	nyl]oxan-4-		(pyridin-2-yl)-6-
	yl}ethyl)amino]methyl}		oxaspiro[4.5]decan-9-
	phenol		yl]ethyl})amine
181	[(5-chlorothiophen-2-	188	{2-[(9R)-9-(4-fluorophenyl)-
	yl)methyl]({2-[2,2-		6-oxaspiro[4.5]decan-9-
	diethyl-4-		yl]ethyl}({[5-
	(4-fluorophenyl)oxan-		(methylsulfanyl)thiophen-2-
	4-yl]ethyl})amine		yl]methyl})amine
182	{[5-(2-	189	{2-[(9R)-9-(pyridin-2-
	methylpropyl)thiophen-		yl)-6-
	2-yl]methyl}({2-[(9R)-		oxaspiro[4.5]decan-9-
	9-(pyridin-2-yl)-6-		yl]ethyl}({[6-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-
	yl]ethyl})amine		3-yl]methyl})amine
183	[(5-butylthiophen-2-	190	[(5-bromofuran-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
184	{4H,5H,6H-	191	(2-{2,2-dimethyl-4-[4-
	cyclopenta[b]thiophen-		(trifluoromethyl)phe-
	2-ylmethyl}({2-		nyl]oxan-4-
	[(9R)-9-(4-fluorophenyl)-6-		yl}ethyl)[(2-
	oxaspiro[4.5]decan-9-		methoxyphenyl)meth-
	yl]ethyl})amine		yl]amine
192	[2-[2,2,6,6-	199	[(4-
	tetramethyl-4-(pyridin-		phenylphenyl)meth-
	2-yl)oxan-4-		yl]({2-[(9R)-9-(pyridin-
	yl]ethyl}({[6-		2-yl)-6-
	(trifluoromethyl)pyridin-		oxaspiro[4.5]decan-9-
	3-yl]methyl})amine		yl]ethyl})amine
193	{[5-(furan-2-	200	[(3-
	yl)thiophen-2-		phenylphenyl)meth-
	yl]methyl}({2-[(9R)-9-		yl]({2-[(9R)-9-(pyridin-
	(pyridin-2-yl)-6-		2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
194	[(5-chlorothiophen-2-	201	benzyl({2-
	yl)methyl]({2-[4-(4-		[9-(4-
	fluorophenyl)-1-		bromophenyl)-6-
	oxaspiro[5.5]undecan-		oxaspiro[4.5]decan-9-
	4-yl]ethyl})amine		yl]ethyl})amine
195	(1-benzothiophen-2-	202	2-amino-4-chloro-5-
	ylmethyl)({2-[(9R)-9-(4-		[({2-[(9R)-9-(pyridin-2-yl)-6-
	fluorophenyl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]
	yl]ethyl})amine		thiophene-3-carbonitrile
196	(1-benzothiophen-	203	{2-[(9R)-9-(4-
	3-ylmethyl)({2-		fluorophenyl)-6-
	[(9R)-9-(4-		oxaspiro[4.5]decan-9-
	fluorophenyl)-6-		yl]ethyl}({2H,3H-
	oxaspiro[4.5]decan-9-		thieno[3,4-b][1,4]dioxin-
	yl]ethyl})amine		5-ylmethyl})amine
197	[(5-fluoro-1-	204	[(4-phenylthiophen-
	benzothiophen-2-		2-yl)methyl]({2-
	yl)methyl]({2-[(9R)-9-		[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
198	[(5-cyclopentylthiophen-2-	205	[(5-phenylthiophen-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
206	[(5-methanesulfonylthiophen-	213	[(4-bromofuran-2-
	2-yl)methyl]({2-		yl)methyl]({2-[(9R)-9-
	[(9R)-9-(pyridin-2-yl)-6-		(4-fluorophenyl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
207	[(4-bromothiophen-3-	214	{2-[(9R)-9-(pyridin-2-yl)-6-
	yl)methyl]({2-[(9R)-9-		oxaspiro[4.5]decan-9-
	(pyridin-2-yl)-6-		yl]ethyl}({[5-(thiophen-
	oxaspiro[4.5]decan-9-		2-yl)thiophen-2-
	yl]ethyl})amine		yl]methyl})amine
208	[(4-bromothiophen-2-	215	{2-[2,2-diethyl-4-(4-
	yl)methyl]({2-[(9R)-9-		fluorophenyl)oxan-4-
	(pyridin-2-yl)-6-		yl]ethyl}({[6-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-
	yl]ethyl})amine		3-yl]methyl})amine
209	[(5-bromothiophen-2-	216	[(5-chloro-1-benzothiophen-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
210	[(2-bromothiophen-3-	217	[(5-bromo-4-methylthiophen-
	yl)methyl]({2-[(9R)-9-		2-yl)methyl]({2-[(9R)-
	(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
211	[(5-bromofuran-2-	218	[(4-bromo-5-methylthiophen-
	yl)methyl]({2-[(9R)-9-		2-yl)methyl]({2-[(9R)-
	(4-fluorophenyl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
212	{2-[(9R)-9-(4-fluorophenyl)-	219	[(3-bromo-5-methylthiophen-
	6-oxaspiro[4.5]decan-9-		2-yl)methyl]({2-[(9R)-
	yl]ethyl}({[6-		9-(pyridin-2-yl)-6-
	(trifluoromethyl)pyridin-		oxaspiro[4.5]decan-9-
	3-yl]methyl})amine		yl]ethyl})amine
220	[(4-bromo-3-methylthiophen-	227	[(4-bromo-3-methylthiophen-
	2-yl)methyl]({2-[(9R)-		2-yl)methyl]({2-[(9R)-
	9-(pyridin-2-yl)-6-		9-(4-fluorophenyl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
221	{2-[4-(4-fluorophenyl)-	228	[(4-bromo-5-methylthiophen-
	1-oxaspiro[5.5]undecan-		2-yl)methyl]({2-[(9R)-
	4-yl]ethyl}({[6-		9-(4-fluorophenyl)-6-
	(trifluoromethyl)pyridin-		oxaspiro[4.5]decan-9-
	3-yl]methyl})amine		yl]ethyl})amine
222	[(4-bromothiophen-3-	229	[(3-bromo-5-methylthiophen-
	yl)methyl]({2-[(9R)-9-		2-yl)methyl]({2-[(9R)-
	(4-fluorophenyl)-6-		9-(4-fluorophenyl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
223	[(4-bromothiophen-2-	230	[(5-bromo-4-methylthiophen-
	yl)methyl]({2-[(9R)-9-		2-yl)methyl]({2-[(9R)-
	(4-fluorophenyl)-6-		9-(4-fluorophenyl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
224	[(5-bromothiophen-2-	231	{2-[2,2-
	yl)methyl]({2-[(9R)-9-		diethyl-4-(4-
	(4-fluorophenyl)-6-		fluorophenyl)oxan-4-
	oxaspiro[4.5]decan-9-		yl]ethyl}bis(thiophen-
	yl]ethyl})amine		2-ylmethyl)amine
225	dibenzyl({2-	232	[(4,5-dibromothiophen-2-
	[(9R)-9-(4-		yl)methyl]({2-[(9R)-9-
	fluorophenyl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
226	dibenzyl({2-	233	[(3,4-dibromothiophen-2-
	[2,2-		yl)methyl]({2-[(9R)-9-
	diethyl-4-(4-		(pyridin-2-yl)-6-
	fluorophenyl)oxan-4-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
234	[(4,5-dibromothiophen-2-	240	{2-[(9R)-9-(pyridin-2-yl)-
	yl)methyl]({2-[(9R)-9-		6-oxaspiro[4.5]decan-
	(4-fluorophenyl)-6-		9-yl]ethyl}({[2-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)phe-
	yl]ethyl})amine		nyl]methyl})amine
235	[(3,4-dibromothiophen-2-	241	2-[({2-[(9R)-9-
	yl)methyl]({2-[(9R)-9-		(pyridin-2-yl)-6-
	(4-fluorophenyl)-6-		oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-9-		9-yl]ethyl}amino)meth-
	yl]ethyl})amine		yl]phenol
236	[(2-fluorophenyl)methyl]	242	[(2-methoxyphenyl)meth-
	({2-[(9R)-9-		yl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
237	[(2-bromophenyl)meth-	243	[(3-fluorophenyl)meth-
	yl]({2-[(9R)-9-		yl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
238	[(2-chlorophenyl)meth-	244	[(3-bromophenyl)meth-
	yl]({2-[(9R)-9-		yl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
239	[(2-methylphenyl)meth-	245	[(3-chlorophenyl)meth-
	yl]({2-[(9R)-9-		yl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
246	[(3-methylphenyl)meth-	252	N-methyl-3-[({2-
	yl]({2-[(9R)-9-		[(9R)-9-(pyridin-2-yl)-
	(pyridin-2-yl)-6-		6-oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-		9-yl]ethyl}amino)meth-
	9-yl]ethyl})amine		yl]benzamide
247	methyl 3-[({2-[(9R)-9-	253	N-ethyl-3-[({2-[(9R)-
	(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl}amino)meth-		yl]ethyl}amino)meth-
	yl]benzoate		yl]benzamide
248	3-[({2-[(9R)-9-	254	[(4-methoxyphenyl)meth-
	(pyridin-2-yl)-6-		yl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}amino)meth-		oxaspiro[4.5]decan-
	yl]phenol		9-yl]ethyl})amine
249	{2-[(9R)-9-(pyridin-2-yl)-6-	255	4-[({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}({[3-		oxaspiro[4.5]decan-9-
	(trifluoromethyl)phe-		yl]ethyl}amino)meth-
	nyl]methyl})amine		yl]phenol
250	N-methyl-5-[({2-	256	[(2,3-difluorophenyl)meth-
	[(9R)-9-(pyridin-2-yl)-		yl]({2-[(9R)-9-
	6-oxaspiro[4.5]decan-		(pyridin-2-yl)-6-
	9-yl]ethyl}amino)meth-		oxaspiro[4.5]decan-
	yl]thiophene-2-carboxamide		9-yl]ethyl})amine
251	N-ethyl-5-[({2-[(9R)-	257	[(2,4-difluorophenyl)meth-
	9-(pyridin-2-yl)-6-		yl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}amino)meth-		oxaspiro[4.5]decan-
	yl]thiophene-2-carboxamide		9-yl]ethyl})amine
258	[(2,5-difluorophenyl)meth-	264	2-methoxy-4-[({2-
	yl]({2-[(9R)-9-		[(9R)-9-(pyridin-2-yl)-
	(pyridin-2-yl)-6-		6-oxaspiro[4.5]decan-
	oxaspiro[4.5]decan-		9-yl]ethyl}amino)meth-
	9-yl]ethyl})amine		yl]phenol
259	[(2,6-difluorophenyl)meth-	265	[(5-fluoropyridin-3-
	yl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
260	[(3,4-difluorophenyl)meth-	266	[(5-bromopyridin-3-
	yl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
261	[(3,5-difluorophenyl)meth-	267	[(5-chloropyridin-3-
	yl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
262	[(2,3-dimethoxyphenyl)meth-	268	[(5-methoxypyridin-
	yl]({2-[(9R)-9-		3-yl)methyl]({2-[(9R)-
	(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-		oxaspiro[4.5]decan-
	9-yl]ethyl})amine		9-yl]ethyl})amine
263	[(3,4-dimethoxyphenyl)meth-	269	5-[({2-[(9R)-9-
	yl]({2-[(9R)-9-		(pyridin-2-yl)-6-
	(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-		yl]ethyl}amino)meth-
	9-yl]ethyl})amine		yl]pyridine-3-carbonitrile
270	[(5-methylpyridin-3-	275	{2-[(9R)-9-(pyridin-2-yl)-
	yl)methyl]({2-[(9R)-9-		6-oxaspiro[4.5]decan-
	(pyridin-2-yl)-6-		9-yl]ethyl}({[3-
	oxaspiro[4.5]decan-		(trifluoromethyl)pyridin-
	9-yl]ethyl})amine		2-yl]methyl})amine
271	{2-[(9R)-9-(pyridin-2-yl)-	276	{2-[(9R)-9-(pyridin-2-yl)-
	6-oxaspiro[4.5]decan-		6-oxaspiro[4.5]decan-
	9-yl]ethyl}({[5-		9-yl]ethyl}({[4-
	(trifluoromethyl)pyridin-		(trifluoromethyl)pyridin-
	3-yl]methyl})amine		3-yl]methyl})amine
272	{[6-chloro-5-	277	{2-[(9R)-9-(pyridin-2-yl)-
	(trifluoromethyl)pyridin-3-		6-oxaspiro[4.5]decan-
	yl]methyl}({2-[(9R)-9-		9-yl]ethyl}({[4-
	(pyridin-2-yl)-6-oxaspiro[4.5]decan-		(trifluoromethyl)pyridin-
	9-yl]ethyl})amine		2-yl]methyl})amine
273	{[2-fluoro-5-	500	[(4-chlorophenyl)meth-
	(trifluoromethyl)pyridin-3-		yl]({2-[4-(4-
	yl]methyl}({2-[(9R)-9-		methoxyphenyl)-
	(pyridin-2-yl)-6-oxaspiro[4.5]decan-		2,2-dimethyloxan-4-
	9-yl]ethyl})amine		yl]ethyl})amine
274	{[6-fluoro-5-	501	[(3,4-di-
	(trifluoromethyl)pyridin-3-		methoxyphenyl)meth-
	yl]methyl}({2-[(9R)-9-		yl][2-(2,2-dimethyl-4-
	(pyridin-2-yl)-6-oxaspiro[4.5]decan-		phenyloxan-4-
	9-yl]ethyl})amine		yl)ethyl]amine
502	2-[({2-[2-ethyl-2-	503	[2-(2,2-dimethyl-4-
	methyl-4-(4-		phenyloxan-4-
	methylphenyl)oxan-4-		yl)ethyl][(2-
	yl]ethyl}amino)methyl]		fluorophenyl)meth-
	phenol		yl]amine
504	4-[({2-[4-(2-	505	2-[({2-[2-ethyl-4-(4-
	methoxyphenyl)-2,2-		fluorophenyl)-2-
	dimethyloxan-4-		methyloxan-4-
	yl]ethyl}amino)methyl]-		yl]ethyl}amino)methyl]
	N,N-dimethylaniline		phenol

Compound	Name	Compound	Name

506.	{2-[(9R)-9-	507.	[(2-methylpyrimidin-5-
	(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}(pyrimidin-5-		oxaspiro[4.5]decan-9-
	ylmethyl)amine		yl]ethyl})amine
508.	{2-[(9R)-9-(pyridin-2-yl)-6-	514.	(pyrazin-2-
	oxaspiro[4.5]decan-9-		ylmethyl)({2-[(9R)-9-
	yl]ethyl}({[2-		(pyridin-2-yl)-6-
	(trifluoromethyl)pyrimidin-5-		oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
509.	[(2-methoxypyrimidin-5-	515.	[(6-methylpyrazin-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-
	(pyridin-2-yl)-6-		9-(pyridin-2-
	oxaspiro[4.5]decan-9-		yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
510.	(pyridazin-4-	516.	{2-[(9R)-9-(pyridin-2-yl)-6-
	ylmethyl)({2-[(9R)-		oxaspiro[4.5]decan-9-
	9-(pyridin-2-yl)-6-		yl]ethyl}({[6-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyrazin-2-
	yl]ethyl})amine		yl]methyl})amine
511.	[(6-methylpyridazin-4-	517.	[(6-methoxypyrazin-2-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
512.	{2-[(9R)-9-(pyridin-2-yl)-6-	518.	[(5-methylpyrazin-2-
	oxaspiro[4.5]decan-9-		yl)methyl]({2-[(9R)-
	yl]ethyl}({[6-		9-(pyridin-2-
	(trifluoromethyl)pyridazin-4-		yl)-6-oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
513.	[(6-methoxypyridazin-4-	519.	{2-[(9R)-9-(pyridin-2-yl)-6-
	yl)methyl]({2-[(9R)-		oxaspiro[4.5]decan-9-
	9-(pyridin-2-		yl]ethyl}({[5-
	yl)-6-oxaspiro[4.5]decan-9-		(trifluoromethyl)pyrazin-2-
	yl]ethyl})amine		yl]methyl})amine
520.	[(5-methoxypyrazin-2-	526.	(1H-pyrazol-4-
	yl)methyl]({2-[(9R)-9-		ylmethyl)({2-[(9R)-
	(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
521.	{2-[(9R)-9-	527.	[(1-methyl-1H-pyrazol-4-
	(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}(quinolin-3-		oxaspiro[4.5]decan-9-
	ylmethyl)amine		yl]ethyl})amine
522.	(1H-pyrazol-3-ylmethyl)({2-[(9R)-	528.	[(5-methyl-1H-pyrazol-4-
	9-(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-(pyridin-2-
	oxaspiro[4.5]decan-9-		yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
523.	[(1-methyl-1H-pyrazol-3-	529.	[(1,5-dimethyl-1H-pyrazol-4-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
524.	[(5-methyl-1H-pyrazol-3-	530.	[(5,6-difluoropyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
525.	[(1,5-dimethyl-1H-pyrazol-3-	531.	[(5-chloro-6-fluoropyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
532.	[(5-bromo-6-fluoropyridin-3-	538.	[(5,6-dichloropyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
533.	[(6-fluoro-5-iodopyridin-3-	539.	[(5-bromo-6-chloropyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
534.	[(6-fluoro-5-methylpyridin-3-	540.	[(6-chloro-5-iodopyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
535.	[(6-fluoro-5-methoxypyridin-3-	541.	[(6-chloro-5-methylpyridin-3-
	yl)methyl]({2-[(9R)-9-		yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
536.	2-fluoro-5-[({2-[(9R)-9-	542.	[(6-chloro-5-methoxypyridin-3-
	(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}amino)methyl]pyridine-		oxaspiro[4.5]decan-9-
	3-carbonitrile		yl]ethyl})amine
537.	[(6-chloro-5-fluoropyridin-3-	543.	2-chloro-5-[({2-[(9R)-9-
	yl)methyl]({2-[(9R)-9-		(pyridin-2-yl)-6-
	(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]pyridine-
	yl]ethyl})amine		3-carbonitrile
544.	3-fluoro-5-[({2-[(9R)-9-(pyridin-	550.	5-[({2-[(9R)-9-(pyridin-
	2-yl)-6-oxaspiro[4.5]decan-9-		2-yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl}amino)methyl]pyridine-		yl]ethyl}amino)methyl]pyridine-
	2-carbonitrile		2,3-dicarbonitrile
545.	3-chloro-5-[({2-[(9R)-9-	551.	5-[({2-[(9R)-9-(pyridin-2-yl)-6-
	(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]-3-
	yl]ethyl}amino)methyl]pyridine-		(trifluoromethyl)pyridine-2-
	2-carbonitrile		carbonitrile
546.	3-bromo-5-[({2-[(9R)-9-	552.	{[5-fluoro-6-
	(pyridin-2-yl)-6-		(trifluoromethyl)pyridin-3-
	oxaspiro[4.5]decan-9-		yl]methyl}({2-[(9R)-9-(pyridin-2-
	yl]ethyl}amino)methyl]pyridine-		yl)-6-oxaspiro[4.5]decan-9-
	2-carbonitrile		yl]ethyl})amine
547.	3-iodo-5-[({2-[(9R)-9-	553.	{[5-chloro-6-
	(pyridin-2-yl)-6-		(trifluoromethyl)pyridin-3-
	oxaspiro[4.5]decan-9-		yl]methyl}({2-[(9R)-9-(pyridin-2-
	yl]ethyl}amino)methyl]pyridine-		yl)-6-oxaspiro[4.5]decan-9-
	2-carbonitrile		yl]ethyl})amine
548.	3-methyl-5-[({2-[(9R)-9-	554.	{[5-bromo-6-
	(pyridin-2-yl)-6-		(trifluoromethyl)pyridin-3-
	oxaspiro[4.5]decan-9-		yl]methyl}({2-[(9R)-9-(pyridin-2-
	yl]ethyl}amino)methyl]pyridine-		yl)-6-oxaspiro[4.5]decan-9-
	2-carbonitrile		yl]ethyl})amine
549.	3-methyl-5-[({2-[(9R)-9-	560.	[(5-fluoro-6-methylpyridin-3-
	(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}amino)methyl]pyridine-		oxaspiro[4.5]decan-9-
	2-carbonitrile		yl]ethyl})amine
555.	{[5-iodo-6-	561.	[(5-chloro-6-methylpyridin-3-
	(trifluoromethyl)pyridin-3-		yl)methyl]({2-[(9R)-9-
	yl]methyl}({2-[(9R)-9-(pyridin-2-		(pyridin-2-yl)-6-
	yl)-6-oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
556.	{[5-methyl-6-	562.	[(5-bromo-6-methylpyridin-3-
	(trifluoromethyl)pyridin-3-		yl)methyl]({2-[(9R)-9-
	yl]methyl}({2-[(9R)-9-(pyridin-2-		(pyridin-2-yl)-6-
	yl)-6-oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
557.	{[5-methoxy-6-	563.	[(5-iodo-6-methylpyridin-3-
	(trifluoromethyl)pyridin-3-		yl)methyl]({2-[(9R)-9-
	yl]methyl}({2-[(9R)-9-(pyridin-2-		(pyridin-2-yl)-6-
	yl)-6-oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
558.	5-[({2-[(9R)-9-(pyridin-2-yl)-6-	564.	[(5,6-dimethylpyridin-3-
	oxaspiro[4.5]decan-9-		yl)methyl]({2-[(9R)-9-
	yl]ethyl}amino)methyl]-2-		(pyridin-2-yl)-6-
	(trifluoromethyl)pyridine-3-		oxaspiro[4.5]decan-9-
	carbonitrile		yl]ethyl})amine
559.	{[5,6-bis(trifluoromethyl)pyridin-	565.	[(5-methoxy-6-methylpyridin-3-
	3-yl]methyl}({2-		yl)methyl]({2-[(9R)-9-
	[(9R)-9-(pyridin-2-yl)-6-		(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
566.	2-methyl-5-[({2-[(9R)-9-	572.	[(6-methoxy-5-methylpyridin-3-
	(pyridin-2-yl)-6-		yl)methyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-yl)-6-
	yl]ethyl}amino)methyl]pyridine-		oxaspiro[4.5]decan-9-
	3-carbonitrile		yl]ethyl})amine
567.	{[6-methyl-5-	573.	[(5,6-dimethoxypyridin-3-
	(trifluoromethyl)pyridin-3-		yl)methyl]({2-[(9R)-9-
	yl]methyl}({2-[(9R)-9-(pyridin-2-		(pyridin-2-yl)-6-
	yl)-6-oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
568.	[(5-fluoro-6-methoxypyridin-3-	574.	2-methoxy-5-[({2-[(9R)-9-(pyridin-
	yl)methyl]({2-[(9R)-9-(pyridin-2-		2-yl)-6-oxaspiro[4.5]decan-9-
	yl)-6-oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]pyridine-
	yl]ethyl})amine		3-carbonitrile
569.	[(5-chloro-6-methoxypyridin-3-	575.	2-methoxy-5-[({2-[(9R)-9-(pyridin-
	yl)methyl]({2-[(9R)-9-(pyridin-2-		2-yl)-6-oxaspiro[4.5]decan-9-
	yl)-6-oxaspiro[4.5]decan-9-		yl]ethyl}amino)methyl]pyridine-
	yl]ethyl})amine		3-carbonitrile
570.	[(5-bromo-6-methoxypyridin-3-	576.	{[6-methoxy-5-
	yl)methyl]({2-[(9R)-9-		(trifluoromethyl)pyridin-3-
	(pyridin-2-yl)-6-		yl]methyl}({2-[(9R)-9-(pyridin-2-
	oxaspiro[4.5]decan-9-		yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
571.	[(5-iodo-6-methoxypyridin-3-
	yl)methyl]({2-[(9R)-9-
	(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-
	l]ethyl})amine
576	[(5-chloropyridin-3-yl)methyl]({2-	582	{2-[(9R)-9-(4-fluorophenyl)-6-
	[(9R)-9-phenyl-6-		oxaspiro[4.5]decan-9-yl]ethyl}({[5-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-3-
	yl]ethyl})amine		yl]methyl})amin
577	{2-[(9R)-9-phenyl-6-	583	{2-[(9R)-9-(4-fluorophenyl)-6-
	oxaspiro[4.5]decan-9-yl]ethyl}({[5-		oxaspiro[4.5]decan-9-
	(trifluoromethyl)pyridin-3-		yl]ethyl}({[4-(trifluoromethyl)pyridin-
	yl]methyl})amine		3-yl]methyl})amine
578	{2-[(9R)-9-phenyl-6-	584	[(3,5-difluorophenyl)methyl]({2-
	oxaspiro[4.5]decan-9-		[(9R)-9-(4-
	yl]ethyl}({[4-(trifluoromethyl)pyridin-		fluorophenyl)-6-oxaspiro[4.5]decan-
	3-yl]methyl})amine		9-yl]ethyl})amine
579	[(3,5-difluorophenyl)methyl]({2-	585	[(5-chloropyridin-3-yl)methyl]({2-
	[(9R)-9-phenyl-6-		[(9R)-9-[4-(trifluoromethoxy)phenyl]-
	oxaspiro[4.5]decan-9-		6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
580	[(3-methylphenyl)methyl]({2-	586	{2-[(9R)-9-[4-(trifluoromethoxy)phenyl]-
	[(9R)-9-phenyl-		6-oxaspiro[4.5]decan-9-yl]ethyl}({[5-
	6-oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-3-
	yl]ethyl})amine		yl]methyl})amine
581	[(5-chloropyridin-3-	587	{2-[(9R)-9-[4-
	yl)methyl]({2-		(trifluoromethoxy)phenyl]-6-
	[(9R)-9-(4-fluorophenyl)-		oxaspiro[4.5]decan-9-yl]ethyl}({[4-
	6-oxaspiro[4.5]decan-		(trifluoromethyl)pyridin-3-
	9-yl]ethyl})amine		yl]methyl})amine
588	[(3,5-difluorophenyl)methyl]({2-	594	[(3-methylphenyl)methyl]({2-
	[(9R)-9-[4-		[(9R)-9-
	(trifluoromethoxy)phenyl]-6-		(pyridin-3-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
589	[(3-methylphenyl)methyl]({2-[(9R)-9-	595	[(5-chloropyridin-3-yl)methyl]({2-
	[4-(trifluoromethoxy)phenyl]-6-		[(9R)-9-(pyridin-4-
	oxaspiro[4.5]decan-9-		yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
590	[(5-chloropyridin-3-yl)methyl]({2-	596	{2-[(9R)-9-(pyridin-4-yl)-6-
	[(9R)-9-(pyridin-3-		oxaspiro[4.5]decan-9-
	yl)-6-oxaspiro[4.5]decan-9-		yl]ethyl}({[5-(trifluoromethyl)pyridin-
	yl]ethyl})amine		3-yl]methyl})amine
591	{2-[(9R)-9-(pyridin-3-yl)-6-	597	{2-[(9R)-9-(pyridin-4-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-yl]ethyl}({[4-
	yl]ethyl}({[5-(trifluoromethyl)pyridin-		(trifluoromethyl)pyridin-3-
	3-yl]methyl})amine		yl]methyl})amine
592	{2-[(9R)-9-(pyridin-3-yl)-6-	598	[(3,5-difluorophenyl)methyl]({2-
	oxaspiro[4.5]decan-9-yl]ethyl}({[4-		[(9R)-9-(pyridin-4-
	(trifluoromethyl)pyridin-3-		yl)-6-oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
593	[(3,5-difluorophenyl)methyl]({2-	599	[(3-methylphenyl)methyl]({2-[(9R)-9-
	[(9R)-9-(pyridin-3-		(pyridin-4-yl)-6-
	yl)-6-oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
600	[(5-chloropyridin-3-yl)methyl]({2-	606	{2-[(9R)-9-[3-
	[(9R)-9-(3-		(trifluoromethoxy)phenyl]-6-
	methylphenyl)-6-		oxaspiro[4.5]decan-9-yl]ethyl}({[5-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-3-
	yl]ethyl})amine		yl]methyl})amine
601	{2-[(9R)-9-(3-methylphenyl)-6-	607	{2-[(9R)-9-[3-
	oxaspiro[4.5]decan-9-		(trifluoromethoxy)phenyl]-6-
	yl]ethyl}({[5-		oxaspiro[4.5]decan-9-yl]ethyl}({[4-
	(trifluoromethyl)pyridin-		(trifluoromethyl)pyridin-3-
	3-yl]methyl})amine		yl]methyl})amine
602	{2-[(9R)-9-(3-methylphenyl)-6-	608	[(3,5-difluorophenyl)methyl]({2-
	oxaspiro[4.5]decan-9-		[(9R)-9-[3-
	yl]ethyl}({[4-		(trifluoromethoxy)phenyl]-6-
	(trifluoromethyl)pyridin-3-		oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
603	[(3,5-difluorophenyl)methyl]({2-	609	[(3-methylphenyl)methyl]({2-[(9R)-9-
	[(9R)-9-(3-methylphenyl)-6-		[3-(trifluoromethoxy)phenyl]-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
604	{2-[(9R)-9-(3-	610	[(5-chloropyridin-3-yl)methyl]({2-
	methylphenyl)-6-		[(9R)-9-[4-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)phenyl]-6-
	yl]ethyl}[(3-		oxaspiro[4.5]decan-9-
	methylphenyl)methyl]amine		yl]ethyl})amine
605	[(5-chloropyridin-3-yl)methyl]({2-	611	{2-[(9R)-9-[4-
	[(9R)-9-[3-		(trifluoromethyl)phenyl]-6-
	(trifluoromethoxy)phenyl]-6-		oxaspiro[4.5]decan-9-yl]ethyl}({[5-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)pyridin-3-
	yl]ethyl})amine		yl]methyl})amine
612	{2-[(9R)-9-[4-	618	[(3,5-difluorophenyl)methyl]({2-
	(trifluoromethyl)phenyl]-6-		[(9R)-9-(3-
	oxaspiro[4.5]decan-9-yl]ethyl}({[4-		fluorophenyl)-6-
	(trifluoromethyl)pyridin-3-		oxaspiro[4.5]decan-
	yl]methyl})amine		9-yl]ethyl})amine
613	[(3,5-difluorophenyl)methyl]({2-	619	{2-[(9R)-9-(3-
	[(9R)-9-[4-		fluorophenyl)-6-
	(trifluoromethyl)phenyl]-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}[(3-
	yl]ethyl})amine		methylphenyl)methyl]amine
614	[(3-methylphenyl)methyl]({2-	620	[(5-chloropyridin-3-yl)methyl]({2-
	[(9R)-9-[4-		[(9R)-9-[3-
	(trifluoromethyl)phenyl]-6-		(trifluoromethyl)phenyl]-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
615	[(5-chloropyridin-3-	621	{2-[(9R)-9-[3-
	yl)methyl]({2-		(trifluoromethyl)phenyl]-6-
	[(9R)-9-(3-		oxaspiro[4.5]decan-9-yl]ethyl}({[5-
	fluorophenyl)-6-oxaspiro[4.5]decan-		(trifluoromethyl)pyridin-3-
	9-yl]ethyl})amine		yl]methyl})amine
616	{2-[(9R)-9-(3-fluorophenyl)-6-	622	{2-[(9R)-9-[3-
	oxaspiro[4.5]decan-9-		(trifluoromethyl)phenyl]-6-
	yl]ethyl}({[5-		oxaspiro[4.5]decan-9-yl]ethyl}({[4-
	(trifluoromethyl)pyridin-		(trifluoromethyl)pyridin-3-
	3-yl]methyl})amine		yl]methyl})amine
617	{2-[(9R)-9-(3-fluorophenyl)-6-	623	[(3,5-difluorophenyl)methyl]({2-
	oxaspiro[4.5]decan-9-		[(9R)-9-[3-
	yl]ethyl}({[4-		(trifluoromethyl)phenyl]-6-
	(trifluoromethyl)pyridin-3-		oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
624	[(3-methylphenyl)methyl]({2-[(9R)-9-	630	{2-[(9R)-9-(pyridin-2-yl)-6-
	[3-(trifluoromethyl)phenyl]-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}({[5-(trifluoromethyl)pyridin-
	yl]ethyl})amine		2-yl]methyl})amine
625	[(5-chloropyridin-3-	631	{2-[(9R)-9-(pyridin-2-yl)-6-
	yl)methyl](methyl){2-[(9R)-9-		oxaspiro[4.5]decan-9-
	(pyridin-2-yl)-6-oxaspiro[4.5]decan-		yl]ethyl}(pyridin-2-
	9-yl]ethyl}amine		ylmethyl)amine
626	methyl({2-[(9R)-9-(pyridin-2-yl)-6-	632	{2-[(9R)-9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-yl]ethyl}){[5-		oxaspiro[4.5]decan-9-
	(trifluoromethyl)pyridin-3-		yl]ethyl}(pyridin-3-
	yl]methyl}amine		ylmethyl)amine
627	[(5-chloropyridin-3-yl)methyl-(2H2)]	633	{2-[(9R)-9-(pyridin-2-yl)-6-
	{2-[(9R)-9-(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-yl]ethyl}amine		yl]ethyl}(pyridin-4-ylmethyl)amine
628	({2-[(9R)-9-(pyridin-2-yl)-6-	634	(1H-imidazol-4-ylmethyl)({2-[(9R)-9-
	oxaspiro[4.5]decan-9-yl]ethyl}){[5-		(pyridin-2-yl)-6-
	(trifluoromethyl)pyridin-3-yl]methyl-		oxaspiro[4.5]decan-9-
	(2H2)}amine		yl]ethyl})amine
629	{2-[(9R)-9-(pyridin-2-yl)-6-	635	[(2-methylpyridin-4-yl)methyl]({2-
	oxaspiro[4.5]decan-9-yl]ethyl}({[6-		[(9R)-9-(pyridin-2-
	(trifluoromethyl)pyridin-2-		yl)-6-oxaspiro[4.5]decan-9-
	yl]methyl})amine		yl]ethyl})amine
636	{2-[(9R)-9-(pyridin-2-yl)-6-	642	[2-(3-methylphenyl)ethyl]({2-[(9R)-9-
	oxaspiro[4.5]decan-9-		(pyridin-2-
	yl]ethyl}({[2-(trifluoromethyl)pyridin-		yl)-6-oxaspiro[4.5]decan-9-
	4-yl]methyl})amine		yl]ethyl})amine
637	[(6-chloropyridin-3-yl)methyl]({2-	643	[2-(3-chlorophenyl)ethyl]({2-[(9R)-9-
	[(9R)-9-(pyridin-2-		(pyridin-2-
	yl)-6-oxaspiro[4.5]decan-9-		yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
638	[(1-methyl-1H-imidazol-2-	644	[2-(3-bromophenyl)ethyl]({2-[(9R)-9-
	yl)methyl]({2-[(9R)-9-		(pyridin-2-yl)-6-
	(pyridin-2-yl)-6-oxaspiro[4.5]decan-		oxaspiro[4.5]decan-9-
	9-yl]ethyl})amine		yl]ethyl})amine
639	(naphthalen-2-ylmethyl)({2-[(9R)-9-	645	[2-(3-fluorophenyl)ethyl]({2-[(9R)-9-
	(pyridin-2-		(pyridin-2-
	yl)-6-oxaspiro[4.5]decan-		yl)-6-oxaspiro[4.5]decan-9-
	9-yl]ethyl})amine		yl]ethyl})amine
640	[(6-bromo-5-fluoropyridin-3-	646	{2-[(9R)-9-(pyridin-2-yl)-6-
	yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}({2-[3-
	yl]ethyl})amine		(trifluoromethyl)phenyl]ethyl})amine
641	[(5-methanesulfonylpyridin-3-	653	[2-(4-methoxyphenyl)ethyl]({2-[(9R)-
	yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
647	[2-(3-methoxyphenyl)ethyl]({2-[(9R)-	654	[2-(2-methylphenyl)ethyl]({2-[(9R)-
	9-(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
648	[2-(4-methylphenyl)ethyl]({2-[(9R)-	655	[2-(2-chlorophenyl)ethyl]({2-[(9R)-
	9-(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
649	[2-(4-chlorophenyl)ethyl]({2-[(9R)-	656	[2-(2-bromophenyl)ethyl]({2-[(9R)-
	9-(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
650	[2-(4-bromophenyl)ethyl]({2-[(9R)-	657	[2-(2-fluorophenyl)ethyl]({2-[(9R)-
	9-(pyridin-2-yl)-6-		9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-		oxaspiro[4.5]decan-9-
	yl]ethyl})amine		yl]ethyl})amine
651	[2-(4-fluorophenyl)ethyl]({2-[(9R)-	658	{2-[(9R)-9-(pyridin-2-yl)-6-
	9-(pyridin-2-yl)-6-		oxaspiro[4.5]decan-9-
	oxaspiro[4.5]decan-9-		yl]ethyl}({2-[2-
	yl]ethyl})amine		(trifluoromethyl)phenyl]ethyl})amine
652	{2-[(9R)-9-(pyridin-2-yl)-6-
	oxaspiro[4.5]decan-9-
	yl]ethyl}({2-[4-
	(trifluoromethyl)phenyl]ethyl})amine
659	[2-(2-methoxyphenyl)ethyl]({2-[(9R)-
	9-(pyridin-2-
	yl)-6-oxaspiro[4.5]decan-9-
	yl]ethyl})amine

Examples

Example 1: Biased ligands do not induce hyperalgesia. Compounds were tested for their potential to induce hyperalgesia in a mouse model of opioid induced hyperalgesia. In this test mice (n=8/group) are given subcutaneous injections of vehicle or mu opioid agonists twice per day for four days. On each of the four drug treatment days a measurement of mechanical allodynia was obtained using a method of repeated stimulation with a single von Frey monofilament (0.4 g). On the fifth day animals are again tested with no additional drug treatments. For testing, the monofilament is delivered to the hind paw for approximately 1-2 seconds. If there is a withdrawal response, that is recorded as a positive response. This is repeated ten times for each mouse. The final measurement for each mouse is the % non-response to stimulation for the ten trials. The results are shown in FIG. 1. Compound A is Compound 265 and Compound B is Compound 54.
The figures illustrate the percent of non-responses to 10 applications of a 0.4 g von Frey filament in mice treated with indicated mu-opioid agonists or vehicle over 4 days. Oxycodone and fentanyl decreased the % non-responses, an indication of increased sensitivity (hyperalgesia) to the von Frey filament, while the biased mu-opioid agonists Compound A and B, did not.
These results demonstrate that the biased ligands that target the mu-opioid receptor do not induce hyperalgesia as compared to the non-biased ligands that are fentanyl and oxycodone. These results were surprising and unexpected. Therefore, based upon these results it is expected that the compounds can be used to treat hyperalgesia or subjects that have hyperalgesia or increased nociceptive sensitization as described herein.
Example 2: Biased ligand reverse opioid induced hyperalgesia. In a mouse model of opioid induced hyperalgesia, compounds were tested for their potential to reverse opioid induced hyperalgesia. In this test mice (n=8/group) were given subcutaneous injections of vehicle or a reference mu opioid agonist twice per day for four days. On each of the four drug treatment days a measurement of mechanical allodynia was obtained using a method of repeated stimulation with a single von Frey monofilament (0.4 g). After behavioral testing on the fifth day animals that had received a reference mu opioid agonist were switched onto Compound B. Twice daily subcutaneous injections continued through Day 12. A behavioral assessment of mechanical allodynia was made on days 5, 6, 7, 8, 10 and 12. For testing, the monofilament is delivered to the hind paw for approximately 1-2 seconds. If there was a withdrawal response, that was recorded as a positive response. This was repeated ten times for each mouse. The final measurement for each mouse is the % non-response to stimulation for the ten trials. Compound B (Compound 54) was able to reverse of opioid induced hyperalgesic activity. Similar results would be expected for Compound 140 and Compound 265 because they are also biased ligands like Compound 54. Accordingly, the results that were produced demonstrate that the biased ligands provided herein can reverse opioid induced hyperalgesic activity. Accordingly, the compounds described herein can be used to reverse opioid induced hyperalgesic activity in humans or other mammals.
Example 3: A human subject who is prescribed morphine presents with symptoms of opioid induced hyperalgesia. The subject stops being administered the morphine and is administered Compound 140 or Compound 265. The subject's opioid induced hyperalgesia is treated and reduced. The subject continues taking Compound 140 or Compound 265 and does not suffer from hyperalgesia while maintaining the pain relief.
Example 4: A subject is identified as having increased nociceptive sensitization due to being administered an opioid for pain relief. The subject is switched from the opioid to a pharmaceutical composition comprising Compound 140 or Compound 265. The subject's nociceptive sensitization is decreased while maintaining the pain relief.
The foregoing examples demonstrate that the compounds described herein do not induce OIH in subjects being administered one or more of the compounds described herein and can be used to treat pain in subjects without causing hyperalgesia or increased nociceptive sensitization. The examples also demonstrate that the biased ligans provided herein can be used to reverse opioid induced hyperalgesic activity in a mammal, such as humans.
While the compounds and methods described herein have been described with reference to examples, those skilled in the art recognize that various modifications may be made without departing from the spirit and scope thereof.
All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety.

Claims

1. A method of treating or reversing hyperalgesia in a subject comprising administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

A₁is selected from the group consisting of null, CH₂, CHR₁, CR₁R₂, CH, CR₁, O, S, SO, SO₂, NH and NR₁;

A₂is selected from the group consisting of null, CH₂, CHR₅, CR₅R₆, CH, CR₅, O, S, SO, SO₂, NH and NR₅;

A₃is selected from the group consisting of null, CH₂, CHR₇, CR₇R₈, O, S, SO, SO₂, NH, NR₇, CH and CR₇;

A₄selected from the group consisting of is null, CH₂, cycle of the formula C(CH₂)_n, where n=2-5, CHR₉, CR₉R₁₀, O, S, SO, SO₂, NH, NR₉, CH and CR₉;

A₅is selected from the group consisting of null, CH₂, CHR₁₁, CR₁₁R₁₂, CH₂CH₂, CHR₁₁CH₂, CH₂CHR₁₁, CHR₁₁CHR₁₂, O, S, SO, SO₂, NH, NR₁₁, CH and CR₁₁;

B₁is selected from the group consisting of CH₂, CHR₁₃, CR₁₃R₁₄, O, S, SO, SO₂, NH, NR₁₃, CR₁₃and CO;

B₂is selected from the group consisting of CH₂, CHR₁₅, CR₁₅R₁₆, CR₁₅and CO;

B₃is selected from the group consisting of H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl;

B₄is selected from the group consisting of null, C₁-C₆alkyl, CH₂, CH₂CH₂, CHR₁₉, CR₁₉R₂₀and CO;

B₅is selected from the group consisting of alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle and arylalkyl;

D₁is an aryl group or a cycle;

R₁, R₂, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₉, and R₂₀are independently selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl and alkoxycarbonyl;

wherein no more than 2 out of 5 of Au, A₂, A₃, A₄, and A₅can be null at the same time,

wherein the number of heteroatoms in Au, A₂, A₃, A₄, A₅cannot exceed 2 at the same time;

wherein the bonds between Au, A₂, A₃, A₄and A₅cannot be S—O, S—S, or S—N; and

wherein alkyl is a linear carbon chain having from 1 to 10 carbon atoms; wherein the cycle is not aromatic;

wherein each aryl group is a monocyclic aromatic group or a bicyclic aromatic group; wherein each cycle is a monocyclic or a bicyclic non-aromatic ring system.

2. The method of claim 1, wherein the hyperalgesia is opioid induced hyperalgesia.

3-4. (canceled)

5. A method of decreasing nociceptive sensitization in a subject comprising administering to the subject a compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

A₃is selected from the group consisting of null, CH₂, CHR₇, CR₇R₈, O, S, SO, SO₂, NH, NR_S, CH and CR₇;

A₅is selected from the group consisting of null, CH₂, CHR₁, CR₁₁R₁₂, CH₂CH₂, CHR₁₁CH₂, CH₂CHR₁, CHR₁₁CHR₁₂, O, S, SO, SO₂, NH, NR₁, CH and CR₁₁;

D₁is an aryl group or a cycle;

R₁, R₂, R₅, R₆, R₇, R₅, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₉, and R₂₀are independently selected from the group consisting of cyano, halogen, hydroxyl, alkyloxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl and alkoxycarbonyl;

6-27. (canceled)

28. The method of claim 1, wherein the compound has a formula of Formula II-1, Formula II-2, or Formula III, or a pharmaceutically acceptable salt thereof:

wherein:

A₂is selected from the group consisting of CH₂, CHR₅and CR₅R₆;

A₄is elected from the group consisting of CH₂, CHR₉, CR₉R₁₀and a cycle of the formula C(CH₂)_n, where n=2-5;

R₅, R₆, R₉and R₁₀are independently selected from the group consisting of CH₃, CH₂CH₃, CH₂F, CHF₂, CF₃, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl;

B₃is selected from the group consisting of H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and alkylsulfonyl;

B₄is selected from the group consisting of null, CH₂, CHR₁₉, CR₁₉R₂₀and CO;

B₅is selected from the group consisting of alkyl, branched alkyl, carbocycle, carbocycle-substituted alkyl, aryl and arylalkyl; and

D₁is aryl.

29-44. (canceled)

45. The method of claim 1, wherein the compound has a formula of Formula IV-1, IV-2, or IV-3, or a pharmaceutically acceptable salt thereof:

wherein R₂₁and R₂₂are independently H or CH₃;

A₄is selected from the group consisting of CH₂, CR₉R₁₀and a cycle of the formula C(CH₂)_n, where n=2-5;

R₉and R₁₀are independently CH₃or CH₂CH₃;

B₃is H, CH₃, or —(CH₂)_nCH₃, where n=2-3;

B₄is selected from the group consisting of null, CH₂, C₁-C₆alkyl, CH₂CH₂or —CHCH₃;

B₅is selected from the group consisting of —(CH₂)_nCH₃, where n=2-3, —C(CH₃)₃, cyclohexyl, cyclopentyl, aryl and arylalkyl;

D₁is a phenyl or 2-pyridyl, wherein the phenyl or 2-pyridyl can be independently mono or multiply substituted with a member of the group consisting of F, Cl, Br, CF₃, OCF₃and CH₃; and

wherein the aryl group is selected from group consisting of

46. (canceled)

47. The method of claim 1, wherein the compound has a formula of Formula V-1, V-2, V-3, VI-1, VI-2, or VI-3, or a pharmaceutically acceptable salt thereof:

wherein D₁is an optionally mono or multiply substituted aryl;

B₅is an optionally mono or multiply substituted aryl or carbocycle;

wherein aryl is selected from the group consisting of:

and

wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

48-54. (canceled)

55. The method of claim 1, wherein the compound has a formula of Formula IV-1, or a pharmaceutically acceptable salt thereof:

wherein:

R₂₁and R₂₂are independently H or CH₃;

A₄is an optionally substituted cycle of the formula C(CH₂)_n, where n=2-5;

B₃is H or an optionally substituted alkyl;

B₄is C₁-C₆alkyl;

D₁is an optionally substituted aryl; and

B₅is an optionally substituted aryl.

56. The method of claim 55, having the structure of Formula VII-1:

wherein R₂₆and R₂₇are independently H or an isotope thereof.

57. The method of claim 56, wherein the compound has the structure of Formula IX, Formula VII-1, or Formula X, or a pharmaceutically acceptable salt thereof:

58-63. (canceled)

64. The method of claim 55, wherein B₅is an optionally substituted aryl selected from the group consisting of

wherein

R₂₃, R₂₄, and R₃₀are each independently null, H, OH, cycle, aryl, branched or unbranched alkyl alcohol, halo, branched or unbranched alkyl, amine, amide, cyano, alkoxy, haloalkyl, aklylsulfonyl, nitrite, alkylsulfanyl; or, R₂₃and R₂₄together form a aryl or cycle that is attached to one or more of the atoms of B₅; and R₂₅is H or an optionally substituted branched or unbranched alkyl.

65. The method of claim 64, wherein R₂₃, R₂₄, and R₃₀are each independently H, NH₂, OH, Cl, Br, F, I, OMe, CN, CH₃, phenyl, C₃-C₆carbocycle, methanesulfonyl, CF₃,

wherein R₂₉is H or an optionally substituted branched or unbranched alkyl.

66. The method of claim 64, wherein B₅is

67. The method of claim 64, wherein B₅is

68. The method of claim 66, wherein R₂₃is alkoxy.

69. (canceled)

70. The method of claim 66, wherein R₂₃is methoxy.

71. (canceled)

72. The method of any one of claim 1, wherein the compound has a formula of:

or a pharmaceutically acceptable salt thereof,

wherein:

D₁is an optionally substituted aryl; and

B₅is an optionally substituted pyridyl.

73-83. (canceled)

84. The method of claim 72, wherein the compound, has the formula of

or a pharmaceutically acceptable salt thereof.

85. (canceled)

86. The method of claim 1, wherein the compound, or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition.

87-89. (canceled)

90. The compound of claim 1, wherein the pharmaceutically acceptable salt is formed from non-toxic inorganic or organic acid.

91. The compound of claim 90, wherein the acid is 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, or toluene sulfonic acid.

92. The compound of claim 90, wherein the pharmaceutically acceptable salt is a fumaric acid salt.

93. The compound of claim 92, wherein the fumaric acid salt of a compound of Formula I is a fumaric acid salt of a compound having the formula of