Methods of treating hyperalgesia

Abstract

The present application relates to methods of treating hyperalgesia. Compounds and methods that may be used to treat, reverse, or avoid hyperalgesia are described. The compound or the pharmaceutically acceptable salt thereof can be used for preparing a medicine for reversing opioid-induced hyperalgesia of a subject in need, and a new therapeutic agent and therapy are provided for treating, reversing or avoiding hyperalgesia.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 267,144, filed December 14, 2015, the entire disclosure of which is incorporated herein by reference. This application is also related to U.S. Non-Provisional Application No. 13 / 428,849, filed March 23, 2012, Provisional Application No. 61 / 596,808, filed February 9, 2012, and U.S. Provisional Application No. 61 / 466,809, filed March 23, 2011, the entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present application relates to a family of compounds that act as opioid receptor ligands and methods of using these compounds to treat or reverse hyperalgesia, treat or reverse induced hyperalgesia, reduce nociceptive sensitization, and the like. Background Art

[0004] Opioid receptors (ORs) mediate the effects 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. In addition, each type is believed to have subtypes. All three of these opioid receptor types appear to share the same functional mechanism at the cellular level. For example, activation of opioid receptors causes inhibition of adenylate cyclase and recruits β-arrestin.

[0005] When therapeutic doses of morphine are given to patients with pain, patients report that the pain is less intense, less uncomfortable, or disappears completely. In addition to experiencing pain relief, some patients experience euphoria. However, when morphine is given to pain-free individuals at doses selected to relieve pain, the experience is not always pleasant; nausea is common, and vomiting may also occur. Drowsiness, inability to concentrate, difficulty with mental state, emotional apathy, decreased physical activity, decreased vision, and sleepiness may ensue. In addition, patients who are administered morphine and similar non-biased ligands may suffer from hyperalgesia. If the cause is due to opioid therapy, it can be called opioid-induced hyperalgesia (OIH).

[0006] There is a continuing need for new OR modulators that do not cause hyperalgesia or that can be used as therapeutic agents to treat humans suffering from opioid or other induced hyperalgesia. The present embodiments meet these needs and others. Summary of the invention

[0007] The present application describes opioid receptor (OR) ligands. Methods for treating or reversing hyperalgesia (such as, but not limited to, opioid-induced hyperalgesia) are also described. Therefore, in some embodiments, methods for treating hyperalgesia in a subject are provided. In some embodiments, methods for reversing hyperalgesia in a subject (including, but not limited to, opioid-induced hyperalgesia) are provided. In some embodiments, the method comprises administering to the subject a compound of any formula described herein or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, methods of reducing nociceptive sensitization in a subject are provided. In some embodiments, the method comprises administering to the subject a compound of any formula described herein, or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, a method of treating pain in a subject is provided. In some embodiments, the method comprises administering an opioid agonist to the subject until the first opioid increases nociceptive sensitization in the subject; and administering a compound of any formula described herein or a pharmaceutically acceptable salt thereof to the patient suffering from increased nociceptive sensitization.

[0010] In some embodiments, a method of treating pain in a subject exposed to an opioid is provided. In some embodiments, the method comprises administering an opioid agonist to the subject; and administering a compound of any formula described herein or a pharmaceutically acceptable salt thereof to the subject of the step in the absence of an opioid.

[0011] In some embodiments, the compound of any formula described herein or a pharmaceutically acceptable salt thereof has the formula of Formula I:

[0012]

[0014] In the above structures, variables A1, A2, A3, A4, A5, B1, B2, B3, B4, B5 and D1 can be selected from various groups of chemical moieties described later. OR ligand derivatives and mimetics are also provided.

[0015] In some embodiments, the compound has the formula,

[0016] or a pharmaceutically acceptable salt thereof,

[0017] wherein D1 is an optionally substituted aryl group; and B5 is an optionally substituted pyridyl group.

[0018] The application also describes pharmaceutical compositions comprising one or more compounds described herein that are pharmaceutically acceptable carriers. As a matter of course, the compounds described herein can be used in any form as further described below, such as solid or solution (e.g., aqueous solution). For example, the compounds described herein can be obtained and used in lyophilized form alone or with suitable additives.

[0019] In some embodiments, provided is the use of a compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or reversing hyperalgesia, opioid-induced hyperalgesia, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It was shown that the biasing ligands described herein do not induce hyperalgesia.

[0021] Figure 2 It was shown that the biasing ligands described herein can reverse opioid-induced hyperalgesia. DETAILED DESCRIPTION

[0022] The present application describes a family of OR ligand compounds with a unique spectrum. The compounds described herein are used as agonists or antagonists of opioid receptor (OR)-mediated signal transduction. The ligands of these receptors can be used to treat pathologies associated with OR, including pain and pain-related disorders, such as but not limited to opioid-induced hyperalgesia and nociceptive sensitization.

[0023] In some embodiments, the compound further comprises Formula I:

[0024]

[0025] Wherein: A1 is empty, CH2, CHR1, CR1R2, CH, CR1, O, S, SO, SO2, NH or NR1; A2 is empty, CH2, CHR5, CR5R6, CH, CR5, O, S, SO, SO2, NH or NR5; A3 is empty, CH2, CHR7, CR7R8, O, S, SO, SO2, NH, NR7, CH or CR7; A4 is empty, CH2, formula C(CH2) n wherein n=2-5, CHR9, CR9R 10 , O, S, SO, SO2, NH, NR9, CH or CR9; and A5 is empty, CH2, CHR 11 , CR 11 R 12 、CH2CH2、CHR 11 CH2、CH2CHR 11 , CHR 11 CHR 12、O、S、SO、SO2、NH、NR 11 , CH or CR 11 .

[0026] 5 A's a At most 2 of them (specifically A1, A2, A3, A4, A5) can be empty at the same time. The number of heteroatoms from A1 to A5 cannot exceed 2 at the same time, and the fragments of OO, SO; SS; SN in the ring structure are excluded from this combination.

[0027] The ring comprising A1, A2, A3, A4, A5 and the carbon connected to D1 can be fused with another ring such as benzene, pyridine, pyrimidine, furan, thiophene or pyridazine, but is not limited to these examples, wherein the obtained bicyclic ring is chemically stable and can be synthesized. It should also be understood that the above-mentioned condensed ring can be multiply substituted by cyano, halogen, alkyl, branched alkyl, haloalkyl, hydroxyl, alkoxy, formyl, acetyl, amino, alkylamino, dialkylamino, sulfhydryl, alkylsulfhydryl and other small substituent groups. The bond between A1 and A2, A2 and A3, A3 and A4, A4 and A5 can be independently single bond or double bond. The bond between A1 and A2, A2 and A3, A3 and A4, A4 and A5 cannot be double bond at the same time.

[0028] A2 and A4 may be linked by a carbon bridge. Examples of such bridges include -CH2- and -CH2CH2-.

[0029] B1 is CH2, CHR 13 , CR 13 R 14 、O、S、SO、SO2、NH、NR 13 , CR 13 or CO. B2 is CH2, CHR 15 , CR 15 R 16 , CR 15 or CO. B3 is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or alkylsulfonyl. B4 is empty, C1-C6 alkyl, CH2, CH2CH2, CHR 19 , CR 19 R 20 or CO. In some embodiments, when B4 is alkyl, one or more of the hydrogens may be replaced by deuterium. B5 is alkyl, branched alkyl, haloalkyl, carbocyclic substituted alkyl, aryl, carbocyclic or arylalkyl.

[0030] Aryl, carbocycle (non-aromatic) / heterocycle (non-aromatic with 1-3 heteroatoms (including O, N, S)) are unsubstituted or substituted with small substituent groups. Small substituent groups can be cyano, halogen, alkyl, branched alkyl, haloalkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, mercapto, alkylthiol, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle or carbocycloalkyl. In some embodiments, the small substituent group is 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, MeSO2, formyl, and acetyl.

[0031] Carbocyclic rings may contain double bonds, but they should not be aromatic.

[0032] D1 is an aryl group or a carbocyclic ring.

[0033] The aryl group is either a monocyclic aromatic group or a bicyclic aromatic group, which may contain heteroatoms (e.g., heteroaryl) in the aromatic group. The following structures are some examples of representative aryl groups, but the aryl groups are not limited to these examples:

[0034]

[0035]

[0036] Carbocycles are either monocyclic or bicyclic non-aromatic ring systems. The following structures are some examples of representative carbocycles, but carbocycles are not limited to these examples:

[0037]

[0038] Wherein X1 and X2 in the carbocyclic ring example are independently O, S, N, NH or NR 18 .

[0039] The aryl group can be independently substituted or multi-substituted by cyano, halogen, alkyl, branched alkyl, haloalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, sulfhydryl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocyclic alkyl and / or other small substituent groups. In some embodiments, the small substituent group is selected from F, Cl, Br, CH, CHCH, CHF, CHF, CF, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF, NH, NHMe, NMe, methoxycarbonyl, methanesulfonyl, Ph, benzyl, formyl and acetyl.

[0040] In some embodiments, D1 is aryl or carbocyclic.

[0041] In some embodiments, R1, R2, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 and R 20 is independently: cyano, halogen, hydroxyl, alkoxy, alkyl, branched alkyl, haloalkyl, branched haloalkyl, aryl, arylalkyl, carbocycle, carbocyclealkyl, alkylcarbonyl, branched alkylcarbonyl, haloalkylcarbonyl, branched haloalkylcarbonyl, arylcarbonyl or alkoxycarbonyl. In some embodiments, R1, R2, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 18 , R 19 and R 20 is 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, Oi-Pr, methoxycarbonyl, phenyl, benzyl, formyl or acetyl, as long as the resulting structure is stable.

[0042] In some embodiments, R1 and R2, R5 and R6, R7 and R8, R9 and R 10, R 11 and R 12 , R 13 and R 14 , R 15 and R 16 , R 19 and R 20 or R 15 and R 19 A single ring can be formed.

[0043] In some embodiments, Me is methyl; Et is ethyl; i-Pr is isopropyl; t-Bu is tert-butyl; Ph is phenyl.

[0044] In some embodiments, the following compounds can be excluded from this class 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}[(1R)-1-phenylethyl]amine; [(4S*,4R*)-2,2-dimethyl-4-(4-methylphenyl)oxan-4-yl]ethyl}[(1S)-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-dimethoxy 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-chlorophenyl)methyl] ({2-[4-(4-methoxyphenyl)-2,2-di ... 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;

[0045] The application also describes compounds of formula II-1 and II-2:

[0046]

[0047] A2 is CH2, CHR5, CR5R6; A4 is CH2, CHR9, CR9R 10 Or formula C(CH2) n wherein n=2-5.

[0048] In addition, in some embodiments, R5R6, R9 and R 10 R5 and R6, or R9 and R 10 A monocyclic carbocyclic ring may be formed.

[0049] In some embodiments, A2 and A4 may be connected by a carbon bridge. The bridge may be -CH2- or -CH2CH2-.

[0050] In addition, in some embodiments, B3 is selected from the following groups: H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl and alkylsulfonyl. In some embodiments, B3 is C1-C5 alkyl. In some embodiments, B3 is H.

[0051] In addition, in some embodiments, B4 is empty, C1-C6 alkyl, CH2, CH2CH2, CHR 19 , CR 19 R 20 or CO. In addition, R 19 and R 20 The formula can be formed (CH2) n wherein n=2-4. B5 is alkyl, branched alkyl, carbocyclic, carbocyclic substituted alkyl, aryl or arylalkyl.

[0052] In some embodiments, D1 is additionally aryl. Examples of aryl groups are shown above.

[0053] Each aryl group can be independently substituted or multiply substituted by F, Cl, Br, CH, CHCH, CHF, CHF, CF, n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-iPr, OCF, NH, NHMe, NMe, methoxycarbonyl, Ph, benzyl, formyl, and acetyl. That is, each aryl group can be multiply substituted by the same substituent (i.e., 2 chloro groups), or just multiply substituted, albeit by different groups (e.g., an aryl group having 1 chloro and 1 methyl group would be considered multiply substituted).

[0054] The application also provides a compound having the structure of Formula III:

[0055]

[0056] A2 is CH2, CHR5 or CR5R6; A4 is CH2, CHR9, CR9R 10 Or formula C(CH2) n wherein n=2-5.

[0057] In addition, R5R6, R9 and R 10 R5 and R6, or R9 and R 10 A monocyclic carbocyclic ring may be formed.

[0058] A2 and A4 may be connected by a carbon bridge. The bridge may be -CH2- or -CH2CH2-.

[0059] Additionally, B3 is selected from H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or alkylsulfonyl.

[0060] In addition, B4 is empty, C1-C6 alkyl, CH2, CH2CH2, CHR 19 , CR 19 R 20 or CO. In addition, R 19 and R 20 The formula can be formed (CH2) n wherein n=2-4. B5 is alkyl, branched alkyl, carbocyclic, carbocyclic substituted alkyl, aryl or arylalkyl.

[0061] In addition, D1 is an aryl group. Examples of aryl groups are shown above.

[0062] The aryl group can be mono- or multiply substituted by 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.

[0063] The application also provides compounds having the formula IV-1, IV-2 or IV-3, V, or VI:

[0064]

[0065]

[0066] Where R 21 and R 22 are independently H or CH3; A4 is CH2, CHR9, CR9R 10 Or formula C(CH2) n wherein n=2-5.

[0067] In addition, R9 and R 10 is independently CH3 or CH2CH3.

[0068] In addition, B3 is H, C1-C6 alkyl or branched alkyl.

[0069] In addition, B4 is empty, C1-C6 alkyl, CH2, CH2CH2 or -CHCH3.

[0070] B5 is -(CH2) n CH3, wherein n=2-3, -C(CH3)3, cyclohexyl, cyclopentyl, aryl or arylalkyl.

[0071] In some embodiments, the aryl group is selected from the following list:

[0072]

[0073] Each aryl group may be mono- or multiply substituted, for example, by F, I, Cl, Br, CH3, CN, OH, OMe, OEt, OCF3, CF3 or methanesulfonyl.

[0074] Additionally, in some embodiments, D1 is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, which may be independently mono- or poly-substituted by F, Cl, Br, OCF3, CF3, or CH3.

[0075] The application also provides compounds having the structure of formula V-1, V-2, V-3, VI-1, VI-2, or VI-3:

[0076]

[0077]

[0078] Wherein D1 is an aryl group; B5 is an aryl group or a carbocyclic ring.

[0079] In some embodiments, each aryl group is independently selected from the following list:

[0080]

[0081] In some embodiments, each aryl group is independently monosubstituted or multi-substituted. In some embodiments, each aryl group can be independently monosubstituted or multi-substituted by I, F, Cl, Br, CH , CN, OH, OMe, OEt, OCF , CF , or methanesulfonyl. In addition, in some embodiments, carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

[0082] In some embodiments, D1 is an optionally monosubstituted or multi-substituted aryl. In some embodiments, B5 is an optionally monosubstituted or multi-substituted aryl or carbocycle. In some embodiments, D1 or B5 are independently selected from the group consisting of the following groups:

[0083]

[0084] as well as

[0085] Wherein the carbocyclic ring is cyclohexyl, cyclohexenyl or cyclopentyl.

[0086] In some embodiments, D1 is optionally monosubstituted or multi-substituted phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl. In some embodiments, D1 is optionally substituted with one or more of F, Cl, Br, I, OCF3, CH3 and CF3. In some embodiments, D1 is unsubstituted.

[0087] In some embodiments, B5 is optionally mono- or poly-substituted

[0088]

[0089] In some embodiments, B5 is substituted with one or more of Cl, Br, F, I, OMe, CN, CH3, methanesulfonyl, and CF3. In some embodiments, B5 is substituted with one or more of Cl, Br, F, I, OMe, CN, CH3, CF3, and methanesulfonyl, or a combination thereof. That is, B5 may have two or more substituents, but not all of the multiple substituents need to be the same.

[0090] In some embodiments, there is provided a compound having formula VII-1, VII-2, or VII-3 A compound of the structure wherein D1 is an optionally substituted heteroaryl or aryl group, B3 is H or an alkyl group, B5 is an optionally substituted aryl or heteroaryl group, and R 26 and R 27 Each is hydrogen or an isotope thereof.

[0091] In some embodiments, R 26 and R 27 In some embodiments, R 26 or R 27 In some embodiments, B3 is C1-C5 alkyl.

[0092] In some embodiments, the compound has the structure of Formula VIII or an enantiomer thereof.

[0093] Wherein D1 is optionally substituted heteroaryl or aryl, B3 is H or alkyl, B5 is 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 C1-C5 alkyl. In some embodiments, the enantiomer is the R or S enantiomer attached to the carbon of D1.

[0094] In some embodiments, the compound has the structure of Formula IX or an enantiomer thereof.

[0095]

[0096] In some embodiments, the enantiomer is the R or S enantiomer at the carbon attached to D1.

[0097] In some embodiments, the compound has the structure of Formula X or an enantiomer thereof.

[0098]

[0099] In some embodiments, the enantiomer is the R or S enantiomer at the carbon attached to D1.

[0100] In some embodiments of the structures described herein, D1 is an optionally substituted pyridine group or a phenyl group. In some embodiments, D1 is an optionally substituted 2-pyridyl, 3-pyridyl or 4-pyridyl or phenyl group. In some embodiments, D1 is optionally substituted with one or more of H, OH, alkyl alcohol, halide, alkyl, amine, amide, cyano, alkoxy, haloalkyl or alkylsulfonyl. In some embodiments, D1 is optionally substituted with one or more of H, OH, Cl, Br, F, I, OMe, CN, CH3, CF3.

[0101] In some embodiments of the structures described herein, B5 is an optionally substituted thiophene group. In some embodiments, B5 is substituted with an alkoxy group. In some embodiments, B5 is substituted with a C1-C5 alkoxy group. In some embodiments, B5 is substituted with a methoxy group. In some embodiments, B5 is In some embodiments, B5 is Where R 23 , R 24 and R 30 Each is independently empty, H, OH, ring, aryl, branched or unbranched alkyl alcohol, halogen, branched or unbranched alkyl, amine, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylthio, and R 25 is H or alkyl. In some embodiments, R 23 and R 24 Together they form an alkyl group or a ring connected to one or more atoms in B5. 23 R 24 and R 30 Can also be further substituted. In some embodiments, R 23 , R 24 and R 30 Each is independently H, NH2, OH, Cl, Br, F, I, OMe, CN, CH3, phenyl, C3-C6 carbocycle, methanesulfonyl, CF3, Where R 29 is H or alkyl. In some embodiments, R 29 is a C1-C6 alkyl group. 23 , R 24 and R 30 One of is H. In some embodiments, R 23 , R 24 and R 30At least one of is H. In some embodiments, R 23 , R 24 and R 30 Two of them are H.

[0102] The following compounds, as well as other compounds described herein, have agonist activity on 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]phenol; [(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 described herein and pharmaceutically acceptable salts thereof.

[0103] In some embodiments, compounds such as those described herein are provided. In some embodiments, compounds selected from the compounds described in the Examples are 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 to treat or reverse hyperalgesia, treat or reverse induced hyperalgesia, reduce nociceptive sensitization, etc. The compounds can also be used to prepare medicaments for treating them. In some embodiments, the use of the compounds for treating pain, treating or reversing hyperalgesia, treating or reversing induced hyperalgesia, reducing nociceptive sensitization, etc. is provided.

[0104] Therefore, the present application provides a method for producing agonist activity on OR-mediated signal transduction by administering one or more of the compounds listed above to a subject or a subject in need thereof.

[0105] Various atoms in the compositions described herein may be isotopes that occur at a lower frequency. Hydrogen at any position in the compositions described herein may be replaced by deuterium. Optionally, hydrogen may also be replaced by tritium. Carbon ( 12 C) can be 13 C or 14 C substitution. Nitrogen (14 N) can be 15 N substitution. Oxygen ( 16 O) can be 17 O or 18 O substitution. Sulfur ( 32 S) can be 33 S. 34 S or 36 S substitution. Chloro ( 35 Cl) can be 37 Cl substitution. Bromine ( 79 Br) can be 81 Br replacement.

[0106] The selected compounds described herein are agonists and antagonists of opioid receptors (OR). The ability of a compound to stimulate OR-mediated signaling can be measured using any assay known in the art to detect OR-mediated signaling or OR activity, or to detect the absence of such signaling / activity. "OR activity" refers to the ability of an OR to transduce a signal. This activity can be measured, for example, by coupling an OR (or chimeric OR) to a downstream effector such as adenylate cyclase in a heterologous cell.

[0107] As used herein, "natural ligand-induced activity" refers to activation of an OR by a natural ligand of the OR. Activity can be assessed using any number of endpoints that measure OR activity.

[0108] In general, assays for testing compounds that modulate OR-mediated signal transduction include determining any parameter that is affected indirectly or directly by the OR, such as a functional, physical or chemical effect.

[0109] The samples or assays comprising OR treated with potential activators, inhibitors or modulators are compared with control samples without inhibitors, activators or modulators to examine the degree of inhibition. A relative OR activity of 100% is assigned to the control sample (not treated with an inhibitor). When the OR activity value is about 80%, 50% or 25% relative to the control, inhibition of the OR is achieved. When the OR activity value is 110%, 150%, 200-500% (i.e., one to four times higher than the control) or, 1000-3000% or higher relative to the control (not treated with an activator), activation of the OR is achieved.

[0110] The effect of compound on OR function can be measured by testing any parameter mentioned above.Any suitable physiological change affecting OR activity can be used to assess the impact of compound on OR and natural ligand-mediated OR activity.When using complete cells or animals to measure functional results, various effects can also be measured, such as changes in intracellular second messengers such as cAMP.

[0111] Use the OR polypeptides described above (or recombinant or naturally occurring) to test modulators of OR activity. Proteins can be isolated, expressed in cells, expressed in membranes derived from cells, expressed in tissues or animals. For example, neuronal cells, immune system cells, transformed cells or membranes can be used to test the GPCR polypeptides described above. Use one of the in vitro or in vivo assays described herein to test regulation. Chimeric molecules such as the extracellular domain of a receptor covalently linked to a heterologous signal transduction domain, or a heterologous extracellular domain covalently linked to a transmembrane and or cytoplasmic domain of a receptor can also be used to examine signal transduction in vitro using a soluble or solid phase reaction. In addition, the ligand binding domain of the target protein can be used in vitro for soluble or solid phase reactions to determine ligand binding.

[0112] The ligands that bind to the OR, domain or chimeric protein can be tested in a variety of forms. Binding can be carried out in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer or in a vesicle. Typically, in the assays described herein, the binding of a natural ligand to its receptor is measured in the presence of a candidate modulator. Alternatively, the binding of a candidate modulator can be measured in the presence of a natural ligand. Typically, a competitive assay that measures the binding competitiveness of a compound with a natural ligand to a receptor is used. Binding can be tested by measuring, for example, changes in spectral properties (e.g., fluorescence, absorbance, refractive index), changes in fluid mechanics (e.g., shape), or changes in chromatographic or solubility properties.

[0113] Regulators can also be identified using assays involving β-inhibitor recruitment. β-inhibitors act as regulatory proteins, which are distributed throughout the cytoplasm in unactivated cells. The ligand bound to the appropriate OR is related to the redistribution of β-inhibitors from the cytoplasm to the cell surface (where it is associated with OR). Therefore, the effects of ligand activation and candidate regulators on ligand-induced receptor activation can be assessed by monitoring β-inhibitor recruitment to the cell surface. Typically, labeled β-inhibitor fusion proteins (e.g., β-inhibitor-green fluorescent protein (GFP)) are transfected into cells and their distribution is detected using a confocal microscope (see, e.g., Groarke et al., J. Biol. Chem. 274 (33): 2326369 (1999)).

[0114] Another technique that can be used to assess OR-protein interactions in living cells involves bioluminescence resonance energy transfer (BRET). A detailed discussion of BRET can be found in Kroeger et al., J. Biol. Chem., 276(16):1273643 (2001).

[0115] Other assays may involve measuring receptor activity, which, when activated by ligand binding, causes changes 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: 1517515180 (1995) can be used to measure the level of cAMP. In addition, the method described in Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11: 159164 (1994) can also be used to measure the level of cAMP. In addition, an assay kit for measuring cAMP is described in U.S. Pat. No. 4,115,538, which is incorporated herein by reference.

[0116] Transcription levels can be measured to assess the effect of test compounds on ligand-induced signal transduction. Host cells containing target proteins are contacted with test compounds in the presence of natural ligands for sufficient time to achieve any interaction, and then the level of gene expression is measured. The amount of time to achieve this interaction can be determined empirically, such as by running a schedule and measuring the transcription level that changes over time. Transcription amount can be measured by using any suitable method known to those skilled in the art. For example, Northern blots can be used to detect the mRNA expression of target proteins, or immunoassays can be used to identify their polypeptide products. Alternatively, transcription-based assays using reporter genes can be used as described in U.S. Patent No. 5,436,128, which is incorporated herein by reference. Reporter genes can be, for example, chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, β-galactosidase, and alkaline phosphatase. In addition, the target protein can be used as an indirect reporter by being connected to a second reporter such as green fluorescent protein (see, for example, Mistili & Spector, Nature Biotechnology 15: 961964 (1997)).

[0117] The amount of transcription is then compared to the amount of transcription in the same cell in the absence of the test compound, or it can be compared to the amount of transcription in substantially the same cell lacking the target protein. Substantially identical cells can be derived from the same cells of the prepared recombinant cells, but they have not been modified by the introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has altered the activity of the target protein in some way.

[0118] Pharmaceutical composition / formulation / preparation

[0119] Pharmaceutical compositions can be formulated using standard techniques for one or more physiologically acceptable carriers or excipients. Formulations may contain buffers and / or preservatives. Compounds and physiologically acceptable salts and solvates thereof may be formulated for administration by any suitable route, including inhalation, topical, nasal, oral, parenteral (e.g., intravenous, intraperitoneal, intravesical or intrathecal) or rectal administration in a vehicle comprising one or more pharmaceutically acceptable carriers, in proportions determined by the solubility and chemical properties of the compound, the route of administration selected, and standard biological practice.

[0120] Pharmaceutical compositions may include an effective amount of one or more compounds described herein and, for example, a pharmaceutically acceptable diluent, preservative, solubilizer, emulsifier, adjuvant, and / or other carrier. These compositions may include diluents of various buffer contents, pH and ionic strength (buffer contents such as TRIS or other amines, carbonates, phosphates, amino acids, for example, glycinamide hydrochloride (especially in the physiological pH range), N-bisglycine, sodium or potassium phosphate (dibasic, tribasic), etc., or TRIS-HCl or acetate); additives such as detergents and solubilizers (e.g., surfactants such as Pluronics, Tween 20, Tween 80 (polysorbate 80), Cremophor, polyols such as polyethylene glycol, propylene glycol, etc.), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimerosal (Thimersol), benzyl alcohol, parabens, etc.) and fillers (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinyl pyrrolidone or dextran, etc.); and / or incorporating the material into a particle formulation of a polymeric compound (such as polylactic acid, polyglycolic acid, etc.) or into liposomes. Hyaluronic acid can also be used. These compositions can be used to affect the physical state, stability, rate of in vivo release and in vivo clearance rate of the compounds described herein. See, for example, Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) 1435-1712 pages, which are incorporated herein by reference. For example, the composition can be prepared in liquid form, or a dry powder such as lyophilized. The specific method of administering these compositions is as follows.

[0121] When a buffer is included in the formulation described herein, the buffer can be selected from sodium acetate, sodium carbonate, citrate, glycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate and tris (hydroxymethyl) -aminomethane or a mixture thereof. The buffer can also be glycine, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium phosphate or a mixture thereof.

[0122] When a pharmaceutically acceptable preservative is included in the formulation of one of the compounds described herein, the preservative can be selected from phenol, m-cresol, methylparaben, propylparaben, 2-phenoxyethanol, butylparaben, 2-phenylethanol, benzyl alcohol, chlorobutanol and thiomercuric, or a mixture thereof. The preservative can also be phenol or m-cresol.

[0123] The preservative is present in a concentration of from about 0.1 mg / ml to about 50 mg / ml, in a concentration of from about 0.1 mg / ml to about 25 mg / ml, or in a concentration of from about 0.1 mg / ml to about 10 mg / ml.

[0124] The use of preservatives in pharmaceutical compositions is well known to the skilled artisan. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0125] The formulation may further comprise a chelating agent, wherein the chelating agent may be selected from salts of ethylenediaminetetraacetic acid (EDTA), citric acid, and aspartic acid, and mixtures thereof.

[0126] The chelating agent may be present in a concentration of from 0.1 mg / ml to 5 mg / ml, from 0.1 mg / ml to about 2 mg / ml, or from 2 mg / ml to 5 mg / ml.

[0127] The use of chelating agents in pharmaceutical compositions is well known to the skilled artisan. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0128] The formulation of the compound described herein may further include a stabilizer selected from high molecular weight polymers and low molecular weight compounds, wherein these stabilizers include but are not limited to polyethylene glycol (e.g., PEG3350), polyvinyl alcohol (PVA), polyvinyl pyrrolidone, carboxymethyl cellulose, 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 may also be L-histidine, imidazole, or arginine.

[0129] The high molecular weight polymer may be present in a concentration of 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.

[0130] The low molecular weight compound may be present in a concentration of 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.

[0131] The use of stabilizers in pharmaceutical compositions is well known to the skilled artisan. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0132] The formulation of the compounds described herein may also include a surfactant. In some embodiments, the surfactant may be selected from detergents, ethoxylated castor oil, polyglycolized 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 thereof (Tweens, e.g., Tween-20 or Tween-80), monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives, glycerol, bile acid or derivatives thereof, lecithin, alcohols and phospholipids, glycerophospholipids (phosphatidylcholine, cephalin, phosphatidylserine), glyceroglycolipids (galactopyranoside), sphingomyelins (sphingomyelin) and glycosphingolipids (sphingomyelin). amide, ganglioside), DSS (docusate sodium, docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoylphosphatidic acid, sodium octanoate, bile acid and its salts and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N,N-dimethyl-3-amino-1-propanesulfonate, anionic (alkyl-aryl-sulfonate) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g., 1-acyl-sn-glyceryl-3-phosphate of ethanolamine, choline, serine or threonine), lysophosphatidylcholine and alkyl, alkoxy (alkyl ester), alkoxy (alkyl ether) derivatives of phosphatidylcholine, such as lysophosphatidylcholine, lauroyl and myristoyl derivatives of dipalmitoylphosphatidylcholine, and modifications of polar head groups, i.e., choline, ethanolamine, phosphatidic acid, serine, threonine, glycerol, inositol, and positively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g., N-alkyl-N,N-dimethylammonium-1-propanesulfonate, 3-cholamido-1-propyldimethylammonium-1-propanesulfonate, dodecylphosphocholine, myristoylphosphatidylcholine ... blood phosphatidylcholine, egg lysolecithin), cationic surfactants (quaternary ammonium bases) (e.g., cetyltrimethylammonium bromide, cetylpyridinium chloride), nonionic surfactants, polyethylene oxide / polypropylene oxide block copolymers (Pluronics / Tetronics, Triton X-100, dodecyl β-D-pyranoglucoside) or polymer surfactants (Tween 40, Tween 80, Brij-35), fusidic acid derivatives-- (e.g., sodium tauro-dihydrofusidate, etc.), long-chain fatty acids and their salts C6-C12 (e.g., oleic acid and octanoic acid), acylcarnitines and derivatives, N-terminals of lysine, arginine or histidine α -acylated derivatives, or side chain acylated derivatives of lysine or arginine, N-terminal dipeptides of any combination of lysine, arginine or histidine and neutral or acidic amino acids α-acylated derivatives, tripeptides comprising any combination of neutral amino acids and two charged amino acids α -acylated derivatives, or a surfactant which may be selected from the group of imidazoline derivatives or mixtures thereof.

[0133] The use of surfactants in pharmaceutical compositions is well known to the skilled artisan. For convenience, reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995.

[0134] 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, dihydrochalcone sweeteners, monellin, stevioside or sucralose (4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose), saccharin, sodium or calcium saccharin, and optional bulking sweeteners, such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel and honey.

[0135] Intense sweeteners are convenient to use in low concentrations. For example, in the case of sodium saccharin, the concentration range can be from 0.04% to 0.1% (w / v), or about 0.06% in low-dose formulations, and about 0.08% in high-dose formulations, based on the total volume of the final formulation. Bulk sweeteners can be effectively used in larger amounts ranging from about 10% to about 35%, or from about 10% to 15% (w / v).

[0136] Formulations of the compounds described herein can be prepared by conventional techniques, for example, as described in Remington's Pharmaceutical Sciences, 1985 or Remington: The Science and Practice of Pharmacy, 19th edition, 1995, wherein conventional techniques of the pharmaceutical industry involve appropriately dissolving and mixing the ingredients to give the desired end product.

[0137] The phrases "pharmaceutically acceptable" or "therapeutically acceptable" refer to molecular entities and compositions that are physiologically tolerable and, preferably, do not typically produce allergic or similar adverse reactions when administered to humans, such as stomach upset, dizziness, etc. 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. (AR Gennaro edit. 1985)) for use in animals, more particularly in humans.

[0138] The administration of the compounds described herein can be carried out using any method known in the art. For example, administration can be transdermal, parenteral, intravenous, intraarterial, subcutaneous, intramuscular, intracranial, intraorbital, ocular, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intraventricular, intrathecal, intranasal, aerosol, by suppository or oral administration. The pharmaceutical compositions of the compounds described herein can be used for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.

[0139] For oral administration, the pharmaceutical compositions of the compounds described herein can be formulated in unit dosage forms, such as capsules or tablets. Tablets or capsules can be prepared by conventional means with pharmaceutically acceptable excipients, including binders, such as pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose; fillers, such as lactose, microcrystalline cellulose or calcium hydrogen phosphate; lubricants, such as magnesium stearate, talc or silicon dioxide; disintegrants, such as potato starch or sodium starch glycolate; or wetting agents, such as sodium lauryl sulfate. Tablets can be coated using 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 dry products for constitution with water or other suitable vehicles before use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspensions, such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats; emulsifiers, such as lecithin or gum arabic; non-aqueous vehicles, such as almond oil, oily esters, ethanol or fractionated vegetable oils; and preservatives, such as methylparaben or propylparaben or sorbic acid. If appropriate, the preparation may also include buffer salts, flavoring agents, coloring agents and / or sweeteners. If desired, preparations for oral administration may be appropriately formulated to provide controlled release of the active compound.

[0140] For topical administration, pharmaceutical compositions of the compounds described herein can be formulated as a pharmaceutically acceptable vehicle containing 0.1 to 10 percent or 0.5 to 5 percent of the active compound. These formulations can be in the form of creams, lotions, sublingual tablets, aerosols and / or emulsions, and can be included in transdermal or oral patches of the matrix or reservoir type, as conventionally used for this purpose in the art.

[0141] As for parenteral administration, the compounds described herein are administered by intravenous, subcutaneous or intramuscular injection in the form of a composition with a pharmaceutically acceptable vehicle or carrier. The compound can be formulated to be administered parenterally by injection, for example, by bolus injection or continuous infusion. The formulation for injection can be presented in the form of a unit dose, for example, in an ampoule with a preservative added or in a multi-dose container. The composition can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and contains a formulation agent (formulatoryagent), such as a suspension, stabilizing and / or dispersing agent. Alternatively, the active ingredient can be in powder form so that it can be constructed with a suitable vehicle, for example, sterile pyrogen-free water before use.

[0142] As for injection, the compound can be used in a sterile aqueous vehicle, which can also contain other solutes, such as buffer or preservatives and a sufficient amount of pharmaceutically acceptable salts or glucose to make the solution isotonic. The pharmaceutical composition of the compound described herein can be formulated with a pharmaceutically acceptable carrier to provide a sterile solution or suspension for injectable administration. Injectables can be prepared in conventional forms, or as liquid solutions or suspensions, suitable for solid forms of liquid solutions or suspensions before injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine ​​hydrochloride, etc. In addition, if necessary, injectable pharmaceutical compositions can include a small amount of non-toxic auxiliary substances, such as wetting agents, pH buffers, etc. If necessary, absorption enhancement preparations (such as liposomes) can be used. Suitable drug carriers are described in "Remington'spharmaceuticalSciences" by EWMartin.

[0143] For administration by inhalation, the compound can be conveniently delivered in the form of an aerosol spray from a pressurized package or sprayer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to deliver a measured amount. Capsules and cartridges such as gelatin for use in an inhaler or insufflator can be formulated as a powder mixture containing the compound and a suitable powder base (e.g., lactose or starch). For intranasal administration, the compounds described herein can be used, for example, as a liquid spray, as a powder or in the form of drops.

[0144] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0145] In addition, the compound can also be formulated as a long-acting preparation. These long-acting preparations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound can be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a sparingly soluble derivative (e.g., as a sparingly soluble salt).

[0146] If desired, the composition may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0147] The compounds described herein also include derivatives known as prodrugs, which can be prepared by modifying the functional groups present in the compound so that the modified compound is cleaved into the parent compound in conventional operations or in vivo. Examples of prodrugs include compounds of the present invention as described herein, which contain one or more molecular moieties of hydroxyl, amino, sulfhydryl or carboxyl groups attached to the compound, and when administered to a patient, they are cleaved in vivo to form free hydroxyl, amino, sulfhydryl or carboxyl groups, 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 present invention. The preparation and use of prodrugs are described in T. Higuchi et al., "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C. Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, the entire contents of which are referenced and as herein.

[0148] dose

[0149] The compounds described herein can be administered to patients in therapeutically effective doses to prevent, treat or control one or more diseases and conditions mediated in whole or in part by OR-ligand interactions. Pharmaceutical compositions comprising one or more compounds described herein can be administered to patients in an amount sufficient to cause an effective protective or therapeutic response in the patient. An amount sufficient to achieve this is defined as a "therapeutically effective dose". The dose will be determined by the efficacy of the specific compound used and the condition of the subject and the body weight or surface area of ​​the area to be treated. The size of the dose will also depend on the presence, nature and extent of any adverse effects associated with the administration of a specific compound or carrier in a specific subject.

[0150] The toxicity and therapeutic efficacy of these compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining LD50 (a dose lethal to 50% of the population) and ED50 (a dose effective for 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as a ratio, LD50 / ED50. In some embodiments, compounds that exhibit a large therapeutic index are used. Although compounds that exhibit toxic side effects can be used, care should be taken to design a delivery system that targets such compounds to the affected tissue site to minimize potential damage to normal cells, thereby reducing side effects.

[0151] The data obtained from cell culture assays and animal studies can be used to formulate dosage ranges for humans. In some embodiments, the dosage of these compounds is within the range of circulating concentrations including ED50, with little or no toxicity. The dosage can vary within this range, depending on the dosage form and route of administration adopted. For any compound described herein, the therapeutically effective dose can first be estimated from a cell culture assay. The dosage can be formulated in an animal model to reach a circulating plasma concentration range, including the IC50 (the concentration of the test compound that reaches half-maximal inhibition of symptoms) measured in cell culture. This information can be used to more accurately determine a dosage useful in humans. For example, the level in plasma can be measured by high performance liquid chromatography (HPLC). In general, for a typical subject, the dosage equivalent of a modulator is from about 1 ng / kg to 10 mg / kg.

[0152] The amount and frequency of administration of the compounds described herein and / or pharmaceutically acceptable salts thereof will be adjusted according to the judgment of the attending clinician, taking into account factors such as the age, condition and size of the patient and the severity of the symptoms to be treated. A doctor or veterinarian of ordinary skill can easily determine and prescribe the effective amount of the drug required to prevent, combat or prevent the progression of the condition. It is generally believed that the effective amount will be from 0.001 mg / kg to 10 mg / kg body weight, and particularly from 0.01 mg / kg to 1 mg / kg body weight. It is appropriate to administer the desired dose in two, three, four or more sub-doses at appropriate intervals throughout the day. The sub-doses can be formulated as unit dosage forms, for example, each unit dosage form contains 0.01 to 500 mg, particularly 0.1 mg to 200 mg of active ingredient.

[0153] In some embodiments, pharmaceutical preparation is a unit dosage form. In this form, preparation is subdivided into unit doses of appropriate size, which contain an appropriate amount of active ingredient, such as an effective amount to achieve the desired purpose. The amount of active compound in the preparation of unit dose can be changed or regulated from about 0.01mg to about 1000mg, from about 0.01mg to about 750mg, from about 0.01mg to about 500mg or from about 0.01mg to about 250mg according to specific application. The actual dosage used can be changed according to the requirements of the patient and the severity of the condition to be treated. The determination of the appropriate dosage regimen for a particular situation is within the technical scope of this area. For convenience, the total dose can be divided into several portions for administration during one day as required.

[0154] In some embodiments, one or more compounds described herein are administered with another compound. Administration may be sequential or simultaneous. The combination may be administered in the same dosage form or in separate doses. In some embodiments, the other compound is another analgesic or pain reliever. In some embodiments, the other compound is a non-opioid analgesic. Examples of useful non-opioid analgesics include, but are not limited to, nonsteroidal 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 analgesics, antipyretics, and nonsteroidal anti-inflammatory drugs: salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicyl salicylic acid, sulfasalazine, and olsalazine; 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 acid (fenamates), including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam) and pyrazolidinedione (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone. For a more detailed description of 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. thed 1996); and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy Vol II 1196-1221 (AR Gennaro ed. 19. sup. thed. 1995), the entire contents of which are incorporated herein by reference.

[0155] The compounds described herein can also be administered with Cox-II inhibitors. Useful Cox-II inhibitors and 5-lipoxygenase inhibitors, and examples of combinations thereof are described in U.S. Patent No. 6,136,839, the entire contents of which are incorporated herein by reference. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

[0156] The compounds described herein can also be administered with an anti-migraine agent. Examples of useful anti-migraine agents include, but are not limited to, alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride The invention relates to lisuride, lomerizine, methylergonovine, methysergide, metoprolol, naratriptan, oxetorone, pizotyline, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan and mixtures thereof.

[0157] The compounds described herein can also be administered with an anti-constipation agent. Examples of anti-constipation agents include, but are not limited to, laxatives or stool softeners. Examples of anti-constipation agents include, but are not limited to, docusate, poloxamer 188, psyllium, methylcellulose, carboxymethylcellulose, polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, disodium hydrogen phosphate, monosodium phosphate, sodium dihydrogen phosphate, or any combination thereof.

[0158] Medical Uses

[0159] The compositions described herein are useful for treating pain or pain-related conditions. The compositions described herein can be used to treat immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric conditions, urinary and reproductive conditions, medications for drug and alcohol abuse, agents for treating gastritis and diarrhea, cardiovascular agents, and agents for treating respiratory diseases and cough.

[0160] In some embodiments, methods of treating pain are provided. In some embodiments, one or more compounds described herein are administered to a subject to treat pain. In some embodiments, the pain may be postoperative 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.

[0161] In some embodiments, one or more compounds can be used to treat or reverse hyperalgesia. Therefore, in some embodiments, a method for treating or reversing hyperalgesia is provided. In some embodiments, the method comprises administering one or more compounds described herein or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, a pharmaceutical composition comprising one or more compounds or a pharmaceutically acceptable salt thereof is administered. As used herein, hyperalgesia refers to a condition in which a subject has increased sensitivity to pain. The increased sensitivity may occur at the site of a previous injury or pain sensation or may occur at a different site. In some embodiments, the pain sensitivity is diffuse pain sensitivity (i.e., at more than one site on the subject) or focal pain sensitivity (i.e., at discrete sites on the subject). In some embodiments, the subject has been administered a first opioid prior to administration of one or more compounds described herein or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, hyperalgesia is opioid-induced hyperalgesia, which may also be referred to as opioid-induced abnormal pain sensitivity or paradoxical hyperalgesia, which is described as a condition caused by the use of opioids. For example, individuals taking opioids may have increased sensitivity to noxious pain stimuli, and even evolve into a pain response (touch pain) to previously non-noxious pain stimuli. This is the result of the subject being exposed to opioids. Opioid-induced hyperalgesia ("OIH") is distinguished from and different from known "tolerance". Without being limited by any specific theory, tolerance is due to the desensitization of anti-nociceptive mechanisms, while OIH is due to the sensitization of pre-nociceptive mechanisms. Therefore, when opioid tolerance is determined to be the subject's condition, tolerance can be minimized by increasing the dose of opioids. On the contrary, increasing the dose of opioids in subjects with OIH will only worsen the condition. In some embodiments, the compounds described herein can be used to prepare a drug for treating hyperalgesia or opioid-induced hyperalgesia.

[0163] In some embodiments, opioid-induced hyperalgesia is hyperalgesia induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and / or heroin. In some embodiments, OIH is induced by a combination of more than one opioid. In some embodiments, OIH is morphine-induced OIH. In some embodiments, OIH is oxycodone-induced OIH. In some embodiments, OIH is hydrocodone-induced OIH. In some embodiments, OIH is hydromorphone-induced OIH. In some embodiments, OIH is fentanyl-induced OIH. In some embodiments, the OIH is buprenorphine-induced OIH. In some embodiments, the OIH is heroin-induced OIH.

[0164] In some embodiments, a method of reducing nociceptive sensitization in a subject is provided. In some embodiments, the method comprises administering to a subject one or more compounds described herein or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprising one or more compounds or a pharmaceutically acceptable salt thereof is administered. In some embodiments, the subject has increased nociceptive sensitization. In some embodiments, nociceptive sensitization is induced by another therapeutic agent. In some embodiments, nociceptive sensitization is nociceptive sensitization induced by an opioid. In some embodiments, nociceptive sensitization induced by an opioid is nociceptive sensitization induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and / or heroin or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, a method of treating pain in a subject is provided, wherein the method comprises administering an opioid agonist to the subject until the opioid increases the nociceptive sensitization of the subject; and then administering one or more compounds described herein, or a pharmaceutically acceptable salt thereof, to the subject suffering from increased nociceptive sensitization. In some embodiments, the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone, and / or heroin, or a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, is administered.

[0166] In some embodiments, a method of treating pain is provided, wherein the method comprises administering an opioid agonist to a subject; and then administering to the subject in the absence of an 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 a pharmaceutically acceptable salt thereof. In some embodiments, a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, is administered.

[0167] In some embodiments, the compound is used to prepare a medicament for treating or reversing OIH, such as opioid-induced OIH. In some embodiments, the use of a compound or a pharmaceutically acceptable salt thereof for treating or reversing OIH is provided. Non-limiting examples of opioid-induced OIH are described above. In some embodiments, the compound is used to prepare a medicament for treating nociceptive sensitization. In some embodiments, the use of a compound or a pharmaceutically acceptable salt thereof for treating nociceptive sensitization is provided. In some embodiments, nociceptive sensitization is opioid-induced. Provided herein are non-limiting examples of opioids that can induce nociceptive sensitization.

[0168] In some embodiments, the compound used in the method, use or preparation of a medicament is

[0169] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound described in Examples 1-4 or a pharmaceutically acceptable salt thereof.

[0170] 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- 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}amino)methyl]phenol 4-[({2-[4-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl]ethyl})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 [(4-methoxyphenyl)methyl]amine; [(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-fluorophenyl)-2,2-dimethyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(3,4-dimethoxyphenyl)methyl][2-(2,2-dimethyl-4-phenyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-methoxyphenyl)-2,2-dimethyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-methoxyphenyl)-4-phenyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-methoxyphenyl)-4-phenyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]amine; [(2-(4-methoxyphenyl)-4-phenyloxan-4-yl)ethyl]amine; [(4-methoxyphenyl)methyl]

[0171] In some embodiments, the compound of formula N-((3-methoxythiophene-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.

[0172] In some embodiments, one or more compounds described herein can be administered by any suitable route, including, but not limited to, inhalation, topical, nasal, oral, parenteral (e.g., intravenous, intraperitoneal, intravesical, or intrathecal), or rectal administration in a vehicle comprising one or more pharmaceutically acceptable carriers, the proportions of which are determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard practice.

[0173] definition

[0174] Unless otherwise limited, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. Although similar or equivalent methods and materials as described herein can be used in the practice or testing of the compositions and compounds described herein, suitable methods and materials are described below. The entire contents of all publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. In the event of a conflict, this specification (including definitions) shall prevail. In addition, materials, methods and examples are exemplary only and are not restrictive. Other features and advantages of the compositions and compounds described herein will be apparent from the following detailed description and claims.

[0175] As used herein, the phrase "in need thereof" means that the subject, animal, or mammal has been identified as being in need of a particular method or treatment. In some embodiments, identification can be by any diagnostic means. In any of the methods and treatments described herein, the subject, animal, or mammal can be in need. In some embodiments, the subject has been identified as suffering from hyperalgesia, such as but not limited to opioid-induced hyperalgesia. In some embodiments, the subject has been identified as suffering from increased nociceptive sensitization. In some embodiments, the increased nociceptive sensitization is opioid-induced nociceptive sensitization.

[0176] 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 "Cx -C y "C1-C4 alkyl" refers to an alkyl group including an alkyl group having from x to y carbon atoms in a branched or unbranched hydrocarbon group. As an illustration and not limitation, the term "C1-C4 alkyl" refers to a straight 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-C4 n-alkyl" refers to a straight chain hydrocarbon moiety having from 1 to 4 carbon atoms, including methyl, ethyl, n-propyl and n-butyl. C x -C y X can be from 1 to 10 and y is from 2 to 20. The term "C3-C6 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C3-C7 cycloalkyl" also includes cycloheptyl. Cycloalkylalkyl refers to the cycloalkyl moiety connected by the alkyl connecting chain, such as but not limited to cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl. Each alkyl, cycloalkyl and cycloalkylalkyl group can be optionally substituted, such as but not limited to as specified herein. In some embodiments, alkyl is C1-C3, C1-C4, C1-C6, C4-C6 or C1-C 10 alkyl.

[0177] The terms "alkoxy", "phenoxy", "benzyloxy" and "pyrimidinyloxy" refer to an alkyl group, a phenyl group, a benzyl group or a pyrimidinyl group, each of which is bonded via an oxygen atom. Each of these groups may be optionally substituted.

[0178] The terms "alkylthio", "phenylthio" and "benzylthio" refer to an alkyl group, a phenyl group or a benzyl group each bonded through a sulfur atom. Each of these groups may be optionally substituted.

[0179] The term "C1-C4 acyl" refers to a formyl group or a C1-C3 alkyl group bonded via a carbonyl moiety. The term "C1-C4 alkoxycarbonyl" refers to a C1-C4 alkoxy group bonded via a carbonyl moiety.

[0180] The term "halogen" refers to fluorine, chlorine, bromine or iodine. In some embodiments, the halogen groups are fluorine, chlorine and bromine. In some embodiments, the halogen groups are fluorine and chlorine.

[0181] As used herein, unless otherwise indicated, "carbocycle" or "carbocyclic ring" is intended to mean any stable 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered monocyclic, bicyclic or tricyclic ring, any of which may be saturated, unsaturated (including partially and fully unsaturated) or aromatic. Examples of these 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). When one or more carbon atoms connect two non-adjacent carbon atoms, a bridged ring is produced. In some embodiments, the bridge is one or two carbon atoms. It should be noted that the bridge generally converts a monocyclic ring into a tricyclic ring. When the ring is bridged, the substituents listed on the ring may also be present on the bridge. Also included are fused rings (e.g., naphthyl and tetrahydronaphthyl) and spirocycles.

[0182] The term "heterocycle" is considered to mean a saturated or unsaturated 5- or 6-membered ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which is optionally fused to benzo. Exemplary heterocycles include furanyl, thienyl (thienyl), pyrrolyl, pyrrolidinyl, pyridyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetylthiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. Benzo-fused heterocycles include isoquinolyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolyl, benzofuranyl, benzothienyl, indolyl, etc., all of which may be optionally substituted, although the heterocycle also includes optionally substituted on the benzo ring when the heterocycle is fused to benzo.

[0183] The term "ring" group is taken to mean a carbocyclic ring, a carbocycle or a heterocarbocycle.

[0184] As used herein, the phrase "ring of a formula" refers to the ring formed by the referenced variables. For example, in the structure Wherein A can be of the formula C(CH2) n wherein n=2-5, which means that A is carbon and forms a ring with 2-5 CH2 groups, which can 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 possible type of atom "A". This is just a non-limiting example. In addition, the ring formed by "A" can also be substituted. Described herein are exemplary substituents.

[0185] In some embodiments, heterocycles include, but are not limited to, pyridyl, indolyl, furanyl, benzofuranyl, thienyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally substituted.

[0186] 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 consisting 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 a bicyclic heterocyclic aromatic ring, only one of the two rings must be aromatic (e.g., 2,3-dihydroindole), although both can be (e.g., quinoline). As defined above for heterocycles, the second ring may also be fused or bridged. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N→O and S(O)p, where p=1 or 2). In certain compounds, the total number of S and O atoms in the aromatic heterocycle is no greater than 1.

[0187] Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofurano[2, 3-b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindolyl, isoindolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxadiazolyl oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl pyridinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidine, 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, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. ,

[0188] Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy or alkylthio means alkyl, cycloalkyl, cycloalkylalkyl, alkoxy or alkylthio groups independently substituted once or multiple times with a substituent selected from the group consisting of halogen, hydroxyl and C1-C3 alkoxy. As an illustration and not limitation, examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3-hydroxypropoxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropoxy, 3-ethoxy-4-chlorocyclohexyl etc. In some embodiments, substitution includes substitution with halogen 1-5 times, each time independently selected, or substitution with halogen 1-3 times and substituted 1-2 times with a group independently selected from hydroxyl and C1-C3 alkoxy, or substituted 1-3 times with a group independently selected from hydroxyl and C1-C3 alkoxy, provided that no more than one hydroxyl and / or alkoxy substituent can be connected by the same carbon.

[0189] The terms "substituted phenyl" and "substituted heterocycle" are taken to mean that the cyclic moiety in either case is substituted. They may independently be substituted by one or more substituents. They may independently be substituted by 1, 2, 3, 4, 5, 1-3, 1-4 or 1-5 substituents. The substituents may independently be halogen, alkyl, such as but not limited to C1-C4 alkyl, alkoxy, such as but not limited to C1-C4 alkoxy, and alkylthio, such as but not limited to C1-C4 alkylthio, wherein each alkyl, alkoxy and alkylthio substituent may also be independently substituted by C1-C2 alkoxy or one to five halogen groups; or substituted by a substituent selected from the group consisting of phenoxy, benzyloxy, phenylthio, benzylthio and pyrimidinyloxy, wherein the phenoxy, benzyloxy, phenylthio, benzylthio and pyrimidinyloxy moieties may also be substituted by one to two substituents selected from the group consisting of halogen, C1-C2 alkyl and C1-C2 alkoxy; or substituted by a substituent selected from the group consisting of C1-C4 acyl and C1-C4 alkoxycarbonyl, and may also be substituted by zero to one substituent selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio. When the substituent is a halogen, in some embodiments, the halogen group is fluorine, chlorine and bromine. The halogen can also be iodine.

[0190] DMF means N,N-dimethylformamide.

[0191] 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.

[0192] "Pharmaceutical formulation" also means that the carriers, solvents, excipients and salts must be compatible with the active ingredients of the formulation (e.g., compounds described herein). One of ordinary skill in the art will appreciate that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and they are so for purposes of this application.

[0193] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing acid or basic salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, these conventional non-toxic salts include, but are not limited to, derivatives selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollyarsanilic acid, hexylresorcinic acid, hydrabamic acid, The salts of inorganic and organic acids of hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid (lactobionic), lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid (napsylic), nitric acid, oxalic acid, pamoic acid (pamoic), pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid and toluenesulfonic acid. The present disclosure includes pharmaceutically acceptable salts of any compound described herein. In some embodiments, the pharmaceutically acceptable salt is a hydrochloride.

[0194] Pharmaceutically acceptable salts can be synthesized from the parent compound containing the basic or acidic moiety by conventional chemical methods. In general, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. For a list of suitable salts, see Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, USA, p. 1445 (1990).

[0195] Since it is known that prodrugs can enhance many desired qualities of drugs (e.g., solubility, bioavailability, preparation, etc.), the compounds described herein can be delivered in the form of prodrugs and administered in this form to treat diseases. "Prodrugs" are intended to include any covalently bonded carriers that release the active parent drug described herein in vivo when such prodrugs are administered to mammalian subjects. Prodrugs can be prepared by modifying the functional groups present in the compound so that the modifier is broken into the parent compound in conventional operations or in vivo. Prodrugs include compounds described herein, wherein hydroxyl, amino or sulfhydryl groups are bonded to any group, and when the prodrug is administered to a mammalian subject, it is broken to form free hydroxyl, free amino or free sulfhydryl groups, 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.

[0196] "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.

[0197] As used herein, "treatment" or "treating" includes any action resulting in an improvement in a condition, disease, disorder, etc., such as alleviation, reduction, regulation, or elimination. "Treatment" or "treatment" of a disease state means treating a disease state in a mammal, particularly a human, and includes: (a) inhibiting an existing disease state, i.e., arresting its development or its clinical symptoms; and / or (c) relieving a disease state, i.e., causing regression of a disease state.

[0198] As used herein, "preventing" means preventing the development of clinical symptoms of a disease state (ie, inhibiting the onset of the disease) in a subject who may be exposed to or predisposed to the disease state but does not yet experience or display symptoms of the disease state.

[0199] As used herein, "mammal" refers to a human or non-human patient.

[0200] As used herein, the term "therapeutically effective amount" refers to a compound or combination of compounds described herein that is present in or on a recipient in an amount sufficient to cause biological activity (e.g., pain relief). In some embodiments, the combination of compounds is a synergistic combination. For example, the synergistic effect described in Chou and Talalay, Adv. Enzyme Regul. vol. 22, pp. 27-55 (1984) occurs when the effect of the compound combination when administered is greater than the cumulative effect of the compound when administered alone as a single agent. In general, the synergistic effect is most evident at suboptimal concentrations of the compound. The synergistic effect can be a combination of lower cytotoxicity, increased pain reduction, or some other beneficial effects compared to the individual components.

[0201] All percentages and ratios used herein are by weight unless otherwise specified.

[0202] Throughout the specification, when a composition is described as having, including or comprising a particular component or when a process is described as having, including or comprising a particular process step, it should be understood that the composition described herein also consists essentially of, or consists of, the listed components, and the process described herein also consists essentially of, or consists of, the listed process steps. In addition, it should be understood that the order of steps or the order in which certain actions are performed is not important as long as the process remains operable. In addition, two or more steps or actions can be performed simultaneously.

[0203] All enantiomers, diastereomers, and mixtures thereof are included within the scope of the compounds described herein. In some embodiments, the composition comprising the R enantiomer is free of or substantially free of the S enantiomer. In some embodiments, the composition comprising the S enantiomer is free of or substantially free of the R enantiomer. In some embodiments, the composition comprises an enantiomeric excess of at least or about 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% of the R or S enantiomer.

[0204] As used throughout this disclosure, the singular forms "a," "an," or "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a plurality of such compositions as well as a single composition, and reference to "a therapeutic agent" refers 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, reference to "a host cell" includes a plurality of such host cells, and reference to "an antibody" refers to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.

[0205] The compounds described herein and used in the various embodiments described herein can be prepared according to any method, such as the method described in US Pat. No. 8,835,488, the entire contents of which are incorporated herein by reference.

[0206] 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. Patent No. 8,835,488, the entire contents of which are incorporated herein by reference.

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

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[0238]

[0239] Example

[0240] Example 1: Biased ligands do not induce hyperalgesia The potential of test compounds to induce hyperalgesia in a mouse model of opioid-induced hyperalgesia. In this test, mice (n=8 / group) were injected subcutaneously with vehicle or μ opioid agonist twice daily for 4 days. On each of the four drug treatment days, measurements of mechanical allodynia were obtained using a method of repeated stimulation with a single von Frey monofilament (0.4 g). On the fifth day, the animals were tested again without additional drug treatment. For the test, the monofilament was applied to the hind paw for approximately 1-2 seconds. If there was a withdrawal reaction, it was recorded as a positive reaction. Ten repeats were performed for each mouse. The final measurement for each mouse was the percentage of no response to the stimulus in the ten trials. The results are shown in Figure 1 Compound A is Compound 265, and Compound B is Compound 54.

[0241] The graph shows the percentage of mice that did not respond to 10 applications of 0.4 g of von Frey filaments over 4 days in mice treated with the indicated μ-opioid agonists or vehicle. Oxycodone and fentanyl reduced the percentage of nonresponse, suggesting increased sensitivity to von Frey filaments (hyperalgesia), while the biased μ-opioid agonists Compounds A and B did not reduce the percentage of nonresponse.

[0242] These results indicate that the biasing ligands targeting the μ-opioid receptor do not induce hyperalgesia compared to the non-biasing ligands fentanyl and oxycodone. These results are surprising and unexpected. Therefore, based on these results, it is expected that the compounds can be used to treat hyperalgesia or subjects suffering from hyperalgesia or increased nociceptive sensitization, as described herein.

[0243] Example 2: Biased ligands reverse opioid-induced hyperalgesia In a mouse model of opioid-induced hyperalgesia, the potential of the test compound to reverse opioid-induced hyperalgesia was tested. In this test, mice (n=8 / group) were subcutaneously injected with vehicle or reference μ opioid agonist twice a day for 4 days. On each of the four drug treatment days, the measurement of mechanical allodynia was obtained using a method of repeated stimulation with a single von Frey monofilament (0.4g). After behavioral testing on the fifth day, animals that had received the reference μ opioid agonist were switched to compound B. Twice daily subcutaneous injections continued until the 12th day. Behavioral assessments of mechanical allodynia were performed on days 5, 6, 7, 8, 10, and 12. For testing, the monofilament was applied to the hind paw for approximately 1-2 seconds. If there was a withdrawal reaction, it was recorded as a positive reaction. Each mouse was repeated ten times. The final measurement for each mouse was the percentage of no response to stimulation in ten trials. Compound B (Compound 54) is able to reverse the hyperalgesic activity induced by opioids. Similar results can be expected for Compound 140 and Compound 265, because they are also biased ligands, such as Compound 54. Therefore, the results generated indicate that the biased ligands provided herein can reverse the hyperalgesic activity induced by opioids. Therefore, the compounds described herein can be used to reverse the hyperalgesic activity induced by opioids in humans or other mammals.

[0244] Example 3: A human subject prescribed morphine presents symptoms of opioid-induced hyperalgesia. The subject ceases morphine administration and is administered Compound 140 or Compound 265. The subject's opioid-induced hyperalgesia is treated and reduced. The subject continues to take Compound 140 or Compound 265 and does not suffer from hyperalgesia while maintaining pain relief.

[0245] Example 4: A subject is identified as suffering from increased nociceptive sensitization due to administration of opioids for pain relief. The subject is switched from opioids to a pharmaceutical composition comprising Compound 140 or Compound 265. The subject's nociceptive sensitization is reduced while pain relief is maintained.

[0246] The foregoing examples show that the compounds described herein do not induce OIH in subjects administered one or more compounds described herein, and can be used to treat pain in subjects without causing hyperalgesia or increased nociceptive sensitization. These examples also show that the biased ligands provided herein can be used to reverse the hyperalgesic activity induced by opioids in mammals, such as humans.

[0247] Although the compounds and methods described herein have been described with reference to the examples, those skilled in the art will recognize that various modifications may be made without departing from the spirit and scope thereof.

[0248] All of the above-mentioned U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in this specification and / or listed in the Application Data Sheet are incorporated herein by reference in their entirety.

Claims

1. Use of a compound of the following formula, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for reversing opioid-induced hyperalgesia in a subject in need thereof:

2. The use according to claim 1, wherein: The compound has the formula:

3. The use according to claim 2, wherein: The compound has the formula:

4. The use according to claim 1 or 2, wherein: The compound or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition.

5. The use according to claim 1 or 2, wherein: The subject has been identified as suffering from opioid-induced hyperalgesia.

6. The use according to claim 1 or 2, wherein: The pharmaceutically acceptable salts are formed from non-toxic inorganic or organic acids.

7. The use according to claim 6, wherein: The acid is 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarsanilic acid, hexylresorcinic acid, hydroxyaminoformic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid or toluenesulfonic acid.

8. The use according to claim 7, wherein: The pharmaceutically acceptable salt is fumarate.

9. The use according to claim 8, wherein: Fumarate is the fumarate salt of the compound of the formula:

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