Hepoxilin analogs, methods, uses, and processes for preparation thereof

Abstract

The present disclosure relates to synthesis of hepoxilin cyclopropane analogs of Formula I: Formula (I), uses, methods, and pharmaceutical compositions thereof. Said hepoxilin cyclopropane analogs are useful for the treatment of diseases and conditions, such as cancer, thromboxane-mediated diseases, cardiovascular diseases, inflammation, fibrosis, analgesia, and for modulating intracellular calcium concentration.

Description

HEPOXILIN ANALOGS, METHODS, USES, AND PROCESSES FOR PREPARATION THEREOF FIELD

[0001] The present disclosure relates to hepoxilin analogs, methods, uses, and processes for preparation thereof. BACKGROUND

[0002] Hepoxilins (Hx) are a set of epoxyalcohol metabolites of polyunsaturated fatty acids (PUFA) that possess both an epoxide and hydroxyl moiety. Hepoxilins are generally derived from arachidonic acid via the lipoxygenase pathway. Generally, there are two types of natural hepoxilins derived from arachidonic acid and are mainly distinguished by the position of their hydroxyl group. The two types include: A-type hepoxilins, consisting of two epimers having a hydroxyl group at carbon 8, i.e.8(S, R) - hydroxy - 11(S), 12(S) - epoxyeicosa - 5Z, 9E, 14Z - trienoic acid; and the B- type, consisting of two epimers having a hydroxyl group at carbon 10, i.e.10(S / R) – hydroxy – 11(S), 12(S) – epoxyeicosa – 5Z, 8Z, 14Z – trienoic acid.

[0003] Hepoxilins may be formed wherever 12-lipoxygenase is present because 12- HPETE (an intermediate) is actively transformed into the hepoxilins by a variety of ferriheme proteins. For example, ferriprotoporphyrin and such containing groups in proteins may catalyze this transformation. Trihydroxy metabolites derived from Hepoxilins may be formed by platelets. Hepoxilins were isolated in rat lung, rat pancreatic islets, aorta and human neutrophils. Hepoxilin B3 has been isolated from marine red algae and hepoxilin A3 has been detected in the Aplysia brain.

[0004] Reviews on hepoxilin formation, synthesis and biological actions have been published. Hepoxilin analogs from unsaturated fatty C18 and C20 acids with various number and position of double bonds, have also been identified.

[0005] Previously described synthetic methods of hepoxilin analogs typically involved cyclopropanation of an allylic alcohol to obtain an intermediate that was used in further transformations. Such methods often suffer from challenges that may prevent or hinder scale-up, such as low yields over one or several steps. Thiiranoanalogs of hepoxilins may be synthesized by direct treatment of the epoxide in A-type hepoxilins with potassium thiocyanate (KSCN), thus yielding desirable thiiranes. Unfortunately, such methods typically only allow access to such analogs from allyl- activated epoxide of A-type hepoxilins.

[0006] There exists a need in the art to address one or more of the deficiencies discussed herein.

[0007] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present disclosure. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present disclosure. SUMMARY

[0008] The present disclosure relates to hepoxilin analogs and more particularly to the synthesis of cyclopropane analogs of hepoxilins (PBT) and to methods of treatment and pharmaceutical compositions employing the individual diastereomers of hepoxilin cyclopropane analogs.

[0009] In an aspect of the present disclosure, there is provided preparation methods of the hydroxy trans-cyclopropyl-containing intermediates. The preparation methods are scalable, and allow for analogs of hepoxilins to be obtained with improved product yield and improved purity.

[0010] In an aspect, a new synthetic method of analogs of hepoxilins (PBTs), such as cyclopropyl analogs, is provided. In accordance with a further aspect, there is provided a synthesis of compounds of general formula I: R25wherein:X is O, CH2, NH, S, N-C1-C6alkyl, (CH2)n, or (CH2)mY1, wherein n = 2, 3, or 4; Y1 is S, NH, or O, and m is 1, 2, or 3; R2 is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H; R3is C4-C10alkyl, C4-C10alkenyl, or C4-C10alkynyl; R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, saturated or unsaturated C1-C4 alcohol, 6-membered aryl, or Y2-R1; wherein the aryl is optionally -(CH2)n-phenyl, wherein n is 1 to 9, wherein Y2 is C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, and said Y2 is optionally substituted by -OH and / or halogen, wherein R1 is OH, halogen, N3, NH2, COOR4 or CONHR4, wherein R4 is H, C1-C6 alkyl, 5-6 membered cycloalkyl, 5-6 membered aryl, carbohydrate group; preferably R4 is CH3, H, or C1- C10 alkyl which can be substituted by COOH or 5-6 membered heterocycle; and Dotted line ( ) is a single, double or triple bond.

[0011] In some aspects, compounds of formula I have the following structure: X is CH2; R2is OH, H, halogen, C1-C6 alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H; R3 is C4-C10 alkyl, C4-C10 alkenyl, or C4-C10 alkynyl; R5 is C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, or Y2-R1, wherein Y2 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, the Y2optionally substituted with - OH and / or halogen; R1 is COOR4 or CONHR4, wherein R4 is H, CH3, 5-6-membered aryl, carbohydrate; and Dotted line ( ) is a single, double or triple bond.

[0012] In some aspects, compounds of formula I have the following structure: X is CH2; R2 is OH;R3is C4-C10alkenyl; Y2-R1, wherein Y2 is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, the Y2 optionally substituted with -OH and / or halogen; R1is COOR4, wherein R4is C1-C10alkyl; and Dotted line ( ) is a double bond.

[0013] According to an aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula III: (III) the process comprising:coupling a compound having formula 2: (2), with a suitable protecting.

[0014] In some aspects, the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0015] According to a further aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 3: ,the process comprising: coupling a compound having formula 2: ,with p-methoxybenzyl chloride.

[0016] According to a further aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula IV: (IV), the process comprising:reacting a compound having formula (III): (III), with: i) I2, PPh3, and a base;iodide; or iii) methanesulfonyl chloride and sodium iodide.

[0017] In some aspects, the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

[0018] According to a further aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 4: ,the process comprising: reacting a compound having formula (3): ,with: i) I2, PPh3, and a base; ii) p-toluenesulfonyl chloride and sodium iodide, or iii) methanesulfonyl chloride and sodium iodide.

[0019] In some aspects, the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

[0020] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula V: , the processreacting 1-heptyne with a metalation agent to yield a first mixture; and reacting a compound having formula (IV): (IV), with the first mixture.

[0021] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0022] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 5: ,the process reacting 1-heptyne with a metalation agent to yield a first mixture; and reacting a compound having formula (4): ,with the first mixture.

[0023] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0024] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 6: , the process comprising:deprotecting a compound having formula V: , via a deprotecting

[0025] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

[0026] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 6: ,the process comprising: deprotecting a compound having formula 5: ,via DDQ.

[0027] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 7: , the process comprising:oxidizing a compound having formula 6: , with an oxidizing

[0028] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0029] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 8: ,the process reacting a compound having formula 7: ,with a second mixture comprising propargyl chloride and a metalation agent.

[0030] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0031] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula X: , reacting a, with a third mixture(IX),CuI, NaI, and a base.

[0032] In some aspects, the base is K2CO3.

[0033] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 10: ,reacting a ,with a third mixture comprising a compound of formula 9:CuI, NaI, and a base.

[0034] In some aspects, the base is K2CO3.

[0035] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula XI: O , the process comprising:partially hydrogenating a compound having formula X: , using a

[0036] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0037] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula XII:O OAlkyl , the process comprising:partially hydrogenating a compound having formula X: , using a

[0038] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0039] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 11: O ,the process comprising: partially hydrogenating a compound having formula 10: ,using a hydrogenation agent.

[0040] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0041] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 12: O O , the process comprising:partially hydrogenating a compound having formula 10: , using a

[0042] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0043] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 13: O ,the process comprising: hydrolyzing a compound having formula 11:O O , in basic conditions.

[0044] In some aspects the basic conditions comprise methanol / water and a base. In further aspects, the base is sodium hydroxide, lithium hydroxide or potassium hydroxide.

[0045] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 14: O ,the process comprising: hydrolyzing a compound having formula 12: O ,in basic conditions.

[0046] In some aspects the basic conditions comprise methanol / water and a base. In further aspects, the base is sodium hydroxide, lithium hydroxide, or potassium hydroxide.

[0047] According to an aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula XI: O , the process comprising:coupling a compound having formula 2: (2), with a suitable protectinghaving formula III: (III);reacting the i) I2, PPh3, and a first base; ii) p-toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide, to yield a compound having formula IV: ;reacting the compound having formula (IV) with a first mixture comprising 1- heptyne with a metalation agent to yield a compound having formula V: ;deprotecting the compound having formula V via a deprotecting agent to yield a compound having formula 6: ; oxidizing theagent to yield a compound having formula 7: ; reacting themixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ; reacting thecomprising a compound of formula IX: , CuI, NaI, and a secondformula X:a hydrogenation agent to yield the compound having formula XI.

[0048] In some aspects, the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0049] In some aspects, the first base is imidazole.

[0050] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0051] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

[0052] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0053] In some aspects, the second base is K2CO3.

[0054] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0055] According to an aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula XII: O , the process comprising:coupling a compound having formula 2: ,with a suitable protecting group a having formula III: ;reacting the compound having formula (III) with: i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide to yield a compound having formula IV: ;reacting the compound having formula (IV) with a first mixture comprising 1- heptyne with a metalation agent to yield a compound having formula V: ; deprotectingagent to yield a compound having formula 6: ; oxidizing theagent to yield a compound having formula 7: ; reacting themixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ; reacting thea comprising a compound of formula IX: (IX), CuI, NaI, and a second base, to yield a compound having formula X:partially hydrogenating the compound having formula X using a hydrogenation agent to yield the compound having formula XII.

[0056] In some aspects, the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0057] In some aspects, the first base is imidazole.

[0058] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0059] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

[0060] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0061] In some aspects, the second base is K2CO3.

[0062] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0063] According to an aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 11: O , the process comprising:coupling a compound having formula 2: ,with p-methoxybenzyl chloride to yield a compound having formula 3: ,reacting the compound having formula 3 with: i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to yield a compound having formula 4: , reacting themixture comprising 1- heptyne with a metalation agent to yield a compound having formula 5: ,agent to yield a compound having formula 6: ; oxidizing theagent to yield a compound having formula 7: ;reacting the a mixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ;reacting the compound having formula 8 with a third mixture comprising a compound of formula 9: ,CuI, NaI, and a second base, to yield a compound having formula 10:hydrogenation agent to yield the compound having formula 11.

[0064] In some aspects, the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0065] In some aspects, the first base is imidazole.

[0066] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0067] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

[0068] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0069] In some aspects, the second base is K2CO3.

[0070] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0071] According to an aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a process for preparing a compound having formula 12: O , the process comprising:coupling a compound having formula 2:(2), with p-methoxybenzylhaving formula 3: , reacting thePPh3, and a first base; or ii) tosyl chloride and sodium iodide, to yield a compound having formula 4: , reacting themixture comprising 1- heptyne with a metalation agent to yield a compound having formula 5: ,agent to yield a compound having formula 6: ;oxidizing the an agent to yield a compound having formula 7: ;reacting the compound having formula 7 with a second mixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8:8); reacting the c ixture comprising a compound of formula 9: , CuI, NaI, and a second base,formula 10:hydrogenation agent to yield the compound having formula 12.

[0072] In some aspects, the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0073] In some aspects, the first base is imidazole.

[0074] In some aspects, the metalation agent is n-BuLi or EtMgBr.

[0075] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

[0076] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0077] In some aspects, the second base is K2CO3.

[0078] In some aspects, the hydrogenation agent is Lindlar catalyst.

[0079] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 4, or enantiomer thereof:4).

[0080] According to anot ure there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 5, or enantiomer thereof: .

[0081] is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 6, or enantiomer thereof: .

[0082] According tothere is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 7, or enantiomer thereof: .

[0083] According to there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 8, or enantiomer thereof: .

[0084] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 10, or enantiomer thereof:0).

[0085] Acc rovided, which may be used alone or in combination with any other aspects described herein, compounds having any one of formula 11, 12, 13 or 14 may be used in the treatment of pain or in the manufacture of a medicament for the treatment of pain.

[0086] According to yet another aspect of the present disclosure, there is provided, which may be used in combination with any other aspects described herein, compounds having any one of formula 11, 12, 13 or 14, may be used in the treatment of inflammation, cancer, diabetes, analgesia, cardiovascular disease, fibrosis, calcium- mediated diseases, and others.

[0087] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a method of treating, ameliorating, or preventing pain in a subject, the method comprising: administering a compound having formula 11: O ,or a pharmaceutically to

[0088] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a method of treating, ameliorating, or preventing pain in a subject, the method comprising: administering a compound having formula 12:O O , or a pharmaceutically

[0089] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a method of treating, ameliorating, or preventing pain in a subject, the method comprising: administering a compound having formula 11: O , or a pharmaceuticallyhaving formula 12: O ,or a pharmaceutically acceptable salt thereof, to the subject.

[0090] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, ananalgesic composition for treating, ameliorating, or preventing pain in a subject, the composition comprising: a compound having formula 11: O O , or a pharmaceuticallymore pharmaceutically acceptable carriers or excipients.

[0091] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, an analgesic composition for treating, ameliorating, or preventing pain in a subject, the composition comprising: a compound having formula 12: O ,or a pharmaceutically one or more pharmaceutically acceptable carriers or excipients.

[0092] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a use of a compound having formula 11:O O , or a pharmaceutically amelioration, orprevention of pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administration to the subject.

[0093] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a use of a compound having formula 12: O , or a pharmaceuticallyamelioration, or prevention of pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administration to the subject.

[0094] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a use of a compound having formula 11: O ,or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment, amelioration, or prevention of pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administration to the subject.

[0095] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a use of a compound having formula 12: O O , or a pharmaceuticallyof a medicament for the treatment, amelioration, or prevention of pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administration to the subject.

[0096] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 11: O , or a pharmaceuticallyameliorating, or preventing pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administrating to the subject.

[0097] According to another aspect of the present disclosure there is provided, which may be used alone or in combination with any other aspects described herein, a compound having formula 12:O O , or a pharmaceutically ameliorating, orpreventing pain in a subject, wherein the compound, or pharmaceutically acceptable salt thereof, is for administrating to the subject.

[0098] Other aspects and features of the disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific aspects and embodiments of the disclosure. This summary does not necessarily describe all features of the disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0099] Embodiments and aspects of the disclosure will now be described in greater detail with reference to the accompanying drawings, in which:

[0100] FIGURE 1 is a general scheme depicting synthesis of compounds 11 and 12;

[0101] FIGURE 2 is a general scheme depicting synthesis of compounds having formulae XI and XII;

[0102] FIGURE 3 is a general scheme depicting synthesis of compounds having formulae 13 and 14;

[0103] FIGURE 4 is a graph depicting effects of PBT-3 (11) and PBT-4 (12) on plantar mechanical pain threshold in surgical model rats; n=6, mean±SEM, *p<0.05, **p<0.01, ***p<0.001; and

[0104] FIGURE 5 depicts a mix of enantiomers that each form PBT-3 and PBT-4.DETAILED DESCRIPTION

[0105] One or more illustrative embodiments and aspects have been described by way of example. Described herein are compositions, processes and methods of preparation, and uses relating to hepoxilin analogs. It will be appreciated that embodiments, aspects, and examples are provided for illustrative purposes intended for those skilled in the art, and are not meant to be limiting in any way. All references to embodiments, examples, aspects, formulas, compounds, compositions, solutions, mixtures, and the like is intended to be illustrative and non-limiting.

[0106] Definitions

[0107] The term "compound" will be understood as referring to the compound and, in certain embodiments, to the extent they are stable, any hydrate or solvate thereof. A hydrate is the compound complexed with water, and a solvate is the compound complexed with a solvent, which may be an organic solvent or an inorganic solvent.

[0108] A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present disclosure are limited to stable compounds embraced by compounds as described herein, or pharmaceutically acceptable salts thereof.

[0109] The term "composition" as used herein is intended to encompass a specified compound in a specified amount, as well as any form that results directly or indirectly, from combination of a specified compound in a specified amount. Such term is intended to encompass a form comprising a compound 11 or 12, or a pharmaceutically acceptable salt of the foregoing, and one or more pharmaceutically acceptable carriers or excipients. Accordingly, the compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure and one or more pharmaceutically acceptable carrier or excipients. By "pharmaceutically acceptable", it is meant the carriers or excipients are compatible with the compound disclosed herein and with other ingredients of the composition.

[0110] The compounds of the present disclosure may be employed in the form of pharmaceutically acceptable salts. Those skilled in the art will recognize those instances in which the compounds of the disclosure may form salts. Examples of such compounds are described herein by reference to possible salts. Such reference is for illustration only. Pharmaceutically acceptable salts can be used with compounds for treating patients. Non-pharmaceutical salts may, however, be useful in the preparation of intermediate compounds.

[0111] The term "pharmaceutically acceptable salt" refers to a salt (including an inner salt such as a zwitterion) that possesses effectiveness similar to the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Thus, an embodiment of the disclosure provides pharmaceutically acceptable salts of the compounds of the disclosure. The term "salt(s)", as employed herein, denotes any of the following: acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Salts of compounds of the disclosure may be formed by methods known to those of ordinary skill in the art, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0112] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (also known as "mesylates"), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, p-toluenesulfonates (also known as “tosylates”) and the like. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.), Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal ofPharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International I of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website).

[0113] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, tert-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0114] Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present, pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0115] Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term "about", may include variations of + 1%, 2%, 3%, 4%, 5%, 10%, + 15%, and 20% and their numerical equivalents.

[0116] Compounds disclosed herein, pharmaceutically acceptable salts of the foregoing, can be administered by means that produces contact of the active agent with the agent's site of action. The compounds can be administered by conventional means available for use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. The compounds can be administered alone, but may be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0117] A composition comprising compounds disclosed herein, or a pharmaceutically acceptable salt of the foregoing, and one or more pharmaceutically acceptable carriers or excipients. The composition may be prepared and packaged in bulk form in which a therapeutically effective amount of a compound of the disclosure can be extracted and then given to a subject, such as with powders or syrups.

[0118] Alternatively, the composition may be prepared and packaged in unit dosage form in which each physically discrete unit contains a therapeutically effective amount of compounds disclosed herein, or a pharmaceutically acceptable salt of the foregoing.

[0119] The compounds disclosed herein, and a pharmaceutically acceptable carrier or excipient(s) may be formulated into a dosage form adapted for administration to a subject by a desired route of administration. For example, dosage forms may include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution.

[0120] Suitable pharmaceutically acceptable carriers or excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable carriers or excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable carriers or excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable carriers or excipients may be chosen for their ability to facilitate the carrying or transporting of a compound disclosed herein, once administered to the subject, from one organ or portion of the body to another organ or another portion of the body. Certainpharmaceutically acceptable carriers or excipients may be chosen for their ability to enhance patient compliance.

[0121] Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.

[0122] A skilled artisan possesses the knowledge and skill in the art to select suitable pharmaceutically acceptable carriers and excipients in appropriate amounts for the use in the compositions of the disclosure. In addition, there are a number of resources available to the skilled artisan, which describe pharmaceutically acceptable carriers and excipients and may be useful in selecting suitable pharmaceutically acceptable carriers and excipients. Examples include REMINGTON’S PHARMACEUTICAL SCIENCES (Mack Publishing Company), THE HANDBOOK OF PHARMACEUTICAL ADDITIVES (Gower Publishing Limited), and THE HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (the American Pharmaceutical Association and the Pharmaceutical Press). The compositions of the disclosure are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Company).

[0123] The terms "treating" or "treatment" of a disease or condition as used herein may include: preventing the disease or condition, i.e. causing the clinical symptoms of the disease or condition not to develop in a subject that may be exposed to or predisposed to the disease or condition but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0124] An “effective amount” of when used in connection with composition described herein is an amount sufficient to produce a therapeutic result in a subject in need thereof. For example, a therapeutic result can include, but isnot limited to, treating, ameliorating, or preventing pain in a subject. An “effective amount” when in used in connection with one or more of the agents disclosed herein is the total amount of one or more of the agents that is useful for the treatment, amelioration, or prevention of pain.

[0125] The term “about” means the referenced numeric indication plus or minus 10% of that referenced numeric indication.

[0126] As used herein, ''alkyl'' is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms unless otherwise specified. For example, C1-C10, as in "C1-C10 alkyl" is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear, branched, or cyclic arrangement. For example, "C1-C10 alkyl" specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.

[0127] If no number of carbon atoms is specified, the term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Thus, "C2-C6 alkenyl" means an alkenyl radical having from 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.

[0128] If no number of carbon atoms is specified, the term "alkynyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon triple bond. Thus, "C2-C6 alkynyl" means an alkynyl radical having from 2 to 6 carbon atoms with at least one triple bond. Alkynyl groups include ethynyl, propynyl, butynyl and cyclohexynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.

[0129] As used herein, “cyclo” is intended to mean any stable monocyclic or bicyclic carbon ring of at least three and up to 12 atoms in each ring. Examples of such elements include cycloalkanes, cycloalkenes, and cycloalkynes.

[0130] As used herein, “heterocyclo” is intended to mean any stable monocyclic or bicyclic carbon ring of at least three and up to 12 atoms in each ring and at least one heteroatom, such as O, N, or S. Examples of such elements include heterocycloalkanes, heterocycloalkenes, and heterocycloalkynes.

[0131] As used herein, ''aryl'' is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0132] The term "heteroaryl”, as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrdazinyl, pyrdopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.

[0133] As appreciated by those of skill in the art, "halo" or ''halogen'' as used herein is intended to include chloro, fluoro, bromo and iodo.

[0134] As appreciated by those of skill in the art, the term “carbohydrate group” as used herein refers to any suitable carbohydrate group such as, but not limited to, glucose, galactose, glucosamine, or galactosamine moieties.

[0135] The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and may occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention, unless specified otherwise. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.

[0136] Embodiments of the current disclosure

[0137] Disclosed herein are synthetic methods and processes for preparation of cyclopropyl analogs of hepoxilins (PBTs). For example, there is provided a synthesis of compounds of general formula I: R25Formula (I) wherein: X is O, CH2, NH, S, N-C1-C6alkyl, (CH2)n, or (CH2)mY1, wherein n = 2, 3, or 4; Y1 is S, NH, or O, and m is 1, 2, or 3; R2 is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H; R3is C4-C10alkyl, C4-C10alkenyl, or C4-C10alkynyl; R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, saturated or unsaturated C1-C4alcohol, 6-membered aryl, or Y2-R1; wherein the aryl is optionally -(CH2)n-phenyl, wherein n is 1 to 9, wherein Y2is C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl,and said Y2is optionally substituted by -OH and / or halogen, wherein R1is OH, halogen, N3, NH2, COOR4 or CONHR4, wherein R4 is H, C1-C6 alkyl, 5-6 membered cycloalkyl, 5-6 membered aryl, carbohydrate group; in some cases R4is CH3, H, or C1-C10 alkyl which can be substituted by COOH or 5-6 membered heterocycle; and Dotted line ( ) is a single, double or triple bond.

[0138] In some embodiments, compounds of formula I have the following structure: X is CH2; R2is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H; R3 is C4-C10alkyl, C4-C10alkenyl, or C4-C10alkynyl; R5 is C1-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, or Y2-R1, wherein Y2 is C1- C10alkyl, C2-C10alkenyl, C2-C10alkynyl, the Y2optionally substituted with -OH and / or halogen; R1 is COOR4 or CONHR4, wherein R4 is H, CH3, 5-6-membered aryl, carbohydrate; and Dotted line ( ) is a single, double or triple bond.

[0139] In some aspects, compounds of formula I have the following structure: X is CH2; R2 is OH; R3 is C4-C10 alkenyl; Y2-R1, wherein Y2is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, the Y2optionally substituted with -OH and / or halogen; R1 is COOR4, wherein R4 is C1-C10 alkyl; and Dotted line ( ) is a double bond.

[0140] Exemplary synthetic schemes for compounds of formula I, such as PBT-3, PBT-4, PCA-3, and PCA-4, are set forth in Figs.1, 2, and 3.

[0141] As shown therein, commercially available trans-dimethyl 1,2- cyclopropanedicarboxylate 1 (B0) [CAS 826-35-7] may be a source of the cyclopropane moiety of compounds 11, 12, XI and XII. trans-dimethyl 1,2- cyclopropanedicarboxylate 1 may be a mixture of enantiomers, such as a racemic mixture.

[0142] In step 1, reduction of compound 1 (B0) may be carried out with a suitable reducing agent, such as lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis(2-methoxyethoxy) aluminium hydride (Red-Al), lithium borohydride, lithium triethylborohydride, or diborane-dimethylsulfide complex, to give trans-cyclopropane-1,2-diyldimethanol 2 (B1).

[0143] In step 2, one of the hydroxyl groups in the symmetrical compound 2 (B1) may be protected with a suitable protecting group. Although p-methoxybenzyl is depicted as the protecting group, others may be used, such as tert-butyldimethylsilyl-, tert-butyldiphenylsilyl- and others. Protecting compound 2 with p-methoxybenzyl yields trans-(2-{[(4-methoxybenzyl)oxy]methyl}cyclopropyl)methanol 3 (B2).

[0144] In step 3, the hydroxyl group in compound 3 (B2) is exchanged to an iodo moiety by treating with I2-in the presence of PPh3and imidazole, or by obtaining corresponding p-toluenesulfonate and treating with sodium iodide, or by obtaining methanesulfonate with sodium iodide, leading to trans-1-({[2- (iodomethyl)cyclopropyl]methoxy}methyl)-4-methoxybenzene 4 (B3). A person of skill in the art will understand that a p-toluenesulfonate or methanesulfonate are examples of suitable leaving groups for the subsequent substitution reaction.

[0145] In step 4, iodide 4 (B3) is treated with 1-heptyne in THF-HMPA, employing n-BuLi or EtMgBr as an agent for metalation, giving trans-1-methoxy-4- {[(2-oct-2-yn-1-ylcyclopropyl)methoxy]methyl}benzene 5 (B4).

[0146] In step 5, compound 5 (B4) is treated with a suitable deprotecting agent, such as DDQ to cleave p-methoxybenzyl moiety, or treated with n-Bu4NF, or Et3N.HF to cleave tert-butyldimethylsilyl- or tert-butyldiphenylsilyl moiety.Deprotecting 5 provides intermediate trans-(2-oct-2-yn-1-ylcyclopropyl)methanol 6 (M3).

[0147] In step 6, the hydroxyl group of alcohol 6 (M3) is oxidized with an oxidizing agent, such as Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO (Swern oxidation), or 2-iodoxybenzoic acid (IBX) to provide trans- (1R,2R)-2-oct-2-yn-1-ylcyclopropanecarbaldehyde 7 (M4).

[0148] In step 7, aldehyde 7 (M4) is treated with propargyl chloride in Et2O or THF, employing n-BuLi or EtMgBr as an agent for metalation, giving (1S*)-and (1R*)-4-chloro-1-[(1R*,2R*)-2-oct-2-yn-1-ylcyclopropyl]but-2-yn-1-ol 8 (M5) as a mixture of epimers at C4.

[0149] In step 8, compound 8 (M5) is reacted with methyl ester of hexynoic acid 9, or other alkyl ester, including ethyl, tert-butyl, benzyl- or the like (formula IX), in the presence of CuI, NaI, and a suitable base, such as K2CO3, in a suitable solvent, such as DMF, DMA, or NMP, at ambient temperature giving precursor methyl (10S*)-and (10R*)-10-hydroxy-10-[(1R*,2R*)-2-oct-2-yn-1- ylcyclopropyl]deca-5,8-diynoate 10 (M6) with 3:5 epimeric ratio at C10 (anti:syn diastereomeric ratio of the hydroxyl and cyclopropyl stereocentres).

[0150] In step 9, partial hydrogenation (or semi-reduction) of triyne 10 (M6) is carried out in the presence of a suitable hydrogenation agent, such as Lindlar catalyst additionally poisoned with quinoline in cyclohexane or benzene, to yield: methyl (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1- yl]cyclopropyl}deca-5,8-dienoate 11 (PBT-3) (minor one, less polar) and methyl (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}deca- 5,8-dienoate 12 (PBT-4) (major one, more polar).

[0151] In step 10, hydrolysis of compound 11 (PBT-3) and compound 12 (PBT-4) in MeOH-H2O is carried out in suitable conditions, such as alkaline conditions to yield the corresponding free acids (Fig.3). For example, hydrolysis of 11 and 12 in the presence of NaOH gave corresponding free acids (5Z,8Z,10S*)-10- hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}deca-5,8-dienoic acid 13 (PCA-3) and (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1- yl]cyclopropyl}deca-5,8-dienoic acid 14 (PCA-4).

[0152] Compounds 11 and 12 may be purified using one or more suitable purification techniques, such as column chromatography on silica gel following by additional purification by preparative RP-HPLC. The target compounds may be obtained in a 3:5 (compound 11:compound 12) diastereomeric ratio as clear oils. The same ratio between more and less polar epimers is obtained for native HxB3 methyl esters when similar condensations of appropriate aldehyde with Li-derivative of terminal acetylene are used (Vasiljeva et al, Tetrahedron 49:1993, 4099). The same relative configuration for less and more polar PBT-3 and PBT-4 is thus expected. The NMR spectra of individual PBT-3 and PBT-4 methyl esters show some differences between epimers: coupling constant J10,11 is larger for the more polar epimer (d, 7.8 Hz) than for the less polar epimer (d, J = 7.3 Hz), and proton at C11 of cyclopropyl group has less chemical shift (0.68 ppm) for the more polar epimer than for the less polar epimer (0.81 ppm). These data are in agreement with those described for α,β- cyclopropylcarbinolic systems (Descotes et al., Tetrahedron 29:2931-2935, 1973).

[0153] Although Figs.1 and 2 depict purification / separation of epimers 11 and 12 after step 9, a person of skill in the art will understand that the hydroxyl epimers may be separated at an earlier step, such as step 8. Epimers 11 and 12 may be separated as free hydroxyls, or, as will be understood by a person of skill in the art, the hydroxyls may first be coupled with chiral resolving agents known in the art. Coupling with chiral resolving agents may improve resolution of the epimers compared to uncoupled epimers.

[0154] As will be understood by a person of skill in the art, the synthetic methodology depicted in Figs.1-3 are examples of suitable methodology to synthesize compounds of Formula I. Modifications known in the art may be made to the synthetic procedures above to access different compounds of Formula I. For example: In embodiments where X is O: epoxide derivative of compound 1 may be obtained by epoxidation of a trans-double bond, or alternatively, a trans-double bond derivative of compound 1 (wherein the cycloalkane is a double bond) is later converted to an epoxide, such as prior to step 9;In embodiments where X is NH: synthesis of similar aziridine intermediates are known in the art, for example: Tetrahedron, 2011, vol.67, # 14, p.2570 – 2578, incorporated herein by reference. In embodiments where X is N-C1-C6alkyl: NH in an aziridine intermediate as discussed above may be alkylated; In embodiments where X is S: an epoxide intermediate as discussed above may be treated with KSCN; In embodiments where R2 is halogen: procedures known in the art may be used to substitute an -OH of R2-OH with Cl, Br, or I; In embodiments where R2 is N3: embodiments where R2 = Br or I may be treated with sodium azide; In embodiments where R2 is NH2: embodiments wherein R2 is azide may be reduced using PPh3 or other the methods known in the art; In embodiments where R2is SH: embodiments with R2= OH may be treated with Lawessons reagent; In embodiments where R2 is PO3H: embodiments with R2 = OH may be phosphorylated with corresponding reagents known in the art, such as triisopropyl phosphate following by isopropyl moieties removal; In embodiments where R3 is C4-C10 alkyl: embodiments with C4-C10 alkynyl precursors may be fully hydrogenated; In embodiments where R3 is C4-C10 alkenyl: corresponding terminal alkynes may be used; In embodiments where R3 is C4-C10 alkynyl: corresponding terminal alkynes may be used; In embodiments where R5is C1-C6alkyl: aldehyde 7 (M4) may be treated with corresponding Grignard reagents derived from alkyl halogenides;In embodiments where R5is C2-C6alkenyl: aldehyde 7 (M4) may be treated with corresponding lithiated terminal acetylenes followed by partial reduction of a triple bond to a double bond; In embodiments where R5 is C2-C6 alkynyl: aldehyde 7 (M4) may be treated with corresponding lithiated terminal acetylenes; In embodiments where R5is saturated or unsaturated C1-C4alcohol: the ester group of PBT-3 (11) and PBT-4 (12) may be reduced using a suitable reducing agent to an alcohol; In embodiments where R5 is 6-membered aryl: aldehyde 7 (M4) may be treated with corresponding lithiated C6 aryl; In embodiments where R5is Y2-R1; wherein the aryl is -(CH2)n-phenyl, wherein n is 1 to 9, wherein Y2 is C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl: such compounds may be obtained by treatment of aldehyde 7 (M4) with corresponding lithiated alkyl, alkenyl, or alkynyl halogens; In embodiments where R5 is Y2 substituted by -OH and / or halogen: aldehyde 7 (M4) may be treated with corresponding lithiated compounds, optionally with protected OH group (for example, an OSiMe2tBu protecting group or others), halogen can be obtained by exchange of OH with Cl, Br, or I using methods known in the art; In embodiments where R1 is OH, halogen, N3, NH2, COOR4 or CONHR4: aldehyde 7 (M4) may be treated with corresponding lithiated compounds, optionally with protected OH group (OSiMe2tBu or the like) following by substitution of OH by halogen, N3, or NH2; for COOR4: esterification of PBT-3 and PBT-4 may be used; for COONH4 amidation of PCA-3 and PCA-4 with corresponding alkyl- or aryl amines, including carbohydrate amines, such as glucosamine or galactosamine may be used; and In embodiments where Dotted line ( ) is a single bond: one or more triple bonds of compound 10 (M6) may be fully hydrogenated to a single bond.

[0155] The present compounds, compositions and methods are useful for treating or preventing pain. In some embodiments, the compound of compositions described hereinare administered in an effective amount. In one embodiment, a method of treating, ameliorating, or preventing pain in a subject is provided, the method comprising administering a compound having formula 11 or a pharmaceutically acceptable salt thereof, to the subject.

[0156] In an embodiment, a method of treating, ameliorating, or preventing pain in a subject is provided, the method comprising administering a compound having formula 12 or a pharmaceutically acceptable salt thereof, to the subject.

[0157] In an embodiment, a method of treating, ameliorating, or preventing pain in a subject is provided, the method comprising administering a compound having formula 11, or a pharmaceutically acceptable salt thereof, and a compound having formula 12, or a pharmaceutically acceptable salt thereof, to the subject.

[0158] In an embodiment, an analgesic composition for treating, ameliorating, or preventing pain in a subject is provided, the composition comprising a compound having formula 11 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0159] In an embodiment, an analgesic composition for treating, ameliorating, or preventing pain in a subject is provided, the composition comprising a compound having formula 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0160] The present disclosure will be further illustrated in the following examples. Examples

[0161] EXAMPLE 1: Synthesis of compounds 11 and 12

[0162] Instruments and reagents

[0163] Preparative HPLC purification of PBT-3 (11) and PBT-4 (12) was performed using a CN-3 column, 4.6 × 250 mm (InertsilTM), using as eluent MeOH- H2O gradient system. GC analysis of tBDMS derivatives of PBT-3 (11) and PBT-4 (12) was carried out on an Agilent 7890B gas chromatograph using a Agilent HPcolumn (30m × 0.32mm × 0.25µm).1H-NMR spectra were obtained on a Bruker- AM400 (500 MHz) spectrometer (Bruker, Karlsruhe, Germany) in CDCl3 with Me4Si as an internal standard (δ=0). LCMS (ESI) analysis of PBT-3 (11) and PBT-4 (12) was performed on an Agilent UItivo instrument.

[0164] trans-(2-{[(4-Methoxybenzyl)oxy]methyl}cyclopropyl)methanol (3, PBT-B2)

[0165] To a mixture of DMF (350g) and PBT-B1 (2, 51.6g, 506 mmol) in a 2000 mL three-necked flask, 60% NaH was added (16.2g, 405 mmol) portionwise at 40-45°C. After the addition was completed, the mixture was stirred at 55-60°C for 1h, then cooled to 20-30°C and NaI was added (1.5g, 10 mmol) following by addition of TBAB (1.5g, 4.7 mmol). To the prepared mixture, PMB-Cl was added (63.4g, 406 mmol) dropwise, and the mixture was stirred at 20-30°C for 2h. The mixture wasquenched with 100g ofNH4Cl (aq.), evaporated at 60°C and 0.5 mm Hg to remove DMF, diluted with water (200g), extracted with dichloromethane (2 × 330g). The combined organic phase was washed with water (200g), and saturated brine (200g), and dried over MgSO4. The solvent was evaporated, and red-brown oil residue (113g) was purified by silica gel eluted with 20% EtOAc in hexane, giving PBT-B2 (3, 46.4g), total yield for two steps was 41.3%.

[0166] 1H-NMR (400MHz, CDCl3, ppm): 0.42-0.49 (m, 2H, cyclopropyl-H), 0.95-1.02 (m, 2H,H2+H3), 2.17 (br.s, 1H, OH), 3.21 (m, 1H, H4), 3.35 (m, 2H, H1), 3.45 (m, 1H, H1’), 3.79 (s, 3H, OCH3), 4.45 (s, 2H, Ar-CH2), 6.86 (d, 2H, Ar- H), 7.24 (d, 2H, Ar-H).

[0167] trans-1-({[2-(iodomethyl)cyclopropyl]methoxy}methyl)-4- methoxybenzene (4, PBT-B3)

[0168] PPh3 (141.6g, 508 mmol), and imidazole (36.8g, 541 mmol) were dissolved into 1200 mL CH2Cl2cooled below 8°C, and I2(137g, 539 mmol) was added portionwise keeping the temperature below 30°C. The mixture was cooled down to -5-0°C and a solution of PBT-B2 (3, 80.0g, 360 mmol) in 400 mL CH2Cl2was added was added dropwise. The mixture was stirred at 10-15°C for 1h and quenched with water (320g). The organic layer was separated, and washed with waterand saturated brine, dried over MgSO4and evaporated. The residue (274g) was passed through silica gel eluting with 10% EtOAc in hexane. The filtrate was evaporated giving 117.0g of PBT-B3 (4) as an oil, yield 97.87%.

[0169] 1H-NMR (400MHz, CDCl3, ppm): 0.52 and 0.76 (m, 2H, cyclopropyl- H), 1.04-1.27 (m, 2H, H2+H3), 2.17 (br.s, 1H, OH), 3.21 (m, 1H, H1), 3.06-3.11 (t, 1H, H4), 3.18-3.35 (m, 3H, H1+H4), 3.79 (s, 3H, OCH3), 4.45 (s, 2H, Ar-CH2), 6.86 (d, 2H, Ar-H), 7.23 (d, 2H, Ar-H).

[0170] trans-1-Methoxy-4-{[(2-oct-2-yn-1- ylcyclopropyl)methoxy]methyl}benzene (PBT-B4, 5)

[0171] A solution of 1-heptyne [CAS 628-71-7] (84.7g, 882 mmol) in THF (1190 mL) was cooled to -60°C under nitrogen. To this solution, 2.5M n-BuLi in hexanes (350 mL, 875 mmol) was added dropwise below -50°C. After stirring for 30min, a mixture of HMPA / THF [189g HMPA + 250ml THF] was added and the mixture was stirred at -50°C for 30min. To the mixture, PBT-B3 (4, 117.0g, 352 mmol) was added in 300 mL THF, and the mixture was stirred at -30°C for 0.5h, and then at 10-20°C for 4 h. The mixture was quenched with saturated NH4Cl solution (500g) at -5-0°C. The organic layer was washed with saturated NH4Cl (500g), and saturated brine (300g), dried over MgSO4and evaporated giving PBT-B4 (5, 105.8g,quant) as an oil, that wasused for the next step without additional purification.

[0172] trans-(2-Oct-2-yn-1-ylcyclopropyl)methanol (PBT-M3, 6)

[0173] To a mixture of PBT-B4 (5, 105.8g, 353 mmol) in CH2Cl2(1000mL) and water (50 mL), DDQ was added (120g, 1892 mmol) and the mixture was stirred for 0.5-1.0h. The mixture was filtered off. The filtrate was washed with saturated NaHCO3 (2 × 525g), saturated NaHSO3 (2 × 525g), and saturated brine (400g), dried over MgSO4 and evaporated. The crude brown-black oil was purified by column chromatography on silica gel eluting with EtOAc-hexane giving 32.5g of M3 (6), total yield 50% from B2 to M3, three steps (iodization, Csp3-Csp coupling, deprotection).

[0174] 1H-NMR (400MHz, CDCl3, ppm): 0.40-0.55 (dt, 2H, cyclopropyl-H), 0.73-0.85 (m, 2H, H2+H3), 0.90 (t, 3H, H11), 1.33 (m, 4H, H9+H10), 1.48 (quintet, 2H,H8), 2.14 (tt, 2H, H7), 2.19 and 2.23 (dt, 1H, H4), 2.32 and 2.35 (dt, 1H, H4’), 3.46 (m, 2H, H1).

[0175] trans-(1R,2R)-2-Oct-2-yn-1-ylcyclopropanecarbaldehyde (PBT-M4, 7)

[0176] To a solution PBT-M3 (6, 10.0g, 55.5 mmol) in CH2Cl2(200 mL), Dess-Martin periodinane was added (35.3g, 83.3 mmol) portionwise at 10-20°C at stirring for 60min. Then water (1g) was added, and the mixture was stirred for 1 h at ambient temperature. The mixture was concentrated in vacuo at 40°C to remove CH2Cl2. Then the residue was diluted with MTBE (200mL) and stirred for 30min. The mixture was filtered, the filtrate was evaporated at 70°C to remove MTBE and AcOH, formed as a by-product. M4 (7), as a light yellow oil was obtained (10.2g, quant), that was used for the next step without additional purification.

[0177] (1S*)-and (1R*)-4-Chloro-1-[(1R*,2R*)-2-oct-2-yn-1- ylcyclopropyl]but-2-yn-1-ol (PBT-M5, 8)

[0178] A solution of propargyl chloride [CAS 624-65-7] (12.4g, 166 mmol) in 300 mL Et2O, was cooled to -60°C.2.5M n-BuLi in hexanes (66mL, 165 mmol) was added dropwise at a temperature below -50°C and the mixture was stirred at -50°C for 30min. Then PBT-M4 (7, 9.89g, 55.6 mmol) in 20 mL Et2O was added dropwise, and the mixture was stirred at -50°C for 30min. The mixture was quenched with water and warmed up to ambient temperature for 10min. The organic layer was separated, dried over MgSO4 and evaporated. The light yellow oil was purified by column chromatography on silica gel eluting with EtOAc in hexane giving 9.6g of M5 (8), total yield for two steps from M3 to M5 (oxidation, aldehyde addition) was 68.5%.

[0179] Note: The intermediated M5 was not stable at room temp. It is stable while stored at -20°C.

[0180] 1H-NMR (400MHz, CDCl3, ppm): 0.57-0.69 (m, 2H, cyclopropyl-H), 0.90 (t, 3H, J=7.1 Hz, H14), 1.03, 1.09 (m, 1H, H5), 1.19 (m, 1H, H6), 1.32 (m, 4H, H12+H13), 1.48 (quintet, 2H, J=7.2 Hz, H11), 1.89 (d, 1H, J=6.4 Hz, OH), 2.13 (tt, 2H, J=2.4 and 7.2 Hz, H10), 2.22-2.40 (m, 2H, H7), 4.15 (t, 2H, J=2.3 Hz, H1), 4.28 (m, 0.3H, H4), 4.35 (m, 0.7H, H4’).

[0181] Methyl (10S*)-and (10R*)-10-hydroxy-10-[(1R*,2R*)-2-oct-2-yn-1- ylcyclopropyl]deca-5,8-diynoate (PBT-M6, 10)

[0182] To a suspension of anhydrous CuI (9.0g, 47.3 mmol), NaI (14.2g, 94.6 mmol) and K2CO3 (13.1g (94.9 mmol) in 120 mL DMF, the solutions of methyl 5- hexynoate [CAS 77758-51-1] (9, 6.6g, 52.3 mmol) in 30 mL DMF, and propargylic chloride PBT-M5 (8, 12.0g, 47.6 mmol), in 30mL DMF were added. The mixture was stirred for 16h at 15-25°C, then aq NH4Cl was added (360 mL). The mixture was extracted with MTBE (360mL), the organic phase was washed with aq NH4Cl (2 × 180 mL), the organic phase was dried over MgSO4, and the residue was purified by column chromatography on silica gel eluting with 16% EtOAc in hexane giving triyne (PBT-M6, 10) as a yellow oil (12.2g, 75.0%), epimer ratio 3:5 (anti:syn diastereomeric ratio of the hydroxyl and cyclopropyl stereocentres) by1H-NMR analysis .

[0183] Note: The intermediated M6 was not stable even upon storage at - 20°C. M6 should be used as quickly as possible.

[0184] 1H-NMR (400MHz, CDCl3, ppm): 0.57-0.64 (m, 2H, cyclopropyl-H), 0.90 (t, 3H, J=7.0 Hz, H20), 1.00-1.22 (m, 2H, H11+H12), 1.33 (m, 4H, H18+H19), 1.48 (quintet, 2H, H17), 1.82 (quintet, 2H, H3), 2.13-2.25 (m, 6H, H4+H13+H16), 2.44 (t, 2H, H2), 3.15-3.30 (m, 2H, H7), 3.68 (s, 3H, COOMe), 4.26 (dt, 0.4H, H10), 4.32 (dt, 0.65H, H10’).

[0185] Methyl (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1- yl]cyclopropyl}deca-5,8-dienoate (PBT-3, 11) and methyl (5Z,8Z,10R*)-10-hydroxy- 10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}deca-5,8-dienoate (PBT-4, 12)

[0186] A solution of triyne M6 (10, 10g, 29.2mmol) in 200 mL cyclohexane was added to a mixture of hydrogen pre-saturated Lindlar catalyst (10g) and quinoline(50g) in 300 mL of cyclohexane and theresulting mixture was stirred for 2h with anH2balloon, the poisoned catalyst was filtered off, and thefiltrate was added to a newportion of hydrogen pre-saturated Lindlar catalyst (10g) and quinoline (10g) in 100mL cyclohexane. During this procedure, the reaction mixture was analyzed by GC, and hydrogenation was carried out until PBT-3 (11) & PBT-4 (12) content in thereaction mixture reached 80%. The catalyst was filtered off, the filtrate was washedwith 5% aq HCl toremove quinoline, dried with MgSO4, and evaporated. The residue was purified by column chromatography on silica geleluting with 15% EtOAc inhexane giving the two crude epimers of PBT-3 (11, less polar, 4.0g, 39.2%), and PBT-4 (12, more polar, 6.0g, 58.8%). The crude PBT-3 (11) and PBT-4 (12) were purified by prep RP-HPLC to afford PBT-3 (11, 2.9g, 29%, and PBT-4 (12, 4.9g, 48%). Diastereomerically pure PBT-3 and PBT-4 were obtained as a mixture of enantiomers, as shown in Figure 5.

[0187] 1H-NMR of PBT-3 (11) (400MHz, CDCl3, ppm):0.34 (dt, 1H, J=4.8,8.4 Hz, cyclopropyl-H), 0.43 (dt, 1H, J=8.4, 5.0 Hz, cyclopropyl-H), 0.75-0.85 (m, 2H, H11+H12), 0.88 (t, 3H, J = 7.0 Hz, H20), 1.24-1.38 (m, 4H, H18+H19), 1.63-1.77 (m, 4H, H3+H17), 1.92-2.15 (m, 6H, H4+H13+H16), 2.31 (t, 2H, J=7.5 Hz, H2), 2.70-2.88 (m, 2H, H7), 3.66 (s, 3H, COOMe), 3.96 (ddd, 1H, J=1.0, 7.3 and 7.3 Hz, H10), 5.33- 5.43 (m, 6H, olefinic).

[0188] MS of PBT-3 (11) (ESI, pos): 331.3[M-OH]+, 371.3[M+Na]+.

[0189] 1H-NMR of PBT-4(12)(400MHz, CDCl3, ppm): 0.39 (dt, 1H, J=4.8and 8.1 Hz, cyclopropyl-H),0.53 (dt, 1H, J=4.8 and 8.5 Hz, cyclopropyl-H), 0.68 (m, 1H, H11), 0.83 (m, 1H, H12), 0.87 (t, 3H, J=6.8 Hz, H20), 1.26-1.36 (m, 6H, H17+H18+H19), 1.70 (quintet, 2H, J=7.5 Hz, H3), 1.90-2.12 (m, 6H, H4+H13+H16), 2.32 (t, 2H, J=7.5 Hz, H2), 2.75 (m, 2H, H7), 3.67 (s, 3H, COOMe), 3.95 (ddd, 1H, J=1.0, 7.8, and 7.8 Hz, H10), 5.36-5.50 (m, 6H, olefinic H).

[0190] MS of PBT-4 (12) (ESI, pos): 331.3[M-OH]+, 371.3[M+Na]+.

[0191] (5Z,8Z,10S*)-10-Hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1- yl]cyclopropyl}deca-5,8-dienoic acid (PCA-3, 13) and (5Z,8Z,10R*)-10-hydroxy-10- {(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}deca-5,8-dienoic acid (PCA-4, 14)

[0192] To a solution of PBT-3 (11) (350mg, 1.0 mmol), or PBT-4 (12) (350mg, 1.0 mmol) in 10 mL MeOH, 10 mL of 0.1N NaOH was added, and the solution was kept at ambient temperature for 5h. MeOH was evaporated, the aqueous solution was extracted with Et2O (2 ×) and the Et2O extracts were discarded. Theaqueous layer was acidified with 0.1N HCl to pH 3, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated giving the two epimers of PCA-3 and PCA-4 (330mg, 98%).

[0193] MS of PCA-3 (13) (ESI, pos): 335.2.[M+H]+; MS of PCA-4 (14) (ESI, pos): 335.2. [M+H]+EXAMPLE 2 – Investigation of biological activity of PBT-3

[0194] Mice

[0195] Experiments were performed on naive, adult (7–8 weeks of age), C57Bl6 / N female mice were obtained from Charles River (Saint Constant, Quebec, Canada). All mice were housed in groups of 4 upon arrival in ventilated cages (5 x 7 x 14 in.) in a closed-circuit atmosphere rack (Techniplast Easy Flow #BOX110EFUL). All mice were maintained within a temperature-controlled environment (20 ± 1° C) with a 12 :12 h light: dark cycle. A compressed cotton nesting square and crinkled paper bedding were provided in each cage as a source of environmental enrichment. All mice had access to food (Harlan Teklad 8604) and water ad libitum. Procedures followed the animal care standards set forth by the Canadian Council on Animal Care (CCAC) and approved by the University of Toronto's Biosciences Panel on Laboratory Animal Care.

[0196] Drugs

[0197] Morphine sulfate was obtained from CDMV (Saint-Hyacinthe, QC) and dissolved in saline. Ketorolac was purchased from Sigma Aldrich (Oakville, ON) and dissolved in saline. PBT-3 (11) was dissolved in Ethanol / PEG400 / PBS. DMSO (1 µl) was added to each sample before injection into the mice. Morphine and ketorolac were administered intraperitoneally (10 ml / kg volume), while PBT-3 (11) was administered subcutaneously (20 µl) into the left hind paw.

[0198] Mechanical sensitivity (von Frey) Test

[0199] All mice were habituated to the testing cubicles for at least 60 minutes before testing commenced. For von Frey experiments, mice were assigned randomly to drug and dose, and experimenters were blinded to drug and dose. The up-downmethod of Dixon was used (PMID: 7990513). Mice were placed on a perforated metal floor (with 5-mm diameter holes placed 7 mm apart) within small Plexiglas cubicles (9 × 5 × 5 cm high), and a set of 8 calibrated von Frey fibers (Stoelting Touch Test Sensory Evaluator Kit 2 to 9; Stoelting Co, Wood Dale, IL; ranging from ≈.015 g to ≈1.3 g of force) were applied to the plantar surface of the hind paw until the fibers bowed and then held for 3 seconds. The threshold force required to elicit withdrawal of the paw (median 50% withdrawal) was determined twice on each hind paw (and averaged) for all baseline measurements, with sequential measurements separated by at least 20 minutes. After drug administration, 1 measurement per hind paw was taken at the indicated time point.

[0200] Carrageenan Hypersensitivity

[0201] λ-Carrageenan (2%; 20 mg / mL; Sigma Aldrich, Oakville, ON) was suspended by sonication in saline and injected subcutaneously in a volume of 20 μL into the left plantar hind paw using a 100-μL microsyringe with a 30-gauge needle. Mice were tested for mechanical sensitivity of both hind paws using the von Frey test before and 3 hours after carrageenan injection. All drugs were injected immediately after the post-carrageenan (3 hour) test, and post-drug measurements were taken 30, 60, and 120 minutes later.

[0202] Table 1: Summary of von Frey test results Drug Baseline 3hr 30 min 60 min 120 min P 26 14 18 19 21

[0203] These results show that PBT compounds described in this specification show analgesic activity dose-dependently. The activity of PBT-3 at 30 min post drug administration (Table 1) at the 10 mg / kg dose being equivalent to that of ketorolac and about 75% that shown by morphine at half the dose. As the PBTs have shown no toxicity or demonstrable side effects in animal models of cancer and lung fibrosis, these studies on analgesia would benefit effects of the compounds in vivo to possibly replace conventional medications or reduce their dose in other diseases indicated to prevent their many known side effects.

[0204] EXAMPLE 3: Investigation of analgesic activity of PBT-4 and comparative study between PBT-3 and PBT-4

[0205] This example investigates whether PBT-4 also has analgesic effects and compare it with the analgesic effect of PBT-3. PBT-3 is a mixture of enantiomers having anti- configuration of the cyclopropyl moiety and the neighboring hydroxyl group, whereas PBT-4 is a mixture of enantiomers having syn- configuration of the cyclopropyl moiety and the neighboring hydroxyl group. PBT-4 is a C10 epimer of PBT-3. While only one enantiomer of each syn and anti products are shown in the syntheses of Figures 1-3, it will be understood that both enantiomers may be present, for example as shown in Figure 5, unless specified otherwise.

[0206] This experiment aims to investigate whether PBT-4 also has analgesic effects and compare it with the analgesic effect of PBT-3 (Table 1). Results herein suggest that the analgesic effect of PBT-4 (10 mg / kg) is similar in potency to that of PBT-3 and their analgesic effect in this model can last for more than 12 hours.

[0207] In contrast to the carrageenan model used above, the surgical modeling study (electronic Von Frey method) was used to test mechanical pain in the absence of a chemical induction (carrageenan). In this model, the intact plantar muscles are elevated and incised longitudinally keeping the starting and attachment points intact (approx.5 min surgery). The skin is then sutured and the wound is disinfected. A stainless steel needle stimulates a certain point on the sole of the rat’s right hind paw (not less than 5mm from the surgical incision) The mechanical trigger withdrawal threshold (PWT) of the rat's hind paw is recorded at measurement times 2h, 4h, 6h, 8h, 10h, and 12h after modeling. PBT-3 and PBT-4 groups (n=6 ea) wereadministered once through the tail vein 30 minutes before modeling establishment, with a dosage of 10 mg / kg and a volume of 5 mL / kg. Sham operated and vehicle groups were also included (n=6 ea). This information is summarized in Table 2, below.

[0208] Experimental animals: SPF grade SD rats, n=24, weight 210-220g, male.

[0209] Experimental instrument: Electronic Von Frey - Italy Ugo Basile Ugo38450

[0210] Table 2: Animal grouping and dosage Group Number of animals Dose (mg / kg)

[0211] Animal model establishment

[0212] After the SD rats were adapted to the environment, the rats were anesthetized with isoflurane inhalation. A 10% povidone-iodine solution was applied to the sole of the right hind paw, and a 1cm long line was made along the proximal 0.5cm of the sole toward the distal toe. The incision is made at the base of the foot, and the plantar muscles are elevated and incised longitudinally. The starting points and attachment points of the muscles are kept intact. The skin is sutured after hemostasis, and the wound is disinfected. The operation lasts 5-10 minutes. Blank groups are not surgical modeling processed. PBT-3 and PBT-4 groups were administered once through the tail vein 30 minutes before modeling establishment, with a dosage of 10 mg / kg and a volume of 5 mL / kg.

[0213] Mechanical pain threshold measurement

[0214] During the measurement, the stainless steel needle stimulated a certain point on the sole of the rat's right hind paw from under the metal mesh (not less than 5mm from the surgical incision). After the stainless steel needles touched the skin of the sole, the stimulation force continued to increase. When the rat felt pain, the right hind limb is raised, and the skin of the sole of the foot is separated from the stainless steel needle. At this time, the value displayed of the measuring instrument is the mechanical trigger withdrawal threshold (PWT) of the rat's hind paw. The measurement times are 2h, 4h, 6h, 8h, 10h, and 12h after modeling.

[0215] Statistical method

[0216] This experiment used IBM SPSS 26.0 software for statistical analysis. The differences between groups were analyzed using one-way ANOVA. When the variances were equal, the LSD t-test was used for inter-group comparisons. When the variances were uneven, Dunnett's T3-test was used for inter-group comparisons. The experimental data were measured using " means ± SEM", and P<0.05 means there is a statistically significant difference.

[0217] Experimental results

[0218] The results of mechanical pain threshold measurement suggest that after surgical modeling, the mechanical pain threshold of the model (or vehicle) group was significantly lower than that of the blank group. Compared with the model group, the mechanical pain thresholds of the PBT-3 group and the PBT-410mg / kg group were significantly increased 2h-12h after surgery, and the drug effect was stable. The mechanical pain threshold of the PBT-410mg / kg group was similar to that of the PBT-310mg / kg group, with no significant difference with no significant difference from each other, and p<0.001 from sham (16%) and vehicle groups (42%) (see Figure 4).

[0219] The in vivo biological experiments herein show that both PBT-3 and PBT-4 have equivalent analgesic effects in the surgical modeling induction of pain. Despite the drugs being administered intravenously through the tail vein, it is important to note that the analgesic effects last at least up to 12h (the end of theexperiment) as shown in Figure 4. Another pain model (the carrageenan model of Example 2) showed that PBT-3 was approx. half as effective as morphine in its analgesic effect when administered in the plantar region of the hind paw at 10 mg / kg dose. Hence the drugs are effective as long lasting analgesics possibly due to their incorporation into lipid pools followed by a gradual slow release into the circulation. REFERENCES C.R. Pace-Asciak, J.M. Martin. Hepoxilin, a new family of insulin secretagogues formed by intact rat pancreatic islets. Prostaglandins Leukotrienes and Medicine 1984, V.16, P.173–180. C.R. Pace-Asciak, J.M. Martin, E.J. Corey, W.-G. Su. Endogenous release of hepoxilin A3 from isolated perifused pancreatic islets of Langerhans. Biochem. Biophys. Res. Commun.1985, V.128, P.942-946. Pace-Asciak et al. (1990) Biolog. Oxidation Systems, Eds C.C. Reddy et al., Academic Press, New York, 725-735. R.W. Bryant, J.M. Bailey. Isolation of a new lipoxygenase metabolite of arachidonic acid, 8,11,12-trihydroxy-5,9,14-eicosatrienoic acid from human platelets. Prostaglandins 1979, V.17, P.9-18. R.L. Jones, P.J. Kerry, N.L. Poyser, Irene C. Walker, N.H. Wilson. The identification of trihydroxyeicosatrienoic acids as products from the incubation of arachidonic acid with washed blood platelets. Prostaglandins, 1978, V.16, P.583-589. C. R. Pace-Asciak, K. Mizuno, S. Yamamoto. Resolution of DEAE-cellulose chromatography of the enzymatic steps in the transformation of arachidonic acid into 8,11,12- and 10,11,12-trihydroxy-eicosatrienoic acid by the rat lung. Prostaglandins, 1983, V.25, P.79-84. C.R. Pace-Asciak, K. Mizuno, S. Yamamoto. The enzymatic conversion of arachidonic acid into 8,11,12-trihydroxyeicosatrienoic acid Resolution of rat lung enzyme into two active fractions. Biochim. Biophys. Acta, 1983, V.712, P.142-145.O. Laneuville, E.J. Corey, R. Couture, C.R. Pace-Asciak. Hepoxilin A3(HxA3) is formed by the rat aorta and is metabolized into HxA3-C, a glutathione conjugate. Biochim. Biophys. Acta, 1991, V.1084, P.60-68. S. Dho, S. Grinstein, E. J. Corey, W.- G. Su, C. R. Pace-Asciak. Hepoxilin A3 induces changes in cytosolic calcium, intracellular pH and membrane potential in human neutrophils. Biochem. J., 1990, V.266, P.63-68. M. F. Moghaddam, W. H. Gerwick, D. L. Ballantine. Discovery of the mammalian insulin release modulator, hepoxilin B3, from the tropical red algae Platysiphonia miniata and Cottoniella filamentosa. J. Biol. Chem., 1990, V.265, P.6126-6130D. Piomelli, E. Shapiro, R. Zipkin, J.H. Schwartz, S.J.Feinmark. Formation and action of 8-hydroxy-11,12-epoxy-5,9,14-icosatrienoic acid in Aplysia: a possible second messenger in neurons. Proc. Natl. Acad. Sci. USA, 1989, V.86, P.1721-1725. C.R. Pace-Asciak, D. Reynaud, P.M. Demin. Hepoxilins: a review on their enzymatic formation and metabolism and their chemical synthesis. Lipids, 1995, V.30, P.107- 114. C. R. Pace-Asciak. The hepoxilins and some analogues: a review of their biology. British J. Pharmacol., 2009, V.158, P.972-981. Y. Y. Toporkova, E. O. Smirnova, T. M. Iljina, L. S. Mukhtarova, S. S. Gorina, A. N. Grechkin. The CYP74B and CYP74D divinyl ether synthases possess a side hydroperoxide lyase and epoxyalcohol synthase activities that are enhanced by the site-directed mutagenesis. Phytochemistry, 2020, V.179, P.112512 Y. Y. Toporkova, V. S. Fatykhova, Y. V. Gogolev, B. I. Khairutdinov, L. S. Mukhtarova, A. N. Grechkin. Epoxyalcohol synthase of Ectocarpus siliculosus. First CYP74-related enzyme of oxylipin biosynthesis in brown algae. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2017, V.1862, P. 167-175. In-Gyu Lee, Jung-Ung An, Yoon-Joo Ko, Jin-Byung Park, Deok-Kun Oh. Enzymatic synthesis of new hepoxilins and trioxilins from polyunsaturated fatty acids. Green Chemistry, 2019, V.21, P.3172–3181.Jin Lee, Tae-Hun Kim, Yoon-Joo Ko, Jin-Byung Park, Deok-Kun Oh. Highlyefficient oxidation of plant oils to C18 trihydroxy fatty acids by Escherichia coli co-expressing lipoxygenase and epoxide hydrolase. Green Chemistry, 2022, V.24, P.2062–2072. Y. Zheng, A. R. Brash. Formation of a Cyclopropyl Epoxide via a Leukotriene A Synthase-related Pathway in an Anaerobic Reaction of Soybean Lipoxygenase-1 with 15S-Hydroperoxyeicosatetraenoic Acid: EVIDENCE THAT OXYGEN ACCESS IS A DETERMINANT OF SECONDARY REACTIONS WITH FATTY ACID HYDROPEROXIDES. Journal of Biological Chemistry, 2010, V.285, P.13427– 13436. P.M. Demin, C.R. Pace-Asciak. Synthesis of racemic 11,12-cyclopropyl analogs of A3and B3. Tetrahedron Lett., 1993, V.34, P.4305-4308. P.M. Demin, D. Reynaud, C.R. Pace-Asciak. Chemical synthesis and actions of 11,12-thiirano-hepoxilin A3. J. Lipid Mediators Cell Signalling, 1996, V.13, P.63-72.

[0220] All citations are hereby incorporated by reference. In the event of conflicting information with statements between any reference to or incorporated herein, and the present disclosure, the present disclosure will act as the guiding authority.

[0221] What has been described is merely illustrative of the application of the principles of the disclosure. However, it will be apparent to a person skilled in the art that a number of variations and modifications can be made without departing from the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound having formula III: (III) the process comprising:coupling a compound having formula 2: (2), with a suitable2. The process of claim 1, wherein the protecting group is p-methoxybenzyl, tert- butyldimethylsilyl, or tert-butyldiphenylsilyl.

3. A process for preparing a compound having formula 3: , the process comprising:coupling a compound having formula 2: ,with p-methoxybenzyl 4. A process for preparing a compound having formula IV: ,the process comprising: reacting a compound having formula (III):(III), with: i) I2, PPh3, andsodium iodide; or iii) methanesulfonyl chloride and sodium iodide.

5. The process of claim 4, wherein the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

6. A process for preparing a compound having formula 4: , the process comprising:reacting a compound having formula (3): , with: i) I2, PPh3,and sodium iodide, or iii) methanesulfonyl chloride and sodium iodide.

7. The process of claim 6, wherein the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

8. A process for preparing a compound having formula V: ,the process comprising: reacting 1-heptyne with a metalation agent to yield a first mixture; and reacting a compound having formula (IV): (IV),with the first mixture.

9. The process of claim 8, wherein the metalation agent is n-BuLi or EtMgBr.

10. A process for preparing a compound having formula 5: , the processreacting 1-heptyne with a metalation agent to yield a first mixture; and reacting a compound having formula (4): , with the first11. The process of claim 10, wherein the metalation agent is n-BuLi or EtMgBr.

12. A process for preparing a compound having formula 6: ,the process comprising: deprotecting a compound having formula V: ,via a deprotecting agent.

13. The process of claim 12, wherein the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

14. A process for preparing a compound having formula 6: , the process comprising:deprotecting a compound having formula 5: , via DDQ.

15. A process for preparing a compound having formula 7: , the process comprising:oxidizing a compound having formula 6: ,with an oxidizing 16. The process of claim 15, wherein the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

17. A process for preparing a compound having formula 8: ,the process comprising:reacting a compound having formula 7: , with a second mixturemetalation agent.

18. The process of claim 17, wherein the metalation agent is n-BuLi or EtMgBr.

19. A process for preparing a compound having formula X: ,, with a third mixture(IX),CuI, NaI, and a base.

20. The process of claim 19, wherein the base is K2CO3.

21. A process for preparing a compound having formula 10: ,reacting a compound having formula 8: ,with a third mixture comprising a compound of formula 9: , CuI, NaI, and a base.

22. The process of claim 21, wherein the base is K2CO3.

23. A process for preparing a compound having formula XI: O , the process comprising:partially hydrogenating a compound having formula X: , using a24. The process of claim 23, wherein the hydrogenation agent is Lindlar catalyst.

25. A process for preparing a compound having formula XII: O ,the process comprising: partially hydrogenating a compound having formula X: , using a26. The process of claim 25, wherein the hydrogenation agent is Lindlar catalyst. A process for preparing a compound having formula 11: O , the process comprising:partially hydrogenating a compound having formula 10: ,using a 28. The process of claim 27, wherein the hydrogenation agent is Lindlar catalyst.

29. A process for preparing a compound having formula 12:O O , the process comprising:partially hydrogenating a compound having formula 10: , using a30. The process of claim 29, wherein the hydrogenation agent is Lindlar catalyst.

31. A process for preparing a compound having formula 13: O ,the process comprising: hydrolyzing a compound having formula 11: O ,in basic conditions.

32. The process of claim 31, wherein the basic conditions comprise methanol / water and a base.

33. The process of claim 32, wherein the base is sodium hydroxide, lithium hydroxide or potassium hydroxide.

34. A process for preparing a compound having formula 14: O , the process comprising:hydrolyzing a compound having formula 12: O ,in basic conditions.

35. The process of claim 34, wherein the basic conditions comprise methanol / water and a base.

36. The process of claim 35, wherein the base is sodium hydroxide, lithium hydroxide, or potassium hydroxide.

37. A process for preparing a compound having formula XI:O OAlkyl , the process comprising:coupling a compound having formula 2: (2), with a suitable protectinghaving formula III: (III); reacting thei) I2, PPh3, and a first base; ii) p-toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide, to yield a compound having formula IV: (IV); reacting the compounda first mixture comprising 1- heptyne with a metalation agent to yield a compound having formula V: ;deprotecting a agent to yield a compound having formula 6: ;oxidizing the compound having formula 6 with an oxidizing agent to yield a compound having formula 7:; reacting themixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ; reacting thecomprising a compound of formula IX: (IX), CuI, NaI, and a second base, to yield a compound having formula X: (X); andX using a hydrogenation agent to yield the compound having formula XI.

38. The process of claim 37, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

39. The process of any one of claims 37-38, wherein the first base is imidazole.

40. The process of any one of claims 37-39, wherein the metalation agent is n- BuLi or EtMgBr.

41. The process of any one of claims 37-40, wherein the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

42. The process of any one of claims 37-41, wherein the oxidizing agent is Dess- Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2- iodoxybenzoic acid (IBX).

43. The process of any one of claims 37-42, wherein the second base is K2CO3.

44. The process of any one of claims 37-43, wherein the hydrogenation agent is Lindlar catalyst.

45. A process for preparing a compound having formula XII: O , the process comprising:coupling a compound having formula 2: (2), with a suitable protectinghaving formula III: (III); reacting thei) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide to yield a compound having formula IV: ;reacting the compound a first mixture comprising 1- heptyne with a metalation agent to yield a compound having formula V: ;deprotecting the compound having formula V via a deprotecting agent to yield a compound having formula 6:; oxidizing theagent to yield a compound having formula 7: ; reacting themixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ; reacting thecomprising a compound of formula IX: , CuI, NaI, and a secondformula X:a hydrogenation agent to yield the compound having formula XII.

46. The process of claim 45, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

47. The process of any one of claims 45-46, wherein the first base is imidazole.

48. The process of any one of claims 45-47, wherein the metalation agent is n- BuLi or EtMgBr.

49. The process of any one of claims 45-48, wherein the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

50. The process of any one of claims 45-49, wherein the oxidizing agent is Dess- Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2- iodoxybenzoic acid (IBX).

51. The process of any one of claims 45-50, wherein the second base is K2CO3.

52. The process of any one of claims 45-51, wherein the hydrogenation agent is Lindlar catalyst.

53. A process for preparing a compound having formula 11: O , the process comprising:coupling a compound having formula 2: ,with p-methoxybenzyl a having formula 3: ,reacting the compound having formula 3 with: i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to yield a compound having formula 4: ,reacting the compound having formula 4 with a first mixture comprising 1- heptyne with a metalation agent to yield a compound having formula 5: ,agent to yield a compound having formula 6: ; oxidizing theagent to yield a compound having formula 7: ; reacting themixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ;reacting the a comprising a compound of formula 9: ,CuI, NaI, and a second base, to yield a compound having formula 10:partially hydrogenating the compound having formula 10 using a hydrogenation agent to yield the compound having formula 11.

54. The process of claim 53, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

55. The process of any one of claims 53-54, wherein the first base is imidazole.

56. The process of any one of claims 53-55, wherein the metalation agent is n- BuLi or EtMgBr.

57. The process of any one of claims 53-56, wherein the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

58. The process of any one of claims 53-57, wherein the oxidizing agent is Dess- Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2- iodoxybenzoic acid (IBX).

59. The process of any one of claims 53-58, wherein the second base is K2CO3.

60. The process of any one of claims 53-59, wherein the hydrogenation agent is Lindlar catalyst.

61. A process for preparing a compound having formula 12: O , the process comprising:coupling a compound having formula 2: ,with p-methoxybenzyl chloride to yield a compound having formula 3:3), reacting the com , PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to yield a compound having formula 4: , reacting themixture comprising 1- heptyne with a metalation agent to yield a compound having formula 5: ,agent to yield a compound having formula 6: ; oxidizing theagent to yield a compound having formula 7: ;reacting the a mixture comprising propargyl chloride and a metalation agent to yield a compound having formula 8: ;reacting the compound having formula 8 with a third mixture comprising a compound of formula 9:(9), CuI, NaI, and a second base,formula 10:hydrogenation agent to yield the compound having formula 12.

62. The process of claim 61, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

63. The process of any one of claims 61-62, wherein the first base is imidazole.

64. The process of any one of claims 61-63, wherein the metalation agent is n- BuLi or EtMgBr.

65. The process of any one of claims 61-64, wherein the deprotecting agent is DDQ, n-Bu4NF, or Et3N.HF.

66. The process of any one of claims 61-65, wherein the oxidizing agent is Dess- Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2- iodoxybenzoic acid (IBX).

67. The process of any one of claims 61-66, wherein the second base is K2CO3.

68. The process of any one of claims 61-67, wherein the hydrogenation agent is Lindlar catalyst.

69. A method of treating, ameliorating, or preventing pain in a subject, the method comprising: administering a compound having formula 11:O O , or a pharmaceutically70. A method of treating, ameliorating, or preventing pain in a subject, the method comprising: administering a compound having formula 12: O , or a pharmaceutically71. An analgesic composition for treating, ameliorating, or preventing pain in a subject, the composition comprising: a compound having formula 11: O ,or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

72. An analgesic composition for treating, ameliorating, or preventing pain in a subject, the composition comprising: a compound having formula 12: O O , or a pharmaceuticallymore pharmaceutically acceptable carriers or excipients.

Images