HK1196035A - Opioid receptor ligands and methods of using and making same - Google Patents

Abstract

This application describes compounds that can act as opioid receptor ligands, which compounds can be used in the treatment of, for example, pain and pain related disorders.

Description

Opioid receptor ligands and methods of using and making the same

Technical Field

The present application relates to a family of compounds useful as opioid receptor ligands. Such compounds may provide therapeutic benefits in the treatment of pain.

Background

Opioid Receptors (ORs) mediate the effects of morphine and morphine 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 considered to have a subtype. All three opioid receptor types appear to share the same mechanism of action at the cellular level. For example, activation of opioid receptors causes inhibition of adenylate cyclase and recruitment of (recruit) β -arrestin.

When a therapeutic amount of morphine is administered to a patient suffering from pain, the patient reports a reduction in pain intensity, a reduction in discomfort, or a complete elimination. In addition to experiencing pain relief, some patients experience euphoria. However, when a pain-reducing dose of morphine selected by an individual without pain is administered, the sensation is not always pleasant; nausea is common and vomiting may also occur. Drowsiness, inability to concentrate, difficulty in mental states, apathy, reduced physical activity, diminished visual acuity, and lethargy may follow.

There is a continuing need for new OR modulators to be used as analgesics. There is a further need for OR agonists that are analgesics with reduced side effects. There is a further need for OR agonists as analgesics for the treatment of pain, immune dysfunction, inflammation, oesophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, drugs for drug and alcohol abuse, drugs for the treatment of gastritis and diarrhoea, cardiovascular drugs and/OR drugs for the treatment of respiratory diseases and cough with reduced side effects.

Disclosure of Invention

Opioid Receptor (OR) ligands are described. It also describes methods of modulating opioid receptor activity using the compositions described herein. Certain compositions described herein are useful as opioid receptor agonists. Other compositions described herein are useful as opioid receptor antagonists.

The present application describes compounds having the structure of formula I:

in the above structure, the variable A₁、A₂、A₃、A₄、A₅、B₁、B₂、B₃、B₄、B₅And D₁May be selected from the corresponding groups of the chemical moieties described later. OR ligand derivatives and mimetics are also provided. Also provided are methods for preparing these compounds.

Also described herein are pharmaceutical compositions comprising one or more of the compounds described herein and a pharmaceutically acceptable carrier. Of course, the compounds described herein can be used in any form, such as a solid or a solution (e.g., an aqueous solution) as described further below. The compounds described herein can be obtained and used, for example, in lyophilized form alone or with suitable additives.

Methods for treating pain and pain-related disorders are also provided. Such methods will comprise administering to a subject in need thereof a therapeutically effective amount of one or more compounds described herein.

Detailed Description

The present application describes a family of compounds (OR ligands) with a unique profile. The compounds described herein are useful as agonists OR antagonists of Opioid Receptor (OR) mediated signal transduction. Ligands for these receptors may be useful in the treatment of OR-related pathologies, including pain and pain-related disorders.

Compounds also include formula I:

wherein; a. the₁Is absent, CH₂、CHR₁、CR₁R₂、CH、CR₁、O、S、SO、SO₂NH or NR₁；A₂Is absent, CH₂、CHR₅、CR₅R₆、CH、CR₅、O、S、SO、SO₂NH or NR₅；A₃Is absent, CH₂、CHR₇、CR₇R₈、O、S、SO、SO₂、NH、NR₇CH or CR₇；A₄Is absent, CH₂Formula C (CH)₂)_nWherein n =2-5, CHR₉、CR₉R₁₀、O、S、SO、SO₂、NH、NR₉CH or CR₉(ii) a And A is₅Is absent, CH₂、CHR₁₁、CR₁₁R₁₂、CH₂CH₂、CHR₁₁CH₂、CH₂CHR₁₁、CHR₁₁CHR₁₂、O、S、SO、SO₂、NH、NR₁₁CH or CR₁₁。

5 of A_a(specifically, A)₁、A₂、A₃、A₄、A₅) No more than 2 of which may be absent simultaneously. A. the₁To A₅The number of heteroatoms cannot exceed 2 simultaneously, and O-O, S-O is in the ring structure; S-S; the S-N fragment is not included in the composition.

Comprises A₁、A₂、A₃、A₄、A₅And is connected to D₁The ring of carbon (a) may be fused with other rings such as benzene, pyridine, pyrimidine, furan, thiophene or pyridazine, but not limited to these examples, wherein the resulting bicyclic ring is chemically stable and synthetically available. It is also understood that the fused rings mentioned above may be multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, formyl, acetyl, amino, alkylamino, dialkylamino, thiol, alkylthiol, and other smaller substituents. A. the₁And A₂、A₂And A₃、A₃And A₄、A₄And A₅The bonds between may independently be single or double bonds. A. the₁And A₂、A₂And A₃、A₃And A₄、A₄And A₅The bonds between cannot be double bonds at the same time.

A₂And A₄May be connected by a carbon bridge. Examples of such bridges include-CH₂-and-CH₂CH₂-。

B₁Is CH₂、CHR₁₃、CR₁₃R₁₄、O、S、SO、SO₂、NH、NR₁₃、CR₁₃Or CO. B is₂Is CH₂、CHR₁₅、CR₁₅R₁₆、CR₁₅Or CO. B is₃Is H, alkyl, branched alkyl, halogenated alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, or alkylsulfonyl. B is₄Is absent, C₁-C₆Alkyl radical, CH₂、CH₂CH₂、CHR₁₉、CR₁₉R₂₀Or CO.In some embodiments, when B₄When alkyl, one or more hydrogens may be replaced with deuterium. B is₅Is alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle, or arylalkyl.

Aryl, carbocyclic (non-aromatic)/heterocyclic (non-aromatic with 1-3 heteroatoms, including O, N, S) is unsubstituted or substituted with smaller substituents. The smaller substituent may be cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthiol, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocyclic, or carbocyclic alkyl. In some embodiments, the smaller substituents are selected from F, Cl, Br, CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃、n-Pr、n-Bu、i-Bu、sec-Bu、i-Pr、t-Bu、CN、OH、OMe、OEt、O-iPr、OCF₃、NH₂、NHMe、NMe₂Methoxycarbonyl, methylsulfonyl, Ph, benzyl, MeSO₂Formyl, and acetyl.

Carbocycles may contain double bonds, but they should not be aromatic.

D₁Is aryl or carbocyclic.

The aryl group can be a monocyclic aryl group or a bicyclic aryl group, which can contain heteroatoms (e.g., heteroaryl groups) in the aryl group. The following structures are some examples of typical aryl groups, but aryl groups are not limited to those examples:

carbocycles are monocyclic or bicyclic non-aromatic ring systems. The following structures are some examples of typical carbocycles, but carbocycles are not limited to those examples:

wherein, in the carbocyclic ring example, X₁And X₂Independently O, S, N, NH or NR₁₈。

Aryl groups may be independently mono-or multiply substituted with cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthiol, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, carbocycle, carbocycloalkyl, and/or other smaller substituents. In some embodiments, the smaller substituents are selected from F, Cl, Br, CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃、n-Pr、n-Bu、i-Bu、sec-Bu、i-Pr、t-Bu、CN、OH、OMe、OEt、O-iPr、OCF₃、NH₂、NHMe、NMe₂Methoxycarbonyl, methylsulfonyl, Ph, benzyl, formyl, and acetyl.

D₁Is aryl, or carbocyclic.

R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₈、R₁₉And R₂₀Independently are: cyano, halogen, hydroxy, alkoxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycleAlkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl or alkoxycarbonyl. In some embodiments, R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₈、R₁₉And R₂₀Independently F, Cl, Br, CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, CN, OH, OMe, OEt, O-i-Pr, methoxycarbonyl, phenyl, benzyl, formyl or acetyl, the resulting structure being stable at any time.

R₁And R₂、R₅And R₆、R₇And R₈、R₉And R₁₀、R₁₁And R₁₂、R₁₃And R₁₄、R₁₅And R₁₆、R₁₉And R₂₀Or R₁₅And R₁₉A single ring may be formed.

Me is methyl; et is ethyl; i-Pr is isopropyl; t-Bu is tert-butyl; ph is phenyl.

In some embodiments, the following compounds may be excluded from this class of compounds:

1)2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

2)2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl-2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

3) {2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

4){2-[(4S^*,4R^*) -2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Ethyl } [ (1R) -1-phenylethyl]Amines as pesticides

5){2-[(4S^*,4R^*) -2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Ethyl } [ (1S) -l-phenylethyl)]Amines as pesticides

6) Benzyl ({2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl }) amine

7)2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

8) Benzyl [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

9) {2- [ 2-Ethyl-4- (4-fluorophenyl-2-methyloxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

10) [ (3, 4-Dimethoxyphenyl) methyl ] ({2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

11) {2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } (l-phenylethyl) amine

12) [ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

13) Benzyl ({2- [ 2-ethyl-4- (2-methoxyphenyl) -2-methyloxacyclohex-4-yl ] ethyl }) amine

14) [ (3, 4-Dimethoxyphenyl) methyl ] ({2- [ 2-ethyl-4- (2-methoxyphenyl) -2-methyloxacyclohex-4-yl ] ethyl }) amine

15)4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline

16) Benzyl ({2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

17) {2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } (l-phenylethyl) amine

18) [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (4-methoxyphenyl) methyl ] amine

19) {2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

20) [ (3, 4-Dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

The present application also describes compounds having the structures of formulas II-1 and II-2:

wherein A is₂Is CH₂、CHR₅、CR₅R₆；A₄Is CH₂、CHR₉、CR₉R₁₀Or formula C (CH)₂)_nWherein n = 2-5.

And R₅、R₆、R₉And R₁₀Independently is CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. And, R₅And R₆Or R₉And R₁₀Monocyclic carbocycles may be formed.

A₂And A₄May be connected by a carbon bridge. The bridge may be-CH₂-or-CH₂CH₂-。

Further, B₃Selected from the following: H. alkyl, branched alkyl, aryl, arylalkyl, alkylCarbonyl, branched alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, and alkyl sulfonyl. In some embodiments, B₃Is C₁-C₅An alkyl group. In some embodiments, B₃Is H.

Further, B₄Is absent, C₁-C₆Alkyl radical, CH₂、CH₂CH₂、CHR₁₉、CR₁₉R₂₀Or CO. Further, R₁₉And R₂₀Can form formula (CH)₂)_nWherein n = 2-4. B is₅Is alkyl, branched alkyl, carbocycle-substituted alkyl, aryl or arylalkyl.

Further, D₁Is an aryl group. Examples of aryl groups are shown above.

Each aryl group can be independently 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、NMe₂Methoxy carbonyl, Ph, benzyl, formyl, or acetyl, singly or multiply substituted. That is, each aryl group can be multiply substituted with the same substituent (i.e., 2 chloro groups) or even with different groups (e.g., an aryl group having 1 chloro and 1 methyl group would be considered multiply substituted).

The present application also describes compounds having the structure of formula III:

wherein A is₂Is CH₂、CHR₅Or CR₅R₆；A₄Is CH₂、CHR₉、CR₉R₁₀Or formula C (CH)₂)_nWherein n = 2-5.

Further, R₅、R₆、R₉And R₁₀Independently is CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu, or phenyl. R₅And R₆Or R₉And R₁₀Monocyclic carbocycles may be formed.

A₂And A₄May be connected by a carbon bridge. The bridge may be-CH₂-or-CH₂CH₂-。

Further, B₃Selected from H, alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl or alkylsulfonyl.

Further, B₄Is absent, C₁-C₆Alkyl radical, CH₂、CH₂CH₂、CHR₁₉、CR₁₉R₂₀Or CO. And, R₁₉And R₂₀Can form formula (CH)₂)_nWherein n = 2-4. B is₅Is alkyl, branched alkyl, carbocycle-substituted alkyl, aryl or arylalkyl.

Further, D₁Is an aryl group. Examples of aryl groups are shown above.

The aryl can be 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、NMe₂Methoxy carbonyl, Ph, benzyl, formyl, or acetyl, singly or multiply substituted.

Also described are compounds having the structure of formula IV-1, IV-2, or IV-3, V, or VI:

wherein R is₂₁And R₂₂Independently is H or CH₃；A₄Is CH₂、CR₉R₁₀Or formula C (CH)₂)_nWherein n = 2-5.

Further, R₉And R₁₀Independently is CH₃Or CH₂CH₃。

Further, B₃Is H, C₁-C₆Alkyl or branched alkyl.

Further, B₄Is absent, C₁-C₆Alkyl radical, CH₂、CH₂CH₂or-CHCH₃。

B₅Is- (CH)₂)_nCH₃Wherein n =2-3, -C (CH)₃)₃Cyclohexyl, cyclopentyl, aryl or arylalkyl.

The aryl group may be selected from the following list:

each aryl group can be F, I, Cl, Br, CH₃、CN、OH、OMe、OEt、OCF₃CF3, or methanesulfonyl.

Also, in some embodiments, D₁Is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, which may be independently substituted with F, Cl, Br, OCF₃、CF₃Or CH₃Single or multiple substitutions.

Also described are compounds having the structure of formula V-1, V-2, V-3, VI-1, VI-2, or VI-3:

wherein D is₁Is an aryl group; b is₅Is aryl or carbocyclic.

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

in some embodiments, each aryl group is independently singly or multiply substituted. In some embodiments, each aryl group can be independently substituted with I, F, Cl, Br, CH₃CN, OH, OMe, OEt, OCF3, CF3, or methanesulfonyl. Also, in some embodiments, the carbocycle is cyclohexyl, cyclohexenyl, or cyclopentyl.

In some embodiments, D₁Is an optionally mono-or multiply-substituted aryl group. In some embodiments, B₅Is an optionally mono-or multiply-substituted aryl or carbocycle. In some embodiments, D₁Or B₅Independently selected from the group consisting of:

wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

In some embodiments，D₁Is optionally mono-or multiply-substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. In some embodiments, D₁Optionally with one or more of F, Cl, Br, I, OCF₃、CH₃And CF₃And (4) substitution. In some embodiments, D₁And are not substituted.

In some embodiments, B₅Is optionally singly or multiply substituted

In some embodiments, B₅With one or more of Cl, Br, F, I, OMe, CN, CH₃Methanesulfonyl, and CF₃And (4) substitution. In some embodiments, B₅With two or more Cl, Br, F, I, OMe, CN, CH₃、CF₃And methylsulfonyl, or a combination thereof. That is to say B₅There may be two or more substituents, but not all of the plurality of substituents need to be the same.

In some embodiments, compounds having the structure of formula VII-1, VII-2, or VII-3 are provided:

wherein D is₁Is optionally substituted heteroaryl or aryl, B₃Is H or alkyl, B₅Is optionally substituted aryl or heteroaryl, and R₂₆And R₂₇Each is hydrogen or an isotope thereof. In some embodiments, R₂₆And R₂₇Is deuterium. In some embodiments, R₂₆Or R₂₇Independently an alkyl group. In some embodiments, B₃Is C₁-C₅An alkyl group.

In some embodiments, the compound has the structure of formula VIII or an enantiomer thereof

Wherein D is₁Is optionally substituted heteroaryl or aryl, B₃Is H or alkyl, B₅Is optionally substituted aryl or heteroaryl, and R₂₆And R₂₇Each is hydrogen or an isotope thereof. In some embodiments, R₂₆And R₂₇Is deuterium. In some embodiments, R₂₆Or R₂₇Independently an alkyl group. A. the₄As described herein. In some embodiments, B₃Is C₁-C₅An alkyl group. In some embodiments, the enantiomer is attached to D₁The R or S enantiomer at the carbon of (a).

In some embodiments, the compound has the structure of formula IX or an enantiomer thereof

In some embodiments, the enantiomer is attached to D₁The R or S enantiomer at the carbon of (a).

In some embodiments, the compound has the structure of formula X or an enantiomer thereof

In some embodiments, the enantiomer is attached to D₁The R or S enantiomer at the carbon of (a).

In some embodiments of the structures described herein, D₁Is optionally substituted pyridyl or phenyl. In some embodiments, D₁Is optionally substituted 2-pyridyl, 3-pyridyl, or 4-pyridyl or phenyl. In some embodiments, D₁Optionally substituted with one or more H, OH, alkyl alcohol, halogen, alkyl, amide, cyano, alkoxy, haloalkyl, or alkylsulfonyl. In some embodiments, D₁With one or more of H, OH, Cl, Br, F, I, OMe, CN, CH₃、CF₃Optionally substituted.

In some embodiments of the structures described herein, B is₅Is an optionally substituted thiophene group. In some embodiments, B₅Substituted with alkoxy. In some embodiments, B₅With C₁-C₅Alkoxy substitution. In some embodiments, B₅Substituted with methoxy. In some embodiments, B₅Is thatIn some embodiments, B₅Is that

Wherein R is₂₃、R₂₄And R₃₀Each independently is absent, H, OH, cyclic, aryl, branched or unbranched alkaneAlcohol, halogen, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylsulfanyl, and R₂₅Is H or alkyl. In some embodiments, R₂₃And R₂₄Together form a connection to one or more of B₅Aryl or ring of the atom(s). R₂₃、R₂₄And R₃₀May be further substituted. In some embodiments, R₂₃、R₂₄And R₃₀Each independently is H, NH₂、OH、Cl、Br、F、I、OMe、CN、CH₃Phenyl, C₃-C₆Carbocyclic ring, methylsulfonyl, CF₃、Wherein R is₂₉Is H or alkyl. In some embodiments, R₂₉Is C₁-C₆An alkyl group. In some embodiments, R₂₃、R₂₄And R₃₀Is H. In some embodiments, R₂₃、R₂₄And R₃₀Is H. In some embodiments, R₂₃、R₂₄And R₃₀Two of which are H.

The following compounds and other compounds described herein have agonist activity for OR-mediated signal transduction:

[ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine [ (3, 4-dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (2-fluorophenyl) methyl ] amine

4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline

2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-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.

In some embodiments, compounds such as those described herein are provided. In some embodiments, a compound selected from the compounds described in the examples is provided. The compounds may be used in any of the methods described herein, including but not limited to the treatment of pain.

Accordingly, the present application provides methods of producing agonist activity in OR-mediated signal transduction by administering to a subject OR a subject in need thereof one OR more of the above compounds.

The various atoms in the compositions described herein may be isotopes that occur at a lower frequency. Deuterium may be substituted for hydrogen at any position of the compositions described herein. Alternatively, hydrogen may also be replaced with tritium. At any location of the compositions described herein, may be used¹³C or¹⁴C replaces carbon (C)¹²C) In that respect Can use¹⁵N replaces nitrogen (¹⁴N). At any location of the compositions described herein, may be used¹⁷O or¹⁸O in place of oxygen (¹⁶O). At any location of the compositions described herein, may be used³³S、³⁴S or³⁶S replaces sulfur: (³²S). At any location of the compositions described herein, may be used³⁷Cl for chlorine (C)³⁵Cl). At any location of the compositions described herein, may be used⁸¹Br for bromine: (⁷⁹Br）。

Selected compounds described herein are agonists and antagonists of the Opioid Receptor (OR). The ability of the compound to stimulate OR-mediated signaling can be measured using any assay known in the art to detect OR-mediated signaling OR activity, OR the absence of such signaling/activity. "OR activity" refers to the ability of OR to transduce a signal. Such activity (e.g., in heterologous cells) can be measured by binding OR (OR chimeric OR) to a downstream effector, such as adenylate cyclase.

As used herein, "natural ligand-induced activity" refers to the activation of OR by a natural ligand of OR. Any number of endpoints can be used to assess activity to measure OR activity.

In general, assays for testing compounds that modulate OR-mediated signal transduction include measuring any parameter, such as a functional effect, a physical effect, OR a chemical effect, either indirectly OR directly under the influence of OR.

A sample OR assay comprising an OR treated with a potential activator, inhibitor, OR modulator is compared to a control sample without the inhibitor, activator, OR modulator to check the extent of inhibition. The relative OR activity value for the control sample (not treated with inhibitor) was assigned to 100%. Inhibition of OR is achieved when the activity value of OR is about 80%, 50%, OR 25% relative to a control. Activation of OR is achieved when the activity value of OR is 110%, 150%, 200-500% (i.e., more than two-to five-fold over the control), OR 1000-3000% OR more relative to the control (not treated with the activator).

The effect of a compound on OR function can be measured by examining any of the parameters described above. Any suitable physiological change that affects OR activity can be used to assess the effect of a compound on OR and natural ligand mediated OR activity. When functional results are determined using intact cells or animals, it is also possible to measure changes in various effects such as intracellular second messengers such as cAMP.

Modulators of OR activity are tested using recombinant OR naturally occurring OR polypeptides as described above. Proteins expressed in cells, expressed in membranes derived from cells, expressed in tissues or animals can be isolated. For example, neuronal cells, cells of the immune system, transformed cells, or membranes may be used to test the GPCR polypeptides described above. Modulation is tested using one of the in vitro or in vivo assays described herein. Signal transduction can also be examined in vitro using soluble or solid state reactions using chimeric molecules such as the ectodomain of a receptor covalently linked to a heterologous signal transduction domain, or the cytoplasmic domain of a receptor and/or a heterologous ectodomain covalently linked to a transmembrane. Furthermore, the ligand binding domain of the protein of interest can be used in vitro in soluble or solid state reactions to determine ligand binding.

Ligand binding to the OR, domain, OR chimeric protein can be tested in a variety of formats. The binding can be performed as follows: 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, binding of the candidate modulator may be measured in the presence of the natural ligand. Typically, competition assays are used that measure the ability of a compound to compete with the natural ligand for binding to the receptor. Binding can be tested by measuring, for example, changes in spectral characteristics (e.g., fluorescence, absorbance, refractive index), fluid mechanics (e.g., shape), or changes in chromatographic or solubility properties.

Modulators may also be identified using assays that include β -arrestin recruitment. Beta-arrestins act as regulatory proteins distributed throughout the cytoplasm of unactivated cells. Ligands that bind to the appropriate OR are involved in the redistribution of β -arrestin from the cytoplasm to the cell surface, where it is associated with OR. Thus, the effects of receptor activation and candidate modulators on ligand-induced receptor activation can be assessed by monitoring β -arrestin recruitment to the cell surface. This is typically done by transfecting labeled β -arrestin fusion proteins (e.g., β -arrestin-Green Fluorescent Protein (GFP)) into cells and monitoring their distribution using confocal microscopy. (see, e.g., Groarke et ai, J.biol. chem.274(33): 2326369 (1999)).

Other techniques that may be used to assess OR-protein interactions in living cells involve Bioluminescence Resonance Energy Transfer (BRET). A detailed discussion of BRET can be found in Kroeger et al, J.biol.chem.,276(16): 1273643 (2001).

Other assays may include determining the activity of the receptor, which when activated by ligand binding, leads to changes in intracellular cyclic nucleotide levels, such as cAMP, by activating or inhibiting downstream effectors, such as adenylate cyclase. Changes in intracellular cAMP can be measured using an immunoassay. The method described in Offermanns & Simon, J.biol.chem.270: 1517515180 (1995) can be used to determine cAMP levels. Similarly, the method described in Felley-Bosco et al, am.J.Resp.cell and mol.biol.11: 159164 (1994) can be used to determine cGMP levels. Furthermore, an assay kit for measuring cAMP is described in U.S. Pat. No. 4,115,538, which is incorporated herein by reference.

The level of transcription can be measured to assess the effect of the test compound on ligand-induced signal transduction. Host cells containing the protein of interest are contacted with the test compound in the presence of the natural ligand for a time sufficient to effect any interaction, and then the level of gene expression is measured. The amount of time to affect such interactions can be determined empirically, such as by running for a period of time and measuring the level of transcription as a function of time. The amount of transcription can be measured by using any method known to those skilled in the appropriate art. For example, southern blotting may be used to detect mRNA expression of proteins of interest or immunoassays may be used to identify their polypeptide products. Alternatively, transcription-based assays using reporter genes, as described in U.S. Pat. No. 5,436,128, which is incorporated herein by reference, may be used. The reporter gene may be, for example, chloramphenicol acetyltransferase, luciferase, bacterial luciferase, beta-galactosidase, and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter by linking to a second reporter such as green fluorescent protein (see, e.g., Mistili & Spector, Nature Biotechnology 15: 961964 (1997)).

The amount of transcription is then compared to the amount of transcription in the same cell in the absence of the test compound, or can be compared to the amount of transcription in substantially the same cell lacking the protein of interest. Substantially identical cells may be derived from the same cell from which the recombinant cell was prepared, but which have not been modified by the introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound alters the activity of the protein of interest in some way.

Pharmaceutical compositions/formulations

The pharmaceutical compositions may be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. The formulation may comprise a buffer and/or a preservative. The compounds and their physiologically acceptable salts and solvates may be formulated for administration by any suitable route, including by inhalation, topical administration, nasal administration, oral administration, parenteral administration (e.g., intravenous, intraperitoneal, intravesical or intrathecal administration), or rectal administration in a vehicle containing one or more pharmaceutically acceptable carriers, the proportions being determined by the solubility and chemical nature of the compounds, the chosen route of administration and standard biological testing practices (practice).

Pharmaceutical compositions may comprise an effective amount of one or more compounds described herein, together with, for example, pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or other carriers. Such compositions may contain diluents of various buffer contents (e.g., TRIS or other amines, carbonates, phosphates, amino acids such as glycinamide hydrochloride (particularly in the physiological pH range), N-glycylglycine, sodium or potassium phosphates (dibasic, tribasic), etc., or TRIS-HCl or acetate), pH and ionic strength; 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, and the like), antioxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimers, benzyl alcohol, parabens, and the like), and bulking substances (e.g., sugars such as sucrose, lactose, mannitol, polymers such as polyvinylpyrrolidone or dextran, and the like); and/or incorporating the substance into a particulate formulation or liposome of polymeric compounds such as polylactic acid, polyglycolic acid, and the like. Hyaluronic acid may also be used. Such compositions can be used to affect the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the compounds described herein. See, e.g., Remington's Pharmaceutical Sciences,18th Ed. (1990, Mack publishing Co., Easton, Pa.18042) pages 1435-1712, which is incorporated herein by reference. The composition may be prepared, for example, in liquid form, or may be in the form of a dry powder, such as lyophilized. Specific methods of administering such compositions are described below.

When a buffer is to be included in the formulations described herein, the buffer may be selected from sodium acetate, sodium carbonate, citrate, glycylglycine, histidine, glycine, lysine, arginine, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, and tris (hydroxymethyl) -aminomethane, or mixtures thereof. The buffer may also be glycylglycine, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate or a mixture thereof.

When a pharmaceutically acceptable preservative is to be included in the formulation of one of the compounds described herein, the preservative may be selected from phenol, m-cresol, methyl paraben, propyl paraben, 2-phenoxyethanol, butyl paraben, 2-phenylethanol, benzyl alcohol, chlorobutanol, and thimerosal (thiomerosal), or mixtures thereof. The preservative may also be phenol or m-cresol.

The preservative is present at a concentration of about 0.1mg/ml to about 50mg/ml, at a concentration of about 0.1mg/ml to about 25mg/ml, or at a concentration of about 0.1mg/ml to about 10 mg/ml.

The use of preservatives in pharmaceutical compositions is well known to the skilled person. For convenience, refer to Remington, The Science and Practice of Pharmacy,19th edition, 1995.

The formulation may further comprise a chelating agent, wherein the chelating agent may be selected from ethylenediaminetetraacetic acid (EDTA) salts, citrates, and aspartate salts, and mixtures thereof.

The chelating agent can be present at a concentration of 0.1mg/ml to 5mg/ml, 0.1mg/ml to 2mg/ml, or 2mg/ml to 5 mg/ml. The use of chelating agents in pharmaceutical compositions is well known to the skilled person. For convenience, refer to Remington, The Science and Practice of Pharmacy,19th edition, 1995.

Formulations of the compounds described herein may further comprise stabilizers selected from high molecular weight polymers and low molecular weight compounds, wherein such stabilizers include, but are not limited to, polyethylene glycol (e.g., PEG 3350), polyvinyl alcohol (PVA), polyvinylpyrrolidone, carboxymethylcellulose, various 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.

The high molecular weight polymer can be present at a concentration of 0.1mg/ml to 50mg/ml, 0.1mg/ml to 5mg/ml, 5mg/ml to 10mg/ml, 10mg/ml to 20mg/ml, 20mg/ml to 30mg/ml, or 30mg/ml to 50 mg/ml.

The low molecular weight compound can be present at a concentration of 0.1mg/ml to 50mg/ml, 0.1mg/ml to 5mg/ml, 5mg/ml to 10mg/ml, 10mg/ml to 20mg/ml, 20mg/ml to 30mg/ml, or 30mg/ml to 50 mg/ml.

The use of stabilizers in pharmaceutical compositions is well known to the skilled person. For convenience, refer to Remington, The Science and Practice of Pharmacy,19th edition, 1995.

The compound formulations described herein may further comprise 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 (tweens such as tween-20 or tween-80), monoglycerides or their ethoxylated derivatives, diglycerides or their polyoxyethylene derivatives, glycerol, cholic acidOr derivatives thereof, lecithin, alcohols and phospholipids, glycerophospholipids (lecithin, cephalin, phosphatidylserine), glyceroglycolipids (galactopyranoside), sphingomyelin (sphingomyelin), and glycosphingolipids (ceramide, gangliosides), DSS (sodium docusate, calcium docusate, potassium docusate, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoylphosphatidic acid (dipalmitoyl phosphatidylcholine acid), sodium caprylate, bile acid and salts thereof and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-aryl-sulfonate) monovalent surfactants, palmitolysophosphatidyl-L-serine, palmitoyl, Lysophospholipids (e.g. 1-acyl-sn-glycerol-3-phosphate ester of ethanolamine, choline, serine or threonine), alkyl, alkoxy (alkyl ester), alkoxy (alkyl ether-derivative) of lysophosphatidylcholine and alkoxy (alkyl ether-derivative) of phosphatidylcholine, such as dodecanoyl and tetradecanoyl derivatives of lysophosphatidylcholine, 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-dimethylammonio-1-propanesulfonate, 3-cholinamido-1-propyldimethylammonio-1-propanesulfonate) Salts, dodecyl phosphorylcholine, myristoyl lysophosphatidylcholine, egg lysolecithin), cationic surfactants (quaternary ammonium bases) (e.g., cetyl-trimethylammonium bromide, cetylpyridinium chloride), nonionic surfactants, polyoxyethylene/polyoxypropylene block copolymers (Pluronics/Tetronics, Triton X-100, dodecyl β -D-glucopyranoside) or polymeric surfactants (tween-40, tween-80, Brij-35 (brize-35)), fusidic acid derivatives (e.g., sodium taurodihydrofusidate, etc.), csubrionic acid, etc.), and mixtures thereof₆-C₁₂Long chain fatty acids and salts thereof (e.g., oleic acid and caprylic acid),N of acylcarnitines and derivatives, lysine, arginine or histidine_αAcylated derivatives, or side chain acylated derivatives of lysine or arginine, N of dipeptides comprising lysine, arginine or histidine and any combination of neutral or acidic amino acids_αN of acylated derivatives, tripeptides comprising any combination of a neutral amino acid and two charged amino acids_αThe acylated derivative, or the surfactant, may be selected from the group of imidazoline derivatives, or mixtures thereof.

The use of surfactants in pharmaceutical compositions is well known to the skilled person. For convenience, refer to Remington, The Science and Practice of Pharmacy,19th edition, 1995.

The pharmaceutical sweetener may be part of the compound formulation described herein. The medicinal 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 saccharin, or calcium saccharin, and optionally a bulking sweetener such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.

Intense sweeteners are conveniently used at low concentrations. For example, in the case of saccharin sodium, the concentration may range from 0.04% to 0.1% (w/v), based on the total volume of the final formulation, or about 0.06% in a low dose formulation and about 0.08% in a high dose formulation. Bulking sweeteners can be effectively used in relatively large amounts ranging from about 10% to about 35%, or about 10% to 15% (w/v).

The compound formulations described herein may 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, where such conventional techniques of The Pharmaceutical industry involve suitably dissolving and mixing The components to give The desired end product.

The phrases "pharmaceutically" or "therapeutically" refer to molecular entities and compositions that, when administered to a human, are physiologically tolerable and preferably do not generally produce an allergic or similar untoward reaction such as upset heart, dizziness and the like. The term "pharmaceutically acceptable" as used herein means approved by an approval authority of a federal or state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans (e.g., Remington's Pharmaceutical Sciences, mack publishing Co. (a.r. gennaro edge. 1985)).

Administration of the compounds described herein can be performed using any method known in the art. For example, administration can be transdermal, parenteral, intravenous, intraarterial, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intracerebroventricular, intrathecal, intranasal, aerosol, by suppository, or oral. Pharmaceutical compositions of the compounds described herein may be for injection, or for oral, pulmonary, nasal, transdermal, ocular administration.

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 may be prepared by conventional methods using pharmaceutically acceptable excipients including binders such as pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose; fillers such as lactose, microcrystalline cellulose, or calcium hydrogen phosphate; lubricants such as magnesium stearate, talc, or silica; disintegrants such as potato starch or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take such forms as solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional methods using pharmaceutically acceptable additives, for example, suspending agents 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, ethyl alcohol, or fractionated vegetable oils; and preservatives such as methyl or propyl paraben or sorbic acid. The formulations may also contain buffer salts, flavoring agents, coloring agents, and/or sweetening agents, as appropriate. Formulations for oral administration may be suitably formulated to give controlled release of the active compound if desired.

For topical administration, pharmaceutical compositions of the compounds described herein can be formulated in a pharmaceutically acceptable carrier containing from 0.1 to 10%, or from 0.5 to 5%, of the active compound. Such formulations may be in the form of creams, lotions, sublingual tablets, aerosols and/or emulsions, and may be contained in transdermal or buccal patches of the matrix or reservoir (depot) type (as are commonly used in the art for this purpose).

For parenteral administration, the compounds described herein are administered by intravenous, subcutaneous, or intramuscular injection in a composition with a pharmaceutically acceptable carrier or vehicle. The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulating agents (formulations) such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

For administration by injection, the compounds can be used in solution in a sterile aqueous vehicle, which may also contain other solutes such as buffers or preservatives and sufficient pharmaceutically acceptable salts or glucose to prepare an isotonic solution. Pharmaceutical compositions of the compounds described herein may be formulated with a pharmaceutical carrier to provide sterile solutions or suspensions for injectable administration. Injectables can be prepared in conventional forms as liquid solutions or suspensions, solid forms suitable for use in solution or suspension in liquid prior to injection, or emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like. In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of non-toxic auxiliary substances such as wetting agents, pH buffering agents and the like. If desired, absorption enhancing formulations (liposomes) may be used. Suitable pharmaceutical carriers are described in "Remington' pharmaceutical Sciences" of e.w. martin.

For administration by inhalation, the compounds may conveniently be delivered in the form of an aerosol spray presentation from a pressurised pack or nebuliser, with the aid of a suitable propellant, e.g. difluorodichloromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. For intranasal administration, the compounds described herein may be used, for example, as a liquid spray, as a powder, or in the form of drops.

The compounds can also be formulated in rectal compositions such as suppositories or retention enemas (retentationemas), e.g., containing conventional suppository bases such as cocoa butter or other glycerides. Furthermore, the compounds can be formulated as depot preparations (depot preparations). Such long-acting formulations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

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

The compounds described herein also include derivatives, referred to as prodrugs, which may be prepared by modifying functional groups present in the compound by cleaving the modified form into the parent compound in routine manipulation or in vivo. Examples of prodrugs include compounds of the invention as described herein that comprise one or more molecular moieties attached to a hydroxyl, amino, sulfhydryl, or carboxyl group of the compound and that when administered to a patient cleave in vivo to form a free hydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. The preparation and use of prodrugs are discussed in t.higuchi et al, "Pro-drugs as novelderlivery Systems," vol.1 of the a.c.s.symposium Series and bioreversiblephariers in Drug Design, ed.edward b.roche, American pharmaceutical association and Pergamon Press,1987, both of which are incorporated herein by reference in their entirety.

Dosage form

The compounds described herein may be administered to a patient at a therapeutically effective dose to prevent, treat OR control one OR more diseases and conditions mediated, in whole OR in part, by OR-ligand interactions. A pharmaceutical composition comprising one or more compounds described herein can be administered to a patient in an amount sufficient to elicit an effective prophylactic or therapeutic response in the patient. An amount sufficient to achieve this is defined as a "therapeutically effective dose". The dosage will be determined by the effectiveness of the particular compound employed, 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 be determined by the presence, nature, and extent of any adverse effects in a particular subject that accompany the administration of a particular compound or vehicle.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED 50. In some embodiments, compounds that exhibit a greater therapeutic index are used. While compounds exhibiting toxic side effects may be used, the delivery system that targets such compounds to the site of the affected tissue should be carefully designed to minimize potential damage to normal cells, thereby reducing side effects.

Data obtained from cell culture assays and animal experiments can be used to elucidate the dosage range for use in humans. In some embodiments, the dosage of such compounds is within a range of circulating concentrations that include little or no toxic ED 50. The dosage may vary within this range depending upon the dosage form employed and the route of administration. For any of the compounds described herein, a therapeutically effective dose can be estimated initially from cell culture assays. The dose can be formulated to achieve a circulating plasma concentration range (the concentration of the test compound that achieves half-maximal inhibition of symptoms) that includes IC50 as determined in cell culture in an animal model. Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by High Performance Liquid Chromatography (HPLC). Generally, for a typical subject, the dose equivalent of modulator is about 1ng/kg to 10 mg/kg.

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 in view of such factors as age, condition, and size of the patient, as well as the severity of the symptoms being treated. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. In general, it is contemplated that an effective amount may be from 0.001mg/kg to 10mg/kg body weight, and specifically from 0.01mg/kg to 1mg/kg body weight. The desired dose can be suitably administered in two, three, four or more sub-doses at suitable intervals throughout the day. The sub-dose may be formulated in unit dosage form, e.g. comprising from 0.01 to 500mg, and in particular from 0.1mg to 200mg of active ingredient per unit dosage form.

In some embodiments, the pharmaceutical formulation is in unit dosage form. In such forms, the preparation may be subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., effective amounts, to achieve the desired purpose. The amount of active compound in a unit dose of formulation may be varied or adjusted depending on the particular application: 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 250 mg. The actual dosage employed may vary depending upon the needs of the patient and the severity of the condition being treated. Determination of an appropriate dosage regimen for a particular situation is within the skill of the art. For convenience, the total dose may be divided and administered in multiple portions as needed during the day.

In some embodiments, one or more compounds described herein are administered with other compounds. Administration may be sequential or simultaneous. The combination may be in the same dosage form or administered as separate doses. In some embodiments, the other compound is another analgesic or analgesic. In some embodiments, the additional compound is a non-opioid analgesic. Examples of useful non-opioid analgesics include, but are not limited to, non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, muroprofen, troloxifen, suprofen, amprofen, tiaprofenic acid, fluprofen, bucloxic acid, anti-inflammatory indoleic acid, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac (oxypinac), paracetamol, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, floroxazac, piroxicam, sudoxicam, isoxicam, and pharmaceutically acceptable salts thereof, and mixtures thereof. Other suitable non-opioid analgesics include the following non-limiting chemical classes of analgesic and antipyretic non-steroidal anti-inflammatory drugs: derivatives of o-hydroxybenzoic acid including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic 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 acids (fenamates) including mefenamic acid and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenbutazone); and alkylketones, including nabumetone. For a more detailed description of NSAIDs, see Paul A. Insel, analytical-inflammatory and pharmaceutical formulations in The Treatment of Gout, ingGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds.,9.sup. th ed 1996); and Glen R.Hanson, Analgesic, antipyrotic and Anti-Inflammatory Drugs in Remington The Science and Practice of Pharmacy Vol II 1196-1221 (A.R.Gennaro ed.19.th. 1995), which is incorporated herein by reference in its entirety.

The compounds described herein can also be administered Cox-II inhibitors. Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, and combinations thereof, are described in U.S. patent No. 6,136,839, which is incorporated herein by reference in its entirety. Examples of Cox-II inhibitors include, but are not limited to, rofecoxib and celecoxib.

The compounds described herein may also be administered with an anti-migraine agent. Examples of useful anti-migraine agents include, but are not limited to, amipride, bromocriptine, dihydroergotamine, dolasetron, ergocornine, ergocyclidine, ergonovine, ergot, ergotamine, flumetenone acetate, xylazine, ketanserin, lisuride, lomerizine, methylergonovine, mexican, metoprolol, naratriptan, oxitropine, pithidine, propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan, and mixtures thereof.

The compounds described herein may also be administered with an anti-constipation agent. Examples of anti-constipation agents include, but are not limited to, laxatives or emollients. Examples of anti-constipation agents include, but are not limited to, docusate, poloxamer 188, flea grass, methyl cellulose, carboxymethyl cellulose, polycarbophil, bisacodyl, castor oil, magnesium citrate, magnesium hydroxide, magnesium sulfate, disodium phosphate, monosodium phosphate, or any combination thereof.

Medical applications

The compositions described herein may be used to treat pain or pain-related diseases. The compositions described herein may be used for the treatment of immune dysfunction, inflammation, esophageal reflux, neurological and psychiatric disorders, urinary and reproductive disorders, agents for drug and alcohol abuse, agents for the treatment of gastritis and diarrhea, cardiovascular agents, and agents for the treatment of respiratory diseases and cough.

In some embodiments, methods of treating pain are provided. In some embodiments, one or more compounds described herein are administered to a subject to treat pain. In some embodiments, the pain may be post-operative pain. In some embodiments, the pain is caused by cancer. In some embodiments, the pain is neuropathic pain. In some embodiments, the pain is caused by trauma, such as, but not limited to, blunt force trauma. In some embodiments, the pain is caused by inflammation.

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

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the compositions and compounds described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other properties and advantages of the compositions and compounds described herein will be apparent from the following detailed description and claims.

General chemical terms used throughout have their usual meanings. For example, the term alkyl refers to a branched or unbranched saturated hydrocarbon group. The term "n-alkyl" refers to an unbranched alkyl group. The term "C_x-C_yAlkyl "refers to an alkyl group containing from x to y carbon atoms, inclusive, in a branched or unbranched hydrocarbon group. By way of example, and not limitation, the term "C₁-C₄Alkyl "refers to a straight or branched chain hydrocarbon moiety having 1 to 4 carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term "C₁-C₄N-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_yX of (a) may be 1 to 10 and y is 2 to 20. The term "C₃-C₆Cycloalkyl "refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C₃-C₇Cycloalkyl "also includes cycloheptyl. "cycloalkylalkyl" refers to a cycloalkyl moiety attached through an alkyl linker chain, such as, but not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropyl-butyl, cyclohexyl-butyl,Cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, and cyclohexylpropyl. Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted, for example, but not limited to, as illustrated herein. In some embodiments, alkyl is C₁-C₃、C₁-C₄、C₁-C₆、C₄-C₆Or C₁-C₁₀An alkyl group.

The terms "alkoxy", "phenoxy", "benzyloxy" and "pyrimidinyloxy" refer respectively to an alkyl, phenyl, benzyl, or pyrimidinyloxy group attached through an oxygen atom. Each of these groups may be optionally substituted.

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

The term "C₁-C₄Acyl "refers to formyl or C attached through a carbonyl moiety₁-C₃An alkyl group. The term "C₁-C₄Alkoxycarbonyl "refers to C attached through a carbonyl moiety₁-C₄An alkoxy group.

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.

As used herein, unless otherwise specified, "carbocycle" or "carbocyclic ring" refers to 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 such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] bicyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydroxynaphthyl. As indicated above, bridged rings are also included in the definition of carbocyclic (e.g., [2.2.2] bicyclooctane). Bridged rings occur when one or more carbon atoms connect two non-adjacent carbon atoms. In some embodiments, the bridge is one or two carbon atoms. It should be noted that bridges always convert a single ring into a tricyclic ring. When a ring is bridged, the substituents listed for that ring may also be present on the bridge. Also included are fused rings (e.g., naphthyl and tetrahydronaphthyl) and spiro rings.

The term "heterocycle" refers to a saturated or unsaturated 5-or 6-membered ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, said ring being optionally benzo-fused. Exemplary heterocycles include furyl, thiophenyl (thienyl), pyrrolyl, pyrrolidinyl, pyridyl, N-methylpyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, N-acetyl thiazolidinyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like. Benzo-fused heterocycles include isoquinolinyl, benzoxazolyl, benzodioxolyl, benzothiazolyl, quinolinyl, benzofuranyl, benzothienyl, indolyl, and the like, all of which may be optionally substituted, and when the heterocycle is benzo-fused (heterocycle), it also includes, of course, optional substitution on the benzo ring.

The term "cyclic" group refers to carbocyclic rings, or heterocyclic rings.

The phrase "ring of this formula" as used herein refers to a ring that can be formed from the variables mentioned. For example, in the structureWherein A may be of the formula C (CH)₂)_nWherein n =2-5, which means that a is carbon and forms itself with 2-5 CH₂A ring of a group, which may also be structurally represented asThe variable "a" is not limited to carbon and may be other atoms such as, but not limited to, heteroatoms, but the context in which the variable is used will indicate the type of atom "a" that may be. This is only a non-limiting example. In addition, the ring formed by "a" may also be substituted. Exemplary substituents are described herein.

In some embodiments, heterocycles include, but are not limited to, pyridyl, indolyl, furyl, benzofuryl, thienyl, benzodioxolyl, and thiazolidinyl, all of which may be optionally substituted.

The term "aromatic heterocycle" or "heteroaryl" as used herein refers to 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, for example, 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 bis-heterocyclic aromatic rings, only one of the two rings must be aromatic (e.g., 2, 3-indoline), although both may be (e.g., quinoline). The second ring may also be fused or bridged, as previously defined for heterocyclic rings. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituent, as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N → O and S (O))_pWhere p =1 or 2). In some compounds, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl (azocinyl), benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromenyl (chromenyl), cinnolinyl, decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indomethacin (indolynyl), indolinyl, indolizinyl, indolyl, 3H-indolyl, isatoiyl, isobenzofuranyl, isochroman, Isoindolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxathiin, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidyl, 4-piperidyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridyl (pyridinyl), pyridyl (pyridinol), pyrimidinyl), pyrimidyl, piperidyl, or a salt thereof, Pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl (xanthenyl).

Substituted alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio, respectively, refers to an alkyl, cycloalkyl, cycloalkylalkyl, alkoxy, or alkylthio group, independently selected from the group consisting of halogen, hydroxy, and C₁-C₃Substituents in the group consisting of alkoxy are substituted one or more times. By way of illustration, but not limitation, examples include trifluoromethyl, pentafluoroethyl, 5-fluoro-2-bromopentyl, 3-hydroxypropoxy, 4-hydroxycyclohexyloxy, 2-bromoethylthio, 3-ethoxypropoxy, 3-ethoxy-4-chlorocyclohexyl, and the like. In some embodiments, a substitution isComprising substitution 1-5 times with halogen, each independently selected, or 1-3 times with halogen and independently selected from hydroxy and C₁-C₃Alkoxy is substituted 1-2 times or independently with a group selected from hydroxy and C₁-C₃The radical of alkoxy is substituted 1-3 times, provided that no more than one hydroxy and/or alkoxy substituent may be attached through the same carbon.

The terms "substituted phenyl" and "substituted heterocycle" mean that in either case the ring moiety is substituted. They may be independently substituted with one or more substituents. They may be independently substituted with 1,2,3, 4,5, 1-3, 1-4, or 1-5 substituents. The substitution may independently be halogen, alkyl such as but not limited to C₁-C₄Alkyl, alkoxy such as but not limited to C₁-C₄Alkoxy, and alkylthio groups such as, but not limited to, C₁-C₄Alkylthio, wherein each alkyl, alkoxy and alkylthio substituent may independently be replaced with C₁-C₂Alkoxy or further substituted with one to five halo groups; or substituted with one substituent selected from the group consisting of: phenoxy, benzyloxy, phenylthio, benzylthio and pyrimidinyloxy, wherein the phenoxy, benzyloxy, phenylthio, benzylthio and pyrimidinyloxy moiety may further be selected from the group consisting of halogen, C₁-C₂Alkyl, and C₁-C₂One to two substituents of the group consisting of alkoxy; or with a compound selected from the group consisting of C₁-C₄Acyl and C₁-C₄One substituent selected from the group consisting of alkoxycarbonyl, and further substituted with a substituent selected from the group consisting of halogen, C₁-C₄Alkyl radical, C₁-C₄Alkoxy, and C₁-C₄0 to 1 substituent in the group consisting of alkylthio. When the substituent is halogen, in some embodiments, the halogen group is fluorine, chlorine, and bromine. The halogen may also be iodine.

DMF means N, N-dimethylformamide.

The phrase "pharmaceutically acceptable" as used herein 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.

The term "pharmaceutical formulation" further means that the carrier, solvent, excipient, and salt must be compatible with the active ingredient(s) (e.g., the compounds described herein) of the formulation. It is understood by one of ordinary skill in the art that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and thus are used as such for the purposes of this application.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines); acidic residues such as alkali metal or organic salts of carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound as formed by non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrocarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycollic arsanilic acid (glycolyarsanilic acid), hexylresorcinol acid, habenamic acid (hydrabamic 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, glycolic acid (subacetic), succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid. The present disclosure includes pharmaceutically acceptable salts of any of the compounds described herein.

Pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two (typically, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or the like). A list of suitable salts exists in Remington's Pharmaceutical Sciences,18th ed., Mack Publishing Company, Easton, PA, USA, p.1445 (1990).

Because prodrugs are known to enhance many desirable properties of drugs (e.g., solubility, bioavailability, preparation, etc.), the compounds described herein can be delivered and administered in the form of a prodrug for the treatment of disease. When such prodrugs are administered to a mammalian subject, "prodrug" is intended to include any covalently linked carrier that releases the active parent drug described herein in vivo. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modification is cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein wherein a hydroxy, amino, or sulfhydryl group is attached to any group that cleaves to form a free hydroxy, free amino, or free sulfhydryl group, respectively, when the prodrug is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds described herein.

"stable compound" and "stable structure" are meant to refer to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

As used herein, "treating" or "treatment" includes any effect, such as alleviation, reduction, modulation, or elimination, that results in the amelioration of a condition, disease, disorder, or the like. "treatment" or "management" of a disease state refers to the treatment of the disease state in mammals, particularly humans, and includes: (a) inhibiting the existing disease state, i.e. delaying its development or its clinical symptoms; and/or (c) alleviating, i.e., causing regression of, the disease state.

As used herein, "preventing" refers to causing clinical symptoms of a disease state not to develop, i.e., inhibiting the onset of disease, in a subject who may be exposed to or susceptible to the disease state but does not yet experience or exhibit symptoms of the disease state.

As used herein, "mammal" refers to both human and non-human patients.

The term "therapeutically effective amount" as used herein means that the compound or combination of compounds described herein is present in or on the recipient in an amount sufficient to cause a biological activity, such as pain relief. In some embodiments, the combination of compounds is a synergistic combination. Synergy occurs when the effect of the compounds when given in combination is greater than the additive effect of the compounds when given as individual agents alone (as described by Chou and Talalay, adv. enzyme Regul. vol.22, pp.27-55 (1984)). In general, the synergistic effect is most clearly shown at sub-optimal concentrations of the compounds. The synergistic effect may be lower cytotoxicity, increased pain reduction, or some other beneficial effect in combination compared to the individual components.

All percentages and ratios used herein are by weight unless otherwise indicated.

Throughout the specification, when a composition is described as having, containing, or comprising a particular component, or when a method is described as having, containing, or comprising a particular process step, it is contemplated that the composition described herein also consists essentially of, or consists of, the component described, and that the process described herein also consists essentially of, or consists of, the process step described. Moreover, it will be appreciated that the order of steps or order for performing certain actions is immaterial so long as the method remains operable. Further, two or more steps or actions may be performed simultaneously.

All enantiomers, diastereomers, and mixtures thereof are included within the scope of the compounds described herein. In some embodiments, a composition comprising the R enantiomer is free or substantially free of the S enantiomer. In some embodiments, a composition comprising the S enantiomer is free or substantially free of the R enantiomer. In some embodiments, 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.

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

The compounds claimed in the present invention can be prepared by the procedures described in the following schemes.

Scheme(s)

The following exemplary scheme illustrates how the compounds described herein can be prepared. The particular solvents and reaction conditions mentioned are also exemplary and are not intended to be limiting. Compounds not described are commercially available or readily prepared by those skilled in the art using available starting materials.

In some embodiments, the same protocol applies to 1-7 and 1-8A.

In some embodiments, the same protocol applies to 1-7 and 1-8A.

In some embodiments, 4-1 is selected from the group consisting of:

intermediates 4-4 can be converted to opioid receptor ligands following the sequence outlined in schemes 2 or 3.

Other schemes may also be used. For example, the following schemes may be used alone or in combination with other schemes to prepare the compounds described herein.

In some embodiments, methods for preparing a peptide having IV-1 are providedA method of a compound of structure (la). In some embodiments, the method comprises subjecting the mixture to conditions suitable for the reactionContact to form a contact havingA compound of structure (la). In some embodiments, the method is performed at room temperature. In some embodiments, the method is performed in the presence of a borohydride salt. In some embodiments, the process is carried out in the presence of sodium borohydride. Solvents may also be used to facilitate this preparation. The process can be modified to produce different alkyl groups, such as but not limited to the scheme shown in scheme 10.

Examples

The following examples of the methods and compositions described herein are illustrative and not limiting. Other suitable variations and adaptations of the various conditions and parameters normally encountered in therapy and which are apparent to those skilled in the art are within the spirit and scope of the compounds and methods described herein.

Example 1:

intermediate 1:methyl 2-cyano-2- (oxacyclohex-4-ylidene) acetate (methyl 2-cyano-2- (oxacyclohex-4-ylidene) acetate) A50-mL round-bottomed flask equipped with a Dean-Stark distillation apparatus and a condenser was charged with tetrahydro-4H-pyran-4-one (4.61 mL, 50 mmol), methyl cyanoacetate (5.3 mL, 60 mmol), ammonium acetate (1 g,13 mmol),Acetic acid (0.57 ml, 10 mmol) and benzene (30 ml). The mixture was refluxed until no more water was collected in Dean-Stark (2 hours), cooled, benzene (30 ml) was added and the organic layer was washed with water (50 ml). By CH₂Cl₂The aqueous layer was extracted (3 x50 ml). The combined organic layers were washed with saturated NaHCO₃(100 ml), washed with brine (100 ml), dried (MgSO)₄) Filtered and concentrated. Through normal phase SiO₂Chromatography (10 to 60% EtOAc/hexanes) to give methyl 2-cyano-2- (oxacyclohex-4-ylidene) acetate (6.30 g, 70%, found M/z: 181.1[ M + H)]⁺) As a colorless oil.

Intermediate 2:2-cyano-2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Acetic acid methyl ester

A round-bottomed flask equipped with a condenser, addition funnel and rubber septum with nitrogen inlet was charged with a solution of p-fluorophenyl magnesium bromide (2.0M in diethyl ether, 1.99ml, 3.97 mmol) and CuI (63 mg, 0.331 mmol) in 10ml of dry diethyl ether (10 ml). Methyl 2-cyano-2- (oxacyclohex-4-ylidene) acetate (600 mg, 3.31 mmol) in diethyl ether (10 ml) was added dropwise over 30 minutes as the reaction flask was cooled in an ice bath. The mixture was then stirred for 3 hours. The reaction mixture was poured into a mixture of 50g ice/1N HCl (25 ml). With Et₂The product was O (3X 50 ml) extracted, washed with brine (50 ml) and dried (Na)₂SO₄) And concentrated. Through normal phase SiO₂Chromatography (7% to 60% EtOAc/hexanes) to afford 2-cyano-2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Methyl acetate (730 mg, 80%, found M/z: 277.1[ M + Na ]]⁺) As a white solid.

Intermediate 3:2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Acetonitrile

To a pre-dissolved solution of KOH (441 mg, 7.87 mmol) in ethylene glycol (20 ml) was added 2-cyano-2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Methyl acetate (1.09 g, 3.93 mmol). The mixture was heated to 120 ℃ for 3 hours and then cooled. Addition of H₂O (50 ml), with Et₂O (3X 50 ml) extraction of the product with H₂Washed with O (50 ml) and washed with Na₂SO₄Dried, filtered and concentrated. Purification by normal phase SiO2 chromatography (5 to 40% EtOAc/hexanes) to give 2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Acetonitrile (450 mg, 78%, found M/z: 219.1[ M + H ]]⁺) As a colorless oil.

Intermediate 4:2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Ethan-1-amines

To 2- [4- (4-fluorophenyl) oxacyclohex-4-yl in anhydrous ether (15 ml) at 0 deg.C]To a solution of acetonitrile (450 mg, 2.05 mmol) was added LAH (1.0M in ether, 4.1ml, 4.11 mmol) dropwise. After 2 hours the reaction was run with 1ml H₂O, 0.1mL15% NaOH then 1mL H₂And quenching O. With Et₂O (3X 20 ml) extraction of the reaction mixture over Na₂SO₄Drying and concentrating to obtain 2- [4- (4-fluorophenyl) oxacyclohex-4-yl]Eth-1-amine as a yellow oil, which was used without further purification (450 mg, 94%, found M/z:223.1[ M + H ]]⁺）。

Example 2:benzyl ({2- [4- (4-fluorophenyl) oxacyclohex-4-yl)]Ethyl }) amine (Compound 8)

At room temperature to the anhydrous CH₂Cl₂2- [4- (4-fluorophenyl) oxacyclohex-4-yl group in (5 ml)]Ethan-1-amine (250 mg,1.12 mmol) and Na₂SO₄To a solution of (159 mg,1.12 mmol) was added benzaldehyde (0.17 ml,1.68 mmol). The reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 5ml MeOH at 0 ℃ and NaBH was added in one portion₄(51 mg,1.34 mmol). The reaction was stirred at 0 ℃ for 1 hour. Then the solution is taken with H₂Quenching with O (10 ml) and CH₂Cl₂(3X 20 ml), washed with brine (10 ml) and washed with Na₂SO₄And drying. Through normal phase SiO₂Chromatography (0 to 10% MeOH/CH)₂Cl₂) Purification to give benzyl ({2- [4- (4-fluorophenyl) oxacyclohex-4-yl)]Ethyl }) amine (2)00mg, 60%, found m/z: 314.2[ M + H]⁺) As a colorless oil.

Intermediate 5:2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-ol

In N₂Next, n-butyllithium (26.3 ml, 1.6M in hexane, 42 mmol) was added dropwise to a solution of 4-bromotoluene (7.70 g, 45 mmol) in THF (100 ml) at-78 ℃. The resulting mixture was stirred at-78 ℃ for 30 minutes and a solution of tetrahydro-2, 2-dimethyl-4H-pyran-4-one (3.84 g, 30 mmol) in THF (20 ml) was added. The resulting mixture was stirred at-78 ℃ for an additional 20 minutes and quenched by addition of MeOH (10 ml). The reaction was concentrated in vacuo and the resulting residue was diluted with EtOAc (500 mL) and saturated NH₄Cl (250 ml), brine (250 ml) washed, dried and concentrated to give 2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-ol as a white solid which was used without further purification (5.41 g, 82%).

¹H NMR(400MHz,CDC13)δ7.36-7.26(m,2H),7.11(d,J=8.0,2H),4.10(td,J=12.0,2.2,1H),3.71(ddd,J=11.8,5.0,2.1,1H),2.28(s,3H),2.11(ddd,J=13.7,12.2,5.0,1H),1.72(dt,J=14.2,8.3,2H),1.58(dq,J=13.8,2.2,1H),1.44(s,3H),1.38(s,1H),1.14(s,3H)。

Intermediate 6:2, 2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxacyclohexane

Allyltrimethylsilane (4.34 ml,27.2 mmol) was added to the solution in dry CH at 0 deg.C₂Cl₂(100 ml) to a solution of 2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-ol (3.0 g,13.6 mmol) was added BF₃-OEt₂(3.42 ml,27.2 mmol). The resulting mixture was stirred at 0 ℃ for 1 hour. Will react with H₂Quenching with O and CH₂Cl₂Diluted (10 ml) and saturated NaHCO₃(20 ml), washed with brine (20 ml), dried and concentrated. Through normal phase SiO₂Chromatography (5 to 40% EtOAc/hexanes)Purification afforded 2, 2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxacyclohexane as a colorless oil, which was used as crude (2.49 g, 75%).

Intermediate 7:2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Acetaldehyde

At-78 deg.C, adding O₃Gas passing at CH₂Cl₂A solution of 2, 2-dimethyl-4- (4-methylphenyl) -4- (prop-2-en-1-yl) oxacyclohexane (1.21 g,5 mmol) in (50 ml) was added until the solution turned pale blue (about 5 min). After a further 5 minutes, the reaction mixture was purged with oxygen for 15 minutes before triphenylphosphine (2.62 g, 10 mmol) was added. The reaction was stirred at room temperature for 4 hours and concentrated. Through normal phase SiO₂Chromatography (10 to 60% EtOAc/hexanes) afforded 2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Acetaldehyde (641 mg, 52%) as a colorless oil.

¹H NMR(400MHz,CDC13)δ9.42-9.27(m,1H),7.26(dd,J=9.9,8.0,2H),7.20(t,J=8.7,2H),3.94-3.75(m,2H),2.69(dd,J=14.6,2.5,1H),2.51-2.38(m,2H),2.35(s,3H),2.26(dd,J=13.9,2.3,1H),1.84(ddd,J=14.3,11.0,4.6,1H),1.76(d,J=13.9,1H),1.23(s,3H),0.73(s,3H)。

Example 3:{2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Ethyl } [ (3-methylphenyl) methyl]Amine (Compound 32)

Will be in CH₂Cl₂2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] in (3 ml)]A mixture of acetaldehyde (61.6 mg, 0.25 mmol), 3-methylbenzylamine (63. mu.l, 0.5 mmol) and acetic acid (50. mu.l, 8.6 mmol) was stirred at room temperature for 1 hour, followed by addition of sodium triacetoxyborohydride (106 mg, 0.50 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated and dissolved in MeOH and purified by HPLC to give {2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl }]Ethyl } [ (3-methylphenyl) methyl]Amine (35 mg, 40%, found M/z:352.3[ M + H]⁺) Is a white solid。

Intermediate 8:2-cyano-2- [ (9Z) -6-oxaspiro [4.5]]Decane-9-ylidene]Acetic acid methyl ester

A100 ml round bottom flask equipped with a Dean-Stark distillation apparatus and condenser was charged with 6-oxaspiro [4.5]]Decan-9-one (6 g, 39mmol, prepared according to Hanschke, E.chem.Ber.1955,88,1053), methyl cyanoacetate (4.1 ml, 46.7 mmol), ammonium acetate (780 mg, 10.1 mmol), acetic acid (0.44 ml, 7.8 mmol) and benzene (40 ml). The mixture was refluxed until no more water was collected in Dean-Stark (2 hours), cooled, benzene (30 ml) was added and the organic layer was washed with water (50 ml). By CH₂Cl₂The aqueous layer was extracted (3 x50 ml). With saturated NaHCO₃The combined organic phases were washed (100 ml), brine (100 ml) and dried (MgSO)₄) Filtered and concentrated. Through normal phase SiO₂Purification by chromatography (7% to 60% EtOAc/hexanes) afforded 2-cyano-2- [ (9Z) -6-oxaspiro [4.5]]Decane-9-ylidene]Methyl acetate (8.93 g, 97.5%, found M/z235.1[ M + H ]]⁺) As a colorless oil.

Replacement of 6-oxaspiro [4.5] with 2, 2-diethyloxacyclohex-4-one]Decan-9-one, preparation of 2-cyano-2- [ (4Z) -2, 2-diethyloxacyclohex-4-ylidene by the procedure used for the preparation of intermediate 8]Methyl acetate (found M/z237.1[ M + H ]]⁺）。

With 1-oxaspiro [5.5 ]]Replacement of 6-oxaspiro [4.5] by undecan-4-one]Decan-9-one preparation of 2-cyano-2- [ (4Z) -1-oxaspiro [5.5 ] by the procedure used for the preparation of intermediate 8]Undec-4-ylidene]Methyl acetate (found M/z249.1[ M + H ]]⁺）。

Intermediate 9:2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetic acid methyl ester

A round-bottom flask fitted with a condenser, addition funnel and rubber septum with nitrogen inlet was charged with a solution of 4-fluoromagnesium bromide (2.0M in ether, 7.5ml, 12.5 mmol) and CuI (200 mg, 1.0 mmol) in 35ml of dry ether. When in an ice bathWhile the reaction flask was cooled, 2-cyano-2- [ (9Z) -6-oxaspiro [4.5] in diethyl ether (35 ml) was placed]Decane-9-ylidene]Methyl acetate (2.5 g, 10.5 mmol) was added dropwise over 30 minutes. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was poured into a mixture of 25g ice/1N HCl (20 ml). With Et₂The product was O (3X 50 ml) extracted, washed with brine (50 ml) and dried (Na)₂SO₄) And concentrated. Through normal phase SiO₂Chromatography (8% to 60% EtOAc/hexanes) afforded 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate (3.24 g, 93%, found M/z331.2[ M + H ]]⁺) As a colorless oil.

With 2-cyano-2- [ (4Z) -2, 2-diethyloxacyclohex-4-ylidene]Methyl acetate instead of 2-cyano-2- [ (9Z) -6-oxaspiro [4.5]]Decane-9-ylidene]Methyl acetate, prepared by the procedure described for the preparation of intermediate 9, 2-cyano-2- [2, 2-diethyl-4- (4-fluorophenyl) oxacyclohex-4-yl]Methyl acetate (found M/z333.2[ M + H ]]⁺）。

With 2-cyano-2- [ (4Z) -1-oxaspiro [5.5 ]]Undec-4-ylidene]Methyl acetate instead of 2-cyano-2- [ (9Z) -6-oxaspiro [4.5]]Decane-9-ylidene]Methyl acetate, preparation of 2-cyano-2- [4- (4-fluorophenyl) -l-oxaspiro [5.5 ] by the procedure described for the preparation of intermediate 9]Undec-4-yl]Methyl acetate (found M/z345.2[ M + H ]]⁺）。

Intermediate 10:2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile

To a pre-dissolved solution of KOH (l.lg, 19.5 mmol) in ethylene glycol (50 ml) was added 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate (3.24 g,9.8 mmol). The mixture was heated to 120 ℃ for 3 hours and then cooled. Water (50 ml) was added and Et used₂O (3X 50 ml) extraction of the product with H₂O (50 ml) wash in Na₂SO₄Dried, filtered and concentrated. Through normal phase SiO₂Chromatography (7% to 60% EtOAc/hexanes) afforded 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro[4.5]Decan-9-yl]Methyl acetate (1.96 g, 73%, found M/z273.2[ M + H ]]⁺）。

Separation of 1.96g of the enantiomer by SFC on an AD-3 column using 15% MeOH (0.05% DEA) as modifier gave 2- [ (9S) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile as colorless oil (faster eluting enantiomer, 635mg, 24%, found M/z274.2[ M + H ]]⁺) And 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile as colorless oil (slower eluting enantiomer, 703mg, 26%, found M/z273.2[ M + H ]]⁺）。

With 2-cyano-2- [2, 2-diethyl-4- (4-fluorophenyl) oxacyclohex-4-yl]Methyl acetate instead of 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate, preparation of 2- [2, 2-diethyl-4- (4-fluorophenyl) oxacyclohex-4-yl by the procedure described for the preparation of intermediate 10]Acetonitrile (found m/z275.2[ + H [ + ]]⁺）。

With 2-cyano-2- [4- (4-fluorophenyl) -1-oxaspiro [5.5]Undec-4-yl]Methyl acetate instead of 2-cyano-2- [9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate, preparation of 2- [4- (4-fluorophenyl) -l-oxaspiro [5.5 ] by the procedure described for the preparation of intermediate 10]Undec-4-yl]Acetonitrile (found M/z287.2[ M + H ]]⁺）。

Intermediate 11:2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethan-1-amines

To 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] in anhydrous ether (30 ml) at 0 deg.C]Decan-9-yl]A solution of acetonitrile (500 mg,1.8 mmol) was added dropwise LAH (in Et)₂1.0M in O, 3.7ml, 3.7 mmol). The reaction was then warmed to room temperature. After 2 hours the reaction was run with 1ml H₂O, 0.2ml of 15% NaOH and then 1ml of H₂And quenching O. The reaction mixture was washed with Et₂O (3X 30 ml) in Na₂SO₄Drying and concentrating to obtain 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethan-1-amine as a yellow oil which is not further purifiedUsed as received (500 mg, 100%, found M/z277.2[ M + H ]]⁺）。

With 2- [2, 2-diethyl-4- (4-fluorophenyl) oxacyclohex-4-yl]Acetonitrile instead of 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile preparation of 2- [2, 2-diethyl-4- (4-fluorophenyl) oxacyclohex-4-yl via the procedure described for the preparation of intermediate 11]Ethan-1-amine (found M/z.279.2[ M + H ]]⁺）。

With 2- [4- (4-fluorophenyl) -1-oxaspiro [5.5 ]]Undec-4-yl]Acetonitrile instead of 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile preparation of 2- [4- (4-fluorophenyl) -1-oxaspiro [5.5 ] by the procedure described for the preparation of intermediate 11]Undec-4-yl]Ethan-1-amine (found M/z.291.2[ M + H ]]⁺）。

Example 4:benzyl ({2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl }) amine (Compound 81)

At room temperature to the anhydrous CH₂Cl₂2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5] in (6 ml)]Decan-9-yl]Ethan-1-amine (100 mg, 0.361 mmol) and Na₂SO₄To the solution (256 mg, 1.80 mmol) was added benzaldehyde (0.055 ml; 0.541 mmol). The reaction was stirred overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 6ml MeOH at 0 ℃ and NaBH was added in one portion₄(16 mg,0.433 mmol). The reaction was stirred at 0 ℃ for 1 hour. Then using H₂O (20 ml) quench solution with CH₂Cl₂(3X 30 ml), washed with brine (10 ml) and washed with Na₂SO₄And drying. Purification of the mixture by HPLC gave benzyl ({2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl }) amine (121 mg, 92%, found M/z368.3[ M + H ]]⁺) As a white solid.

Intermediate 12:2, 2-diethyloxacyclohex-4-ol.

To 3-buten-1-ol (19.8 ml; 233 mmol) and 3-pentanone (12.3 ml; 116 mmol) at 0 deg.CTo the mixture of (1), (2), (334) 75% sulfuric acid (19.8; 334 mmol; prepared by diluting 79ml of concentrated sulfuric acid to 100ml with distilled water) was added dropwise. The reaction was warmed to room temperature and stirred overnight. Water (70 ml) was added to the mixture and then neutralized with NaOH (pellet) to pH8 and extracted with ether (3 x150 ml). The ether extract was washed with aqueous sodium bisulfite (40 ml) and washed at K₂CO₃Dried and the ether evaporated under vacuum. The residue was distilled under reduced pressure to give 2, 2-diethyloxacyclohex-4-ol (4.89 g,27%, B.Pt.65-70 ℃ C. at 1mm Hg).

¹H NMR(400MHz,CDCl3)δ4.04-3.86(m,1H),3.84-3.66(m,1H),3.65-3.38(m,1H),2.06-1.95(m,1H),1.92-1.76(m,2H),1.78-1.63(m,1H),1.63-1.50(m,1H),1.51-1.31(m,3H),1.28-1.10(m,1H),0.92-0.68(m,6H)。

Intermediate 13:2, 2-Diethyloxacyclohex-4-ones

To be in CH₂Cl₂To a solution of crude 2, 2-diethyloxacyclohex-4-ol (500 mg, 3.2 mmol) in (10 ml) was added NMO (750 mg, 6.41 mmol) and 4A molecular sieves (2 g). The solution was stirred for 30 minutes, then TPAP (34 mg, 0.096 mmol) was added in one portion. The reaction was allowed to stir for 10 hours. After checking TLC, ethanol was removed. Passing it through SiO₂Filtering with a short pad. The filtrate was concentrated and passed through normal phase SiO₂Chromatography (0% to 50% EtOAc/hexanes) afforded 2, 2-diethyloxacyclohex-4-one (365 mg, 73%).

¹H NMR(400MHz,CDC13)δ3.75-3.66(m,2H),3.44-3.29(m,2H),2.51-2.31(m,4H),1.25-1.4(m,4H),0.75(m,6H)。

Intermediate 14:2- (magnesium bromide) pyridine

Into a flask was placed 2.0M isopropylmagnesium chloride in THF (6 mL, 12 mmol) and added dropwise in anhydrous Et₂2-bromopyridine (1.2 mL, 12 mmol) in O (4 mL). The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was used as a 1M Grignard solution (Grignard sol)ution）。

Example 5:dibenzyl ({2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [ 4.5)]Decan-9-yl]Ethyl }) amine (Compound 225)

At room temperature to the anhydrous CH₂Cl₂(3 ml) and Na₂SO₄(92.3 mg,0.65 mmol) of 2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]To a solution of acetonitrile (30 mg, 0.13 mmol) was added 2.3 equivalents of benzaldehyde (0.032 ml,0.32 mmol); the reaction was stirred overnight. Add NaBH (OAc) in one portion₃(6.6 mg,0.31 mmol). Then the solution is taken with H₂Quenching with O (10 ml) and CH₂Cl₂(3X 20 ml), washed with brine (10 ml) and washed with Na₂SO₄And drying. The solvent was evaporated in vacuo and the residue was purified by HPLC to give dibenzyl ({2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl }) amine (37.4 mg, 50%, found M/z458.3[ M + H ]]⁺）。

Example 6:{2- [ (9R) -9- (4-fluorophenyl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl } { (3-methylphenyl) methyl]Amine (Compound 122)

Following a similar procedure to that described for compound 81, compound 122 (slower moving fraction on AD-3 column) was obtained from the corresponding intermediate after chiral HPLC separation. The absolute configuration of compound 122 (ex.122) was determined by X-ray crystallography.

Example 7:{2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl } [2- (pyridin-3-yl) ethyl]Amine (Compound 75)

To 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] in 7mL of toluene at-78 deg.C]Decan-9-yl]A solution of acetonitrile (350 mg, 1.4 mmol) in toluene (3.0 ml, 3 mmol) was added dropwise to a solution of 1.0M DIBAL. The resulting mixture was stirred at-78 ℃ until completion (1.5 h). The reaction was then quenched with 5 equivalents of MeOH (0.28 mL) and 0.1mL of water, heated while stirring, and 175mg addedNa₂SO₄Stirring was carried out at room temperature for 2 hours to give 310mg (80%) of 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Acetaldehyde. Measured value LCMS M/z250.6(M + 1).

To 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Acetaldehyde (50 mg, 0.19 mmol), 5mL DCM and Na₂SO₄(134 mg, 0.95 mmol) to the solution was added 2- (pyridin-3-yl) ethan-1-amine (31 mg, 0.25 mmol) and the reaction was stirred overnight. Adding NaBH₄(9.5 mg, 0.25 mmol), stirred for 10 min, 2 drops of MeOH added, stirred for 1 h, quenched with water, the organic layer separated and evaporated. The residue was subjected to Gilson reverse phase HPLC to give {2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl } [2- (pyridin-3-yl) ethyl]Amine, 65.3mg (71%). Measured value LCMS M/z367.1(M + 1).

Example 8:2- [ (9R) -9- (2- {4H,5H, 6H-thieno [2, 3-c)]Pyrrol-5-yl } ethyl) -6-oxaspiro [4.5]Decan-9-yl]Pyridine (Compound 82)

To 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] in dry ACN (5.8 mL)]Decan-9-yl]Ethyl-1-amine (0.030 g, 0.115 mmol; prepared by the sequence described for Compound 81) to a stirred solution was added 2, 3-bis (bromomethyl) thiophene (31.1 mg, 0.115 mmol) followed by K₂CO₃(79.62 mg,0.576 mmol). After 30 min LCMS showed the reaction was complete and the major peak was the corresponding mass of the desired product. It was then subjected to HPLC purification. HPLC purification method: luna acid medium column in H₂10-50% acetonitrile in O for 15 min, followed by 100% acetonitrile, 0.1% TFA modifier was used. Fractions containing the desired product were combined, basified with 2N NaOH and extracted with DCM (3 × 20 mL). The combined organic layers were concentrated and purified by flash chromatography (10 g silica gel column, eluted with 0-10% MeOH in DCM, measured by TLC: DCM/MeOH (10/1) Rf = 0.60) to give 5mg2- [ (9R) -9- (2- {4H,5H, 6H-thieno [2,3-c ])]Pyrrol-5-yl } ethyl) -6-oxaspiro [4.5]Decan-9-yl]Pyridine as colorless oil in 12% yield. Found LCMS M/z369(M + 1).

Example 9:{2- [9- (lH-pyrazol-l-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl } (thien-2-ylmethyl) amine (compound 26)

Placing a drying flask with a Dean-Stork device and a condenser in a nitrogen atmosphere₂Cooling down to room temperature under reduced pressure and charging 6-oxaspiro [4.5]]Decan-9-one (0.50 g, 3.24 mmol), (tert-butoxy) carbohydrazide (0.42 g, 3.24 mmol) and hexane (10 mL). The resulting solution was heated to reflux overnight.

It was cooled to room temperature and the solid was collected by vacuum filtration. The solid was washed with hexane and air dried to give (tert-butoxy) -N' - [ (9Z) -6-oxaspiro [4.5] decan-9-ylidene ] carbohydrazide (0.84 g, 96% yield). Measured value LCMS M/z213(M + 1-tert-butyl).

The oven-dried flask was charged with (tert-butoxy) -N' - [ (9Z) -6-oxaspiro [4.5]]Decane-9-ylidene]Carbohydrazide (0.42 g, 1.56 mmol) and THF. The solution was cooled to 0 ℃ and allylmagnesium chloride (2.0M, 1.60 mL) was added dropwise. The reaction was stirred at 0 ℃ for 1 hour and warmed to room temperature overnight. LC-MS indicated that the reaction did not proceed to completion. An additional 2 equivalents of allyl magnesium chloride were added at room temperature. The solution was stirred for 1 hour and then quenched with MeOH. With DCM (60 mL) and H₂The solution was diluted O (20 mL). A number of precipitates formed and the solid was filtered through a pad of Celite. The organic layer was then separated and the aqueous layer was extracted with 10mL EtOAc. The combined organic layers were concentrated and the residue was purified on a 25g Snap column (0-20% EtOAc in hexane, 12 CV) to give (tert-butoxy) -N' - [9- (prop-2-en-1-yl) -6-oxaspiro [4.5]]Decan-9-yl]Carbohydrazide (0.33 g, 68% yield). Measured LCMS M/z333(M + Na).

To a solution of (tert-butoxy) -N' - [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] decan-9-yl ] carbohydrazide (0.33 g, 1.06 mmol) in 4mL EtOAc was added 4M HCl in dioxane at room temperature. The solution was stirred at room temperature until the reaction was complete by LC-MS (30 hours). The solvent was then removed to give [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] decan-9-yl ] hydrazine (250 mg). Measured value LCMS M/z211.1(M + 1).

To [9- (prop-2-en-1-yl) -6-oxaspiro [4.5] in 4mL of i-PrOH (isopropanol)]Decan-9-yl]Et was added to a solution of hydrazine (250 mg, 1.0 mmol)₃N and 3-dimethylaminoacrolein. The solution was refluxed for 3 hours and then at 50 ℃ for two days. The solvent was removed and the residue purified on a 25g Biotage snap column, eluting with 0-18% EtOAc in hexane (12 CV) to give 1- [9- (prop-2-en-l-yl) -6-oxaspiro [4.5]]Decan-9-yl]-lH-pyrazole (80 mg, 31% yield). Found LCMS M/z247.1(M + 1).

To 1- [9- (prop-2-en-l-yl) -6-oxaspiro [4.5] in DCM (5 mL) at-78 deg.C]Decan-9-yl]-lH-pyrazole (80 mg, 0.32 mmol) in solution by O₃Bubbling was continued until the solution turned blue. The resulting solution is treated with N₂Bubbling for 5 minutes. Adding PPh thereto₃(168 mg, 0.64 mmol). And the solution was stirred at room temperature for 4 hours. After removal of the solvent, the residue was purified by flash column chromatography to give 2- [9- (lH-pyrazol-1-yl) -6-oxaspiro [4.5]]Decan-9-yl]Acetaldehyde (15 mg, 23% yield). Measured value LCMS M/z249(M + 1).

2- [9- (lH-pyrazol-1-yl) -6-oxaspiro [4.5] at room temperature]Decan-9-yl]A mixture of acetaldehyde (15 mg, 0.06 mmol) and thiophen-2-ylmethylamine (19 uL,0.18 mmol) was stirred for 1 hour, after which NaBH (OAc) was added₃(25.4 mg, 12 mmol). The solution was stirred overnight. After removal of the solvent, the residue was purified by HPLC to give {2- [9- (lH-pyrazol-1-yl) -6-oxaspiro [4.5 [)]Decan-9-yl]Ethyl } (thiophen-2-ylmethyl) amine (17 mg, 61% yield) as a TFA salt. Measured value LCMS M/z346(M + 1).

Example 10: the basic procedure for the preparation of the compound of the formula:

according to scheme 8, 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] in the presence of an organic solvent (i.e., DCM, MeOH, EtOH, etc.)]Decan-9-yl]Ethan-1-amine (which can be prepared by following the sequence described for compound 81 (compound 4) and in analogy to the sequence for intermediate 11) is reacted with an appropriately substituted heteroaromatic aldehyde or an appropriately substituted aromatic aldehyde (1 equivalent) to form the corresponding imine, which is reduced by a suitable reducing agent to give the compound. (R)_nAnd R_mRefers to optional substituents. In addition, the phenyl group may be replaced with other rings or aryl groups described herein.

Example 11: the basic procedure for the preparation of the compound of the formula:

according to scheme 9, 9-1, (which can be prepared by following the sequence described for compound 81 (compound 4) and similar to the sequence for intermediate 11) is reacted with an appropriately substituted heteroaryl aldehyde or an appropriately substituted aryl aldehyde (1 equivalent) in the presence of an organic solvent (i.e. DCM, MeOH, EtOH, etc.) to form the corresponding imine, which is reacted with an appropriate reducing agent (i.e. NaBH)₄) Reducing to obtain the compound. (R)_nAnd R_mRefers to optional substituents. In addition, the phenyl group may be replaced with other rings or aryl groups described herein.

Example 12: opioid receptor ligands

The opioid receptor ligands and compounds listed in the following tables may be prepared or prepared from suitable starting materials and suitable reagents according to the procedures described above. The compounds which have been prepared are listed with NMR data and prophetic examples are not listed with NMR data.

Example 13: opioid receptor ligands

The following compounds in table 2 can also be prepared from suitable starting materials and suitable reagents according to the procedures described above, which can be expected to also have similar properties and therapeutic effects to the other compounds described herein. In addition to the specific structures shown, other isomers or enantiomers are included in the description herein. The compounds which have been prepared list NMR data and the prophetic examples do not.

Table 2: examples with chemical name and/or characterization data

Example 14: opioid receptor ligands

The following compounds in table 3 can also be prepared from suitable starting materials and suitable reagents according to the procedures described above, which can be expected to also have similar properties and therapeutic effects to the other compounds described herein. In addition to the specific structures shown, other isomers or enantiomers are included in the description herein. The compounds which have been prepared list NMR data and the prophetic examples do not.

Table 3: opioid receptor ligands

Example 15: synthesis of [ (3-methoxythien-2-yl) methyl ] ({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl }) amine (Compound 140).

2-cyano-2- [ 6-oxaspiro [4.5] decan-9-ylidene ] acetic acid methyl ester (mixture of E and Z isomers)

6-oxaspiro [4.5] in benzene (75 ml) in a 250ml round bottom flask fitted with Dean-Stark and reflux condenser]A mixture of decan-9-one (13.74 g,89.1 mmol), methyl cyanoacetate (9.4 ml, 106.9 mmol), ammonium acetate (1.79 g, 26.17 mmol) and acetic acid (1.02 ml, 17.8 mmol) was heated at reflux. 3After h, TLC (25% EtOAc in hexanes, PMA staining) showed the reaction was complete. After cooling, benzene (50 ml) was added and the layers were separated, the organic layer was washed with water (120 ml) and CH₂Cl₂The aqueous layer was extracted (3 x120 ml). With saturated NaHCO₃The combined organic phases were washed with brine, dried and concentrated, and the residue was purified by flash chromatography (340 g silica gel column, eluting with EtOAc in hexane: 5% EtOAc, 2 CV; 5-25%, 14 CV; 25-40%, 8 CV) to give a mixture of E and Z isomers: 2-cyano-2- [ 6-oxaspiro [4.5]]Decane-9-ylidene]Methyl acetate (18.37 g, 87.8% yield; found M/z236.0[ M + H ]]⁺) It was a clear oil.

2-cyano-2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] acetic acid methyl ester

At 0 ℃ under N₂A solution of 2-bromopyridine (14.4 ml,150 mmol) in THF (75 ml) was added dropwise to a solution of isopropylmagnesium chloride (75 ml, 2M in THF), then the mixture was stirred at room temperature for 3 hours, ketone iodide (2.59 g,13.6 mmol) was added and allowed to stir at room temperature for another 30 minutes, then 2-cyano-2- [ 6-oxaspiro [4.5] in THF (60 ml) was added over 30 minutes]Decane-9-ylidene]Methyl acetate (16 g, 150 mmol) in a mixture of E and Z isomers. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was poured into a mixture of 200g ice/2N HCl (100 ml). The product is taken up in Et₂O (3X 300 ml), washed with brine (200 ml) and dried (Na)₂SO₄) And concentrated. The residue was purified by flash chromatography (100 g silica gel column, eluting with EtOAc in hexane: 3%2 CV; 3-25%, 12 CV; 25-40%6 CV) to give 2-cyano-2- [9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate (15.44 g, 72% yield, found M/z315.0[ M + H ]]⁺) As an amber (amber) oil.

2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] acetonitrile

Ethylene glycol (300 ml) was added to 2-cyano-2- [9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Methyl acetate (15.43 g, 49 mmol) and then potassium hydroxide (5.5 g, 98 mmol) were added and the resulting mixture was heated to 120 ℃ for 3 hours, after which the reaction mixture was cooled and water (300 ml) was added and used with Et₂The product was extracted with O (3X 400 ml), washed with water (200 ml) and dried (Na)₂SO₄) And concentrated and the residue purified by flash chromatography (340 g silica gel column, eluting with EtOAc in hexanes: 3%2 CV; 3-25%, 12 CV; 25 to 40 percent, 6 CV) to obtain 2- [9- (pyridine-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Acetonitrile (10.37 g, 82% yield, found M/z257.0[ M + H)]⁺）。

2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] acetonitrile

Separation of racemic 2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] by chiral HPLC column under the following preparative-SFC conditions]Decan-9-yl]Acetonitrile: the instrument comprises the following steps: SFC-80 (thumb, Waters); column: chiralpak AD-H (Daicel); column temperature: 40 ℃; mobile phase: methanol/CO₂= 40/60; flow rate: 70 g/min; back pressure: 120 bar; cycle time of stack injection (stack injection): 6.0 minutes; load per injection: 225 mg; under these conditions, 2- [9- (pyridin-2-yl) -6-oxaspiro [4.5] is isolated]Decan-9-yl]Acetonitrile (4.0 g) to afford the desired isomer, 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [ 4.5%]Decan-9-yl]Acetonitrile (2.0 g of acetonitrile,>99.5% enantiomerExcess) as a slow moving fraction. The absolute (R) configuration of the desired isomer is determined by subsequent X-ray crystal structure analysis of compound 140.

2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethan-1-amine

At 0 ℃ under N₂Next, LAH (in Et)₂1M in O, 20ml, 20 mmol) was added to the solution in Et₂2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] in O (100 ml, 0.1M)]Decan-9-yl]Acetonitrile (2.56 g, 10 mmol). The resulting mixture was stirred and allowed to warm to room temperature. After 2 hours LCMS showed the reaction was complete. The reaction was cooled to 0 ℃ and quenched with water (1.12 ml), NaOH (10%, 2.24 ml) and another 3.36ml of water. The solid was filtered and the filter pad was washed with diethyl ether (3 × 20 ml). The combined organic phases were dried and concentrated to give 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethan-1-amine (2.44 g, 94% yield, found M/z260.6[ M + H ]]⁺) As a light amber colored oil.

Alternatively, 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethan-1-amine was prepared by Raney nickel catalysed hydrogenation.

An autoclave vessel (autoclave vessel) was charged with 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4,5] decan-9-yl ] acetonitrile and ammonia (7N solution in methanol). The resulting solution was stirred at ambient conditions for 15 minutes and treated with Raney 2800 nickel and slurried in water. The vessel was pressurized with nitrogen to 30psi and briefly agitated. The autoclave was vented and the nitrogen purge repeated two additional times. The vessel was pressurized with hydrogen to 30psi and briefly agitated. The vessel was vented and purged two additional times with hydrogen. The vessel was pressurized to 85-90psi with hydrogen and the mixture was heated to 25-35 ℃. The internal temperature was raised to 45-50 ℃ in 30-60 minutes. The reaction mixture was stirred at 45-50 ℃ for 3 days. The reaction was monitored by HPLC. Once the reaction was deemed complete, it was cooled to room temperature and filtered through Celite. The filter cake was washed with methanol (2 ×). The combined filtrates were concentrated under reduced pressure at 40-45 ℃. The resulting residue was co-evaporated with EtOH (3X) and dried to a thick slurry of 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl-1-amine.

[ (3-Methoxythiophen-2-yl) methyl ] ({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl }) amine

To a vial was added 2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethan-1-amine (500 mg, 1.92 mmol), 18mL CH₂Cl₂And sodium sulfate (1.3 g,9.6 mmol). 3-Methoxythiophene-2-carboxaldehyde (354 mg,2.4 mmol) was then added and the mixture was stirred overnight. Reacting NaBH₄(94 mg,2.4 mmol) was added to the reaction mixture, stirred for 10 min, then MeOH (6.0 mL) was added, stirred for 1 h, and finally quenched with water. The organics were separated and evaporated. The crude residue was purified by gilson preparative HPLC. The desired fractions were collected and concentrated, lyophilized. After lyophilization, in CH₂Cl₂And 2N NaOH, and the organic layer was collected. After concentrating the solvent to half volume, add in Et₂1.0 equivalent of 1N HC1 in O, and the bulk of the solvent was evaporated under reduced pressure. The solid obtained is used in Et₂O is washed several times and dried to provide [ (3-methoxythiophen-2-yl) methyl group]({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5]]Decan-9-yl]Ethyl }) amine monohydrochloride (336 mg, 41% yield, found M/z387.0[ M + H.sub.]⁺) As a white solid. NMR of compound 140 is described herein.

Example 16: biological examples

Procedure for testing the anti-pain Effect

The hotplate assay adapts the procedure originally described by O' Callaghan and Holtzman (JPET,192,497,1975) and is commonly used to determine the potential analgesic efficacy of opioid agonists. The analgesic effect of the compositions in the heating plate described herein is expressed as MPE% (maximum possible effect).

Rats (175-250 g) or mice (20-30 g) were acclimated to the zoo for at least 48 hours prior to behavioral testing. The test drug was administered by the Subcutaneous (SC) route. The animals were placed on a hot plate set at 50-56 ℃. Depending on the in vitro potency of the compound. A cut-off time of 30-60 seconds was used depending on the temperature of the hot plate so that the paw of the animal exhibiting analgesia was not damaged by the thermal stimulus. The cut-off time is considered to be 100% response to the thermal stimulus. Each animal was tested to determine baseline response prior to drug treatment. Thirty minutes after dosing, animals were again tested. Dose response experiments were performed to evaluate the efficacy of the test compounds when various doses were given at the time points where maximal analgesia was observed.

Calculate% MPE according to the formula: % MPE = [ (post drug latency) -baseline latency)/(60 or 30-baseline latency) ] x 100.

ED50 values were calculated from the mean% MPE values of each group by least squares regression analysis using dose-response log curves.

TABLE 4

Compound (I)	ED50 or% MPE
		Morphine (morphine)	3.8mg/kg SC
Compound 81	100% in 10mg/kg SC
		Compound 122	1.1mg/kg SC
Compound 28	1.2mg/kg SC
		Compound 145	5.9mg/kg SC

The results are shown in table 4. Naive or control mice typically exhibit a 10-15 second reaction time in a hot plate. The ED50 for morphine in the mouse hot plate was 3.8mg/kg, with full efficacy observed at a dose of 10mg/kg SC. For control, compound 122 and compound 28 produced potential therapeutic effects with ED50 of 1.1 and 1.2mg/kg SC, respectively. These results indicate that compound 122 and compound 28 produced a greater analgesic effect in the mouse hot plate assay than morphine.

Example 17: administration to humans in vivo (prophetic examples)

One or more compounds are administered to a human subject at a dose ranging from 0.15mg to 4 mg. The compound was administered as a continuous infusion over one hour. The dosage can be increased to obtain pain relief when deemed appropriate. The increase in dosage compared to the previous dose is usually not more than 5 fold. However, the dosage may be repeated or reduced as deemed appropriate. Subjects were tested for their ability to tolerate or experience no pain as compared to the control (placebo) group.

Cold pain tests have been demonstrated to be a reproducible and sensitive measure of the effect of opioids and other centrally acting drugs (Van F and road PE. the utility of the cold pain test from the organic in vivo. Br. J. Clin. Pharmacol. 1996; 42: 663. 664; Posner J. Pain Models in health volumes. in: Nimmo WS, Tucker G, edge. clinical laboratory in Drug evaluation.1991, Wolfe publication Limited, UK.; Wolsonon HA, Kenny GNC, McArdle. analytical impact of control of surgery, III. Pharmacologne. 1991; thermal impact of Controlled-Release-Drug, III. J. 1988; gradient J. Press J. 35. 9. Press J. blend. 12. and J. blend. 12. 9. the first publication of the Drug discovery. Ab et al. J. the Cold pain test is a reproducible and sensitive measure of the effects of opioids of drugs J. 9. the Drug effects of the Drug delivery. In the test, the hands of the subjects were immersed in cold water frozen in the range of 1 to 3 ℃. The initial cold sensation of the hand is replaced by the discomfort of deep burning, mediated by nociceptors in the veins. Discomfort gradually builds up until a plateau period of about 90 seconds elapses, and then remains or decreases slightly. The stimulus is easily controlled and the response is repeatable. This technique has proven to be sensitive to varying doses of analgesics.

During the cold pain test, the subject will sit down and place his/her non-dominant hand in a stirred, thermostatically controlled water bath at about 2 ℃. The subject can adjust the visual analog scale on the computer screen with the other hand using the arrow keys on the keypad. One end of the scale is marked as "no pain" and the other end is "maximum pain". The pointer will initially be at the "painless" end and the subjects will move the pointer across the line to continuously rate their sensation over the trial period. At the end of the 2 minutes, the computer will automatically instruct the subject to remove his/her hands, which can then be dried. The cold pain test has been widely used in healthy volunteer studies and is non-invasive.

It is expected that administration of the compound will enable the human subject to feel no pain or less pain compared to the control group.

While the compounds 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.

All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference in their entirety, including, but not limited to, U.S. provisional application No. 61/596,808 filed on 9/2/2012, and U.S. provisional application No. 61/466,809 filed on 23/3/2011.

Claims (75)

1. A compound having the structure of formula IV-1:

wherein:

R₂₁and R₂₂Independently is H or CH₃；

A₄Is of the formula C (CH)₂)_nWherein n = 2-5;

B₃is H or optionally substituted alkyl;

B₄is C₁-C₆An alkyl group;

D₁is optionally substituted aryl; and is

B₅Is an optionally substituted aryl group.

2. The compound of claim 1, having the structure of formula VII-1:

wherein R is₂₆And R₂₇Independently H or an isotope thereof.

3. The compound of claim 2, wherein the compound has the structure of formula IX

4. The compound of claim 2, wherein said compound has the structure of formula VII-1

5. The compound of claim 2, wherein the compound has the structure of formula X

6. The compound of claim 1, wherein D1 is optionally substituted phenyl or optionally substituted pyridyl.

7. The compound of claim 1, wherein B₅Is an optionally substituted heteroaryl.

8. The compound of claim 1, wherein B₅Is an optionally substituted aryl selected from the group consisting of:

9. the compound of claim 1, wherein B₅Is an optionally substituted aryl selected from the group consisting of:

wherein R is₂₃、R₂₄And R₃₀Each independently is absent, H, OH, cyclic, aryl, branched or unbranched alkyl alcohol, halogen, branched or unbranched alkyl, amide, cyano, alkoxy, haloalkyl, alkylsulfonyl, nitrite, alkylsulfanyl; or, R₂₃And R₂₄Together form a connection to B₅Aryl or cyclic group of one or more atoms of (a); and R is₂₅Is H, or optionally substituted branched or unbranched alkyl.

10. The compound of claim 9, wherein，R₂₃、R₂₄And R₃₀Each independently is H, NH₂、OH、Cl、Br、F、I、OMe、CN、CH₃Phenyl, C₃-C₆Carbocyclic ring, methylsulfonyl, CF₃、Wherein R is₂₉Is H or optionally substituted branched or unbranched alkyl.

11. The compound of claim 9, wherein B₅Is that

12. The compound of claim 9, wherein B₅Is that

13. The compound of claim 11, wherein R₂₃Is an alkoxy group.

14. The compound of claim 11, wherein R₂₄Is H.

15. The compound of claim 11, wherein R₂₃Is methoxy.

16. The compound of claim 1, wherein B₃Is H or C₁-C₅An alkyl group.

17. The compound of claim 1, having the structure

18. A compound having the structure of formula I:

wherein:

A₁selected from the group consisting of: absent, CH₂、CHR₁、CR₁R₂、CH、CR₁、O、S、SO、SO₂NH and NR₁；

A₂Selected from the group consisting of: absent, CH₂、CHR₅、CR₅R₆、CH、CR₅、O、S、SO、SO₂NH and NR₅；

A₃Selected from the group consisting of: absent, CH₂、CHR₇、CR₇R₈、O、S、SO、SO₂、NH、NR₇CH and CR₇；

A₄Selected from the group consisting of: absent, CH₂Formula C (CH)₂)_nWherein n =2-5, CHR₉、CR₉R₁₀、O、S、SO、SO₂、NH、NR₉CH and CR₉；

A₅Selected from the group consisting of: absent, CH₂、CHR₁₁、CR₁₁R₁₂、CH₂CH₂、CHR₁₁CH₂、CH₂CHR₁₁、CHR₁₁CHR₁₂、O、S、SO、SO₂、NH、NR₁₁CH and CR₁₁；

B₁Selected from the group consisting of: CH (CH)₂、CHR₁₃、CR₁₃R₁₄、O、S、SO、SO₂、NH、NR₁₃、CR₁₃And CO;

B₂selected from the group consisting of: CH (CH)₂、CHR₁₅、CR₁₅R₁₆、CR₁₅And CO;

B₃selected from the group consisting of: H. alkyl, branched alkyl, halogenated alkyl, aryl, alkylaryl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl;

B₄selected from the group consisting of: absence, C₁-C₆Alkyl radical, CH₂、CH₂CH₂、CHR₁₉、CR₁₉R₂₀And CO;

B₅selected from the group consisting of: alkyl, branched alkyl, halogenated alkyl, carbocycle-substituted alkyl, aryl, carbocycle, and arylalkyl;

D₁is aryl or a ring;

R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₉and R₂₀Independently selected from the group consisting of: cyano, halogen, hydroxy, alkoxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl, and alkoxycarbonyl;

wherein A is₁、A₂、A₃、A₄And A₅No more than 2 of the 5 may be simultaneously absent,

wherein A is₁、A₂、A₃、A₄、A₅The number of middle heteroatoms cannot exceed 2 at the same time;

wherein A is₁、A₂、A₃、A₄And A₅The bond between cannot be S-O, S-S, or S-N; and is

Wherein alkyl is a linear carbon chain having 1 to 10 carbon atoms; wherein the ring is non-aromatic;

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

Wherein the following compounds are excluded:

1)2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

2)2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl-2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

3) {2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

4){2-[(4S^*,4R^*) -2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Ethyl } [ (1R) -1-phenylethyl]Amines as pesticides

5){2-[(4S^*,4R^*) -2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl]Ethyl } [ (1S) -l-phenylethyl)]Amines as pesticides

6) Benzyl ({2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl }) amine

7)2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

8) Benzyl [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

9) {2- [ 2-Ethyl-4- (4-fluorophenyl-2-methyloxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

10) [ (3, 4-Dimethoxyphenyl) methyl ] ({2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

11) {2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } (l-phenylethyl) amine

12) [ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

13) Benzyl ({2- [ 2-ethyl-4- (2-methoxyphenyl) -2-methyloxacyclohex-4-yl ] ethyl }) amine

14) [ (3, 4-Dimethoxyphenyl) methyl ] ({2- [ 2-ethyl-4- (2-methoxyphenyl) -2-methyloxacyclohex-4-yl ] ethyl }) amine

15)4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline

16) Benzyl ({2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

17) {2- [2, 2-dimethyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } (l-phenylethyl) amine

18) [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (4-methoxyphenyl) methyl ] amine

19) {2- [4- (4-fluorophenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } [ (4-methoxyphenyl) methyl ] amine

And

20) [ (3, 4-Dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

19. The compound of claim 18, wherein said aryl or cyclic group has 1-3 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N and S.

20. The compound of claim 18 or 19, wherein each aryl or each cyclic group is independently substituted with one or more substituents selected from the group consisting of: 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、OCF₃Methoxycarbonyl, methylsulfonyl, Ph, benzyl, formyl, and acetyl.

21. The compound of any one of claims 18-20, wherein each aryl is independently selected from the group consisting of:

22. the compound of any one of claims 18-21, wherein said ring is selected from the group consisting of:

wherein X in the ring₁And X₂Independently selected from the group consisting of O, S, N, NH, and NR₁₈Wherein R is₁₈Selected from the group consisting of: cyano, halogen, hydroxy, alkoxy, alkyl, branched alkyl, halogenated alkyl, branched halogenated alkyl, aryl, arylalkyl, carbocycle-alkyl, alkylcarbonyl, branched alkylcarbonyl, halogenated alkylcarbonyl, branched halogenated alkylcarbonyl, arylcarbonyl, and alkoxycarbonyl.

23. The compound of any one of claims 18-23, wherein a₂And A₄Connected by a carbon bridge.

24. The compound of claim 23, wherein said bridge comprises-CH₂-or-CH₂CH₂-。

25. The compound of any one of claims 18-24, wherein, when attached to D₁When carbon of (A) is fused with other rings, A₁、A₂、A₃、A₄、A₅Forming a ring selected from the group consisting of: benzene, pyridine, pyrimidine, furan, thiophene and pyridazine.

26. The compound of claim 25, wherein A is₁、A₂、A₃、A₄、A₅The rings formed are independently multiply substituted with a member of the group consisting of: cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, formyl, acetyl, amino, alkylamino, dialkylamino, thiol, and alkylthiol.

27. The compound of any one of claims 18-26, wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₈、R₁₉And R₂₀Independently selected from the group consisting of: F. cl, Br, CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃N-propyl, n-butyl, isobutyl, sec-butyl, isopropyl, tert-butyl, CN, OH, OCH₃、OCH₂CH₃O-isopropyl, methoxycarbonyl, phenyl, benzyl, CHO, and COCH₃。

28. The compound of any one of claims 18-27, wherein R₁And R₂、R₅And R₆、R₇And R₈、R₉And R₁₀、R₁₁And R₁₂、R₁₃And R₁₄、R₁₅And R₁₆、R₁₉And R₂₀Or R₁₅And R₁₉Independently form a single ringOr a heterocyclic ring.

29. The compound of any one of claims 18-28, wherein each aryl is independently multiply substituted with a group selected from: cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthiol, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, cyclic or cyclic alkyl.

30. The compound of any one of claims 18-29, wherein each ring is independently multiply substituted with a group selected from: cyano, halogen, alkyl, branched alkyl, halogenated alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, thiol, alkylthiol, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, arylalkyl, cyclic or cyclic alkyl.

31. The compound of any one of claims 18-30, wherein a₁And A₂、A₂And A₃、A₃And A₄、A₄And A₅、A₅And A₆、A₆And A₁And A₆And A₇Independently a single or double bond.

32. Root of herbaceous plantThe compound of any one of claims 18-31, wherein a₁And A₂、A₂And A₃、A₃And A₄、A₄And A₅、A₅And A₆、A₆And A₁And A₆And A₇Are not simultaneously double bonds.

33. The compound of any one of claims 18-32, wherein R₁、R₂、R₅、R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₈、R₁₉And R₂₀Independently selected from the group consisting of: F. cl, Br, CH₃、CH₂CH₃、CH₂F、CHF₂、CF₃N-propyl, n-butyl, isobutyl, sec-butyl, isopropyl, tert-butyl, CN, OH, OCH₃、OCH₂CH₃O-isopropyl, methoxycarbonyl, phenyl, benzyl, formyl, and acetyl.

34. A compound having the structure of formula II:

wherein:

A₂selected from the group consisting of: CH (CH)₂、CHR₅And CR₅R₆；

A₄Selected from the group consisting of: CH (CH)₂、CHR₉、CR₉R₁₀And formula C (CH)₂)_nWherein n = 2-5;

R₅、R₆、R₉and R₁₀Independently selected from the group consisting of: CH (CH)₃、CH₂CH₃、CH₂F、CHF₂、CF₃n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl;

B₃selected from the group consisting of: H. alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl;

B₄selected from the group consisting of: absent, CH₂、CHR₁₉、CR₁₉R₂₀And CO;

B₅selected from the group consisting of: alkyl, branched alkyl, carbocycle-substituted alkyl, aryl and arylalkyl; and is

D₁Is an aryl group.

35. The compound of claim 34, wherein each aryl is independently substituted with one or more of: 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、NMe₂Methoxycarbonyl, methanesulfonyl, Ph, benzyl, formyl and acetyl.

36. The compound of claim 34, wherein N is not directly attached to a heteroatom.

37. The compound of claim 34, wherein R₅And R₆Or R₉And R₁₀Forming a monocyclic carbocyclic ring.

38. The compound of claim 34, wherein a₂And A₄Connected by a carbon bridge.

39. The compound of claim 38, wherein said bridge comprises-CH₂-or-CH₂CH₂-。

40. The compound of claim 34, wherein each aryl or ring independently has 1-3 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N and S, are unsubstituted or substituted with substituents selected from the group consisting of: 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、OCF₃Methoxycarbonyl, methylsulfonyl, Ph, benzyl, formyl, and acetyl.

41. The compound of claim 34, wherein said each aryl is independently selected from the group consisting of:

42. a compound having the structure of formula III:

wherein:

A₂selected from the group consisting of: CH (CH)₂、CHR₅And CR₅R₆；

A₄Selected from the group consisting of: CH (CH)₂、CHR₉、CR₉R₁₀And formula C (CH)₂)_nWherein n = 2-5;

R₅、R₆、R₉and R₁₀Independently selected from the group consisting of: CH (CH)₃、CH₂CH₃、CH₂F、CHF₂、CF₃n-Pr, n-Bu, i-Bu, sec-Bu, i-Pr, t-Bu and phenyl;

B₃selected from the group consisting of: H. alkyl, branched alkyl, aryl, arylalkyl, alkylcarbonyl, branched alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, and alkylsulfonyl;

B₄selected from the group consisting of: absent, CH₂、CHR₁₉、CR₁₉R₂₀And CO;

B₅selected from the group consisting of: alkyl, branched alkyl, carbocycle-substituted alkyl, aryl and arylalkyl; and is

D₁Is an aryl group.

43. The compound of claim 42, wherein each aryl is independently substituted with one or more of: 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、NH₂NHMe and NMe₂Methoxycarbonyl, methylsulfonyl, Ph, benzyl, formyl, or acetyl.

44. The compound of claim 43, wherein N is not directly attached to a heteroatom.

45. A compound according to claim 42, wherein R₅And R₆Or R₉And R₁₀Forming a monocyclic carbocyclic ring.

46. The compound of claim 42, wherein A₂And A₄Connected by a carbon bridge.

47. The compound of claim 46, wherein said bridge comprises-CH₂-or-CH₂CH₂-。

48. The compound of claim 42, wherein said aryl and/or cyclyl has 1-3 heteroatoms, wherein said heteroatoms are selected from the group consisting of O, N and S.

49. The compound of claim 48, wherein each aryl and/or cyclic group is independently substituted with one or more of: 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、OCF₃Methoxycarbonyl, methylsulfonyl, Ph, benzyl, formyl, and acetyl.

50. The compound of claim 42, wherein each aryl is independently selected from the group consisting of:

51. a compound having the structure of formula IV-1, IV-2, or IV-3:

wherein R is₂₁And R₂₂Independently is H or CH₃；

A₄Selected from the group consisting of: CH (CH)₂、CR₉R₁₀And formula C (CH)₂)_nWherein n = 2-5;

R₉and R₁₀Independently is CH₃Or CH₂CH₃；

B₃Is H, CH₃Or is- (CH)₂)_nCH₃Wherein n = 2-3;

B₄selected from the group consisting of: absent, CH₂、C₁-C₆Alkyl radical, CH₂CH₂or-CHCH₃；

B₅Selected from the group consisting of: - (CH)₂)_nCH₃Wherein n =2-3, -C (CH)₃)₃Cyclohexyl, cyclopentyl, aryl, and arylalkyl;

D₁is phenyl or 2-pyridyl, wherein the phenyl or 2-pyridyl can be replaced by F, Cl, Br, CF₃、OCF₃And CH₃Members of the group consisting are independently single or multiple substituted; and is

Wherein the aryl group is selected from the group consisting of:

52. the compound of claim 51, wherein each aryl group,Phenyl, or 2-pyridyl, is substituted with one or more of the following independently: F. cl, Br, CH₃、CN、OH、OMe、OEt、CF₃、OCF₃Or a methanesulfonyl group.

53. A compound having the structure of formula V-1, V-2, V-3, VI-1, VI-2, or VI-3:

wherein D is₁Is an optionally mono-or multiply-substituted aryl group;

B₅is an optionally mono-or multiply-substituted aryl or carbocycle;

wherein aryl is selected from the group consisting of:

and is

Wherein the carbocycle is cyclohexyl, cyclohexenyl or cyclopentyl.

54. A compound according to claim 53, wherein D₁Independently an optionally mono-or multiply-substituted phenyl group, a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group.

55. A compound according to claim 53 or 54, wherein D₁Optionally using F, Cl, Br, I, OCF₃、CH₃Or CF₃Independently substituted.

56. A compound according to claim 53 or 54, wherein D₁Is unsubstituted.

57. The compound of any one of claims 53-56, wherein B₅Independently optionally mono-or multiply-substituted

58. The compound of any one of claims 53-57, wherein B₅Independently by one or more of: cl, Br, F, I, OMe, CN, CH₃、CF₃Or a methanesulfonyl group.

59. The compound of any one of claims 53-58, wherein B₅Independently by two or more of: cl, Br, F, I, OMe, CN, CH₃、CF₃Or a methanesulfonyl group.

60. A compound selected from the group consisting of:

[ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine;

[ (3, 4-dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine;

2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol;

[2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (2-fluorophenyl) methyl ] amine;

4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline;

2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol; and

[ (3-methoxythiophen-2-yl) methyl ] ({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl }) amine.

61. A compound having the structure:

62. a pharmaceutical composition comprising one or more compounds of any one of claims 1-61 and a pharmaceutically acceptable carrier.

63. The pharmaceutical composition of claim 62, further comprising at least one additional analgesic or non-opioid analgesic.

64. The pharmaceutical composition of claim 62 or 63, further comprising at least one additional anti-constipation agent.

65. A method of treating pain comprising administering to a subject or a subject in need thereof a compound according to any one of claims 1-61 or a composition according to any one of claims 62-64.

66. A method as claimed in claim 65, wherein said compound is selected from the group consisting of:

[ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine;

[ (3, 4-dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine;

2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol;

[2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (2-fluorophenyl) methyl ] amine;

4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline;

2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol; and

[ (3-methoxythiophen-2-yl) methyl ] ({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl }) amine.

67. The method of claim 65 or 66, wherein two or more of said compounds are administered.

68. The method of any one of claims 65-67, wherein said compound and additional analgesic are co-administered simultaneously or sequentially.

69. The method of any one of claims 65-68, wherein the compound and anti-constipation agent are co-administered simultaneously or sequentially.

70. A process for preparing a compound of any one of claims 1-61 comprising

71. A method of treating pain comprising administering to a subject in need thereof a therapeutically effective amount of one or more of the following compounds:

[ (4-chlorophenyl) methyl ] ({2- [4- (4-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl }) amine

[ (3, 4-Dimethoxyphenyl) methyl ] [2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] amine

2- [ ({2- [ 2-ethyl-2-methyl-4- (4-methylphenyl) oxacyclohex-4-yl ] ethyl } amino) methyl ] phenol

[2- (2, 2-dimethyl-4-phenyloxacyclohex-4-yl) ethyl ] [ (2-fluorophenyl) methyl ] amine

4- [ ({2- [4- (2-methoxyphenyl) -2, 2-dimethyloxacyclohex-4-yl ] ethyl } amino) methyl ] -N, N-dimethylaniline

2- [ ({2- [ 2-ethyl-4- (4-fluorophenyl) -2-methyloxacyclohex-4-yl ] ethyl } amino) methyl ] phenol; and

[ (3-methoxythiophen-2-yl) methyl ] ({2- [ (9R) -9- (pyridin-2-yl) -6-oxaspiro [4.5] decan-9-yl ] ethyl }) amine.

72. A compound or composition according to any one of claims 1-64, for use in the prevention or treatment of pain in a mammal.

73. A compound or composition according to any one of claims 1-64, for use in the manufacture of a medicament for preventing or treating pain in a mammal.

74. Use of any compound or composition of any one of claims 1-64 for preventing or treating pain in a mammal.

75. Use of any compound or composition of claims 1-64 in the manufacture of a medicament for preventing or treating pain in a mammal.