Hydroxyl epoxide analogue, preparation method, application and method thereof

Abstract

The present disclosure relates to the synthesis, uses, methods and pharmaceutical compositions of hydroxyepoxide cyclopropane analogs of Formula I: Formula (I). The hydroxyepoxide cyclopropane analogs are useful in the treatment of diseases and conditions, such as cancer, thromboxane-mediated diseases, cardiovascular diseases, inflammation, fibrosis, pain deficiency, and in the modulation of intracellular calcium concentration. Formula (I)

Description

TECHNICAL FIELD

[0001] The present disclosure relates to hepoxilin analogs, methods of making, uses, and methods thereof. BACKGROUND

[0002] Hepoxilins (Hx) are a group of epoxy alcohol metabolites of polyunsaturated fatty acids (PUFAs) with both epoxide and hydroxyl moieties. Hepoxilins are typically derived from arachidonic acid via the lipoxygenase pathway. Generally, there are two types of natural hepoxilins derived from arachidonic acid and are distinguished primarily by the position of their hydroxyl groups. The two types include: Type A hepoxilins, which consist of two epimeric isomers with a hydroxyl group at carbon 8 (i.e., 8(S, R)-hydroxy-11(S), 12(S)-epoxyeicosa-5Z, 9E, 14Z-trienoic acid); and Type B, which consists of two epimeric isomers with a hydroxyl group at carbon 10 (i.e., 10(S / R)-hydroxy-11(S), 12(S)-epoxyeicosa-5Z, 8Z, 14Z-trienoic acid).

[0003] Hepoxilins can be formed wherever 12-lipoxygenase is present, as 12-HPETE, an intermediate, is actively converted to hepoxilins by a variety of heme proteins. For example, heme protoporphyrin and groups containing it in proteins can catalyze this conversion. Trihydroxy metabolites derived from hepoxilins can be formed by platelets. Hepoxilins have been isolated in rat lung, rat islets, aorta, and human neutrophils. Hepoxilin B3 has been isolated from marine red algae, and hepoxilin A3 has been detected in the brain of sea hares.

[0004] Reviews have been published on the formation, synthesis, and biological actions of hepoxilins. Hepoxilin analogs from unsaturated fatty C18 and C20 acids with different numbers and positions of double bonds have also been identified.

[0005] Synthetic methods for previously described hepoxilin analogs typically involve cyclopropanation of an allylic alcohol to obtain an intermediate for further conversion. Such methods often face challenges that can prevent or hinder scale-up, such as low yield in one or several steps. Thiapropyl analogs of hepoxilins can be synthesized by direct treatment of the epoxide in Type A hepoxilins with potassium thiocyanate (KSCN), resulting in the desired thiapropyl ring. Unfortunately, such methods typically only allow for obtaining such analogs from allylic activated epoxides of Type A hepoxilins.

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

[0007] The purpose of providing this background information is to convey to the Applicant information that he believes may be of possible relevance to the present disclosure. It is not necessarily intended to be a comprehensive or exhaustive overview of the pertinent art. It is not intended to be an acknowledgment or citation that the preceding information constitutes prior art merely because it is referenced or discussed in this overview. Rather, factual statements in this overview are often found in the art, and the intent is to enhance understanding of the present disclosure. SUMMARY

[0008] The present disclosure relates to hydroxylated oxepin analogs, more particularly to the synthesis of cyclopropane analogs (PBTs) of hydroxylated oxepins, and to therapeutic methods and pharmaceutical compositions employing individual diastereomers of hydroxylated oxepin cyclopropane analogs.

[0009] In one aspect of the present disclosure, a method of preparing intermediates containing a hydroxyl trans-cyclopropyl group is provided. The method of preparation is scalable and allows for obtaining hydroxylated oxepin analogs in increased product yield and increased purity.

[0010] In one aspect, a new method of synthesis of hydroxylated oxepin analogs (PBTs) such as cyclopropyl analogs is provided. According to another aspect, the synthesis of compounds of general formula I is provided:

[0011]

[0012] Formula (I)

[0013] wherein:

[0014] X is O, CH2, NH, S, N-C1-C6alkyl, (CH2) n or (CH2) m Y1, wherein n = 2, 3 or 4; Y1is S, NH or O, and m is 1, 2 or 3;

[0015] R2is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3or PO3H;

[0016] R3is C4-C 10 alkyl, C4-C 10 alkenyl or C4-C 10 alkynyl;

[0017] R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, saturated or unsaturated C1-C4alcohol, 6-membered aryl or Y2-R1; wherein aryl is optionally -(CH2) n -phenyl, wherein n is 1 to 9, wherein Y2is C1-C 10 alkyl, C2-C 10 alkenyl or C2-C 10alkyl, C2-C6alkenyl, C2-C6alkynyl, and Y2is optionally substituted with -OH and / or halo; and R1is COOR4or CONHR4, wherein R4is H, C1-C6alkyl, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, carbohydrate radical; preferably R4is CH3, H, or C1-C6alkyl which can be substituted with COOH or 5- to 6-membered heterocycle. 10 alkyl; and

[0018] The dashed line (— ) is a single, double, or triple bond.

[0019] In some aspects, the compound of Formula I has the following structure:

[0020] X is CH2;

[0021] R2is OH, H, halo, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H;

[0022] R3is C4-C10alkyl, C4-C10alkenyl, or C4-C10alkynyl;

[0023] R5is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or Y2-R1, wherein Y2is C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, Y2is optionally substituted with -OH and / or halo;

[0024] R1is COOR4or CONHR4, wherein R4is H, CH3, 5- to 6-membered aryl, carbohydrate radical; and

[0025] The dashed line (— ) is a single, double, or triple bond.

[0026] In some aspects, the compound of Formula I has the following structure:

[0027] X is CH2;

[0028] R2is OH;

[0029] R3is C4-C 10 alkenyl;

[0030] Y2-R1, wherein Y2is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, Y2is optionally substituted with -OH and / or halo;

[0031] R1is COOR4, wherein R4is C1-C 10 alkyl; and

[0032] The dashed line (— ) is a double bond.

[0033] According to an aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula III:

[0034] (III)

[0035] The method comprises:

[0036] coupling a compound of Formula 2:

[0037] (2),

[0038] with a suitable protecting group (PG).

[0039] In some aspects, the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0040] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 3:

[0041] (3),

[0042] The method comprises:

[0043] coupling a compound of Formula 2:

[0044] (2),

[0045] with p-methoxybenzyl chloride.

[0046] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula IV:

[0047] (IV),

[0048] The method comprises:

[0049] reacting a compound of Formula (III):

[0050] (III),

[0051] with i) I2, PPh3, and a base; ii) tosyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide.

[0052] In some aspects, the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

[0053] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 4:

[0054] (4),

[0055] The method comprises:

[0056] reacting a compound of Formula (3):

[0057] (3),

[0058] with i) I2, PPh3, and a base; ii) p-toluenesulfonyl chloride and sodium iodide, or iii) methanesulfonyl chloride and sodium iodide.

[0059] In some aspects, the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

[0060] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula V:

[0061] (V),

[0062] The method comprises:

[0063] reacting 1-heptine with a metallating agent to obtain a first mixture; and

[0064] reacting a compound of Formula (IV):

[0065] (IV),

[0066] with the first mixture.

[0067] In some aspects, the metallating agent is n-BuLi or EtMgBr.

[0068] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 5:

[0069] (5),

[0070] The method comprises:

[0071] reacting 1-heptine with a metallating agent to obtain a first mixture; and

[0072] reacting a compound of Formula (4):

[0073] (4),

[0074] in reaction with the first mixture.

[0075] In some aspects, the metallating agent is n-BuLi or EtMgBr.

[0076] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 6:

[0077] (6),

[0078] The method comprises:

[0079] deprotecting a compound of Formula V via a deprotecting agent:

[0080] (V),

[0081] The method comprises:

[0082] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N*HF.

[0083] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 6:

[0084] (6),

[0085] The method comprises:

[0086] deprotecting a compound of Formula 5 via DDQ:

[0087] (5),

[0088] The method comprises:

[0089] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 7:

[0090] (7),

[0091] The method comprises:

[0092] oxidizing a compound of Formula 6 with an oxidizing agent:

[0093] (6),

[0094] The method comprises:

[0095] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0096] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 8 is provided:

[0097] (8),

[0098] The method comprises:

[0099] reacting a compound of Formula 7:

[0100] (7),

[0101] with a second mixture comprising propargyl chloride and a metallating agent.

[0102] In some aspects, the metallating agent is n-BuLi or EtMgBr.

[0103] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula X is provided:

[0104] (X),

[0105] reacting a compound of Formula 8:

[0106] (8),

[0107] with a third mixture comprising a compound of Formula IX:

[0108] (IX),

[0109] CuI, Nal, and a base.

[0110] In some aspects, the base is K2CO3.

[0111] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 10 is provided:

[0112] (10),

[0113] reacting a compound of Formula 8:

[0114] (8),

[0115] with a compound of Formula 9:

[0116] (9)、

[0117] a third mixture of Cul, Nal, and a base.

[0118] In some aspects, the base is K2CO3.

[0119] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula XI is provided:

[0120] (XI),

[0121] The method comprises:

[0122] using a hydrogenation agent to partially hydrogenate a compound of Formula X:

[0123] (X),

[0124]

[0125] In some aspects, the hydrogenation agent is a Lindlar catalyst.

[0126] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula XII is provided:

[0127] (XII),

[0128] The method comprises:

[0129] using a hydrogenation agent to partially hydrogenate a compound of Formula X:

[0130] (X),

[0131]

[0132] In some aspects, the hydrogenation agent is a Lindlar catalyst.

[0133] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 11 is provided:

[0134] (11),

[0135] The method comprises:

[0136] using a hydrogenation agent to partially hydrogenate a compound of Formula 10:

[0137] ​​(10),

[0138] partial hydrogenation.

[0139] In some aspects, the hydrogenation agent is a Lindlar catalyst.

[0140] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 12 is provided:

[0141] (12),

[0142] The method comprises:

[0143] using a hydrogenation agent to form a compound of Formula 10:

[0144] (10),

[0145] partial hydrogenation.

[0146] In some aspects, the hydrogenation agent is a Lindlar catalyst.

[0147] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 13 is provided:

[0148] (13),

[0149] The method comprises:

[0150] under basic conditions to form a compound of Formula 11:

[0151] (11),

[0152] hydrolysis.

[0153] 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.

[0154] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, a method for preparing a compound of Formula 14 is provided:

[0155] (14),

[0156] The method comprises:

[0157] under basic conditions to form a compound of Formula 12:

[0158] (12),

[0159] hydrolysis.

[0160] 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.

[0161] According to one aspect of the disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula XI:

[0162] (XI),

[0163] The method comprises:

[0164] coupling a compound of Formula 2:

[0165] (2),

[0166] with a suitable protecting group (PG) to give a compound of Formula III:

[0167] (III);

[0168] reacting the compound of Formula (III) with i) I2, PPh3, and a first base; ii) p-toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide, to give a compound of Formula IV:

[0169] (IV);

[0170] reacting the compound of Formula (IV) with a first mixture comprising 1-heptine and a metallating agent, to give a compound of Formula V:

[0171] (V);

[0172] deprotecting the compound of Formula V via a deprotecting agent, to give a compound of Formula 6:

[0173] (6);

[0174] oxidizing the compound of Formula 6 with an oxidizing agent, to give a compound of Formula 7:

[0175] (7);

[0176] reacting the compound of Formula 7 with a second mixture comprising propargyl chloride and a metallating agent, to give a compound of Formula 8:

[0177] (8);

[0178] reacting the compound of Formula 8 with a third mixture comprising a compound of Formula IX:

[0179] (X) and

[0180] CuI, Nal, and a second base to yield a compound of Formula X:

[0181] (X); and

[0182] partially hydrogenating the compound of Formula X using a hydrogenation agent to yield the compound of Formula XI.

[0183] In some aspects, the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0184] In some aspects, the first base is imidazole.

[0185] In some aspects, the metalating agent is n-BuLi or EtMgBr.

[0186] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N*HF.

[0187] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0188] In some aspects, the second base is K2CO3.

[0189] In some aspects, the hydrogenation agent is Lindlar's catalyst.

[0190] According to one aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula XII:

[0191] (XII),

[0192] The method comprises:

[0193] coupling a compound of Formula 2:

[0194] (2),

[0195] with a suitable protecting group (PG) to yield a compound of Formula III:

[0196] (III);

[0197] reacting the compound of Formula (III) with i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to obtain a compound of Formula IV:

[0198] (IV);

[0199] reacting the compound of Formula (IV) with a first mixture comprising 1-heptyne and a metalating agent, to obtain a compound of Formula V:

[0200] (V);

[0201] deprotecting the compound of Formula V via a deprotecting agent, to obtain a compound of Formula 6:

[0202] (6);

[0203] oxidizing the compound of Formula 6 with an oxidizing agent, to obtain a compound of Formula 7:

[0204] (7);

[0205] reacting the compound of Formula 7 with a second mixture comprising propargyl chloride and a metalating agent, to obtain a compound of Formula 8:

[0206] (8);

[0207] reacting the compound of Formula 8 with a third mixture comprising a compound of Formula IX:

[0208] (IX),

[0209] CuI, Nal, and a second base, to obtain a compound of Formula X:

[0210] (X); and

[0211] partially hydrogenating the compound of Formula X using a hydrogenating agent, to obtain the compound of Formula XII.

[0212] In some aspects, the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0213] In some aspects, the first base is imidazole.

[0214] In some aspects, the metalating agent is n-BuLi or EtMgBr.

[0215] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N*HF.

[0216] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0217] In some aspects, the second base is K2CO3.

[0218] In some aspects, the hydrogenating agent is Lindlar’s catalyst.

[0219] According to one aspect of the disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 11:

[0220] (11),

[0221] The method comprises:

[0222] coupling a compound of Formula 2:

[0223] (2),

[0224] with p-methoxybenzyl chloride to obtain a compound of Formula 3:

[0225] (3);

[0226] reacting the compound of Formula 3 with i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to obtain a compound of Formula 4:

[0227] (4);

[0228] reacting the compound of Formula 4 with a first mixture comprising 1-heptine and a metallating agent, to obtain a compound of Formula 5:

[0229] (5);

[0230] deprotecting the compound of Formula 5 via a deprotecting agent, to obtain a compound of Formula 6:

[0231] (6);

[0232] oxidizing the compound of Formula 6 with an oxidizing agent, to obtain a compound of Formula 7:

[0233] (7);

[0234] reacting the compound of Formula 7 with a second mixture comprising propargyl chloride and a metalating agent to give a compound of Formula 8:

[0235] (8);

[0236] reacting the compound of Formula 8 with a third mixture comprising a compound of Formula 9:

[0237] (9),

[0238] CuI, Nal, and a second base to give a compound of Formula 10:

[0239] (10), and

[0240] partially hydrogenating the compound of Formula 10 using a hydrogenating agent to give the compound of Formula 11.

[0241] In some aspects, the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0242] In some aspects, the first base is imidazole.

[0243] In some aspects, the metalating agent is n-BuLi or EtMgBr.

[0244] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N HF.

[0245] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0246] In some aspects, the second base is K2CO3.

[0247] In some aspects, the hydrogenating agent is Lindlar's catalyst.

[0248] According to one aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method for preparing a compound of Formula 12:

[0249] (12),

[0250] The method comprises:

[0251] a compound of Formula 2:

[0252] (2),

[0253] with p-methoxybenzyl chloride to obtain a compound of Formula 3:

[0254] (3);

[0255] reacting the compound of Formula 3 with i) I2, PPh3, and a first base; or ii) tosyl chloride and sodium iodide, to obtain a compound of Formula 4:

[0256] (4);

[0257] reacting the compound of Formula 4 with a first mixture comprising 1-heptine and a metallating agent, to obtain a compound of Formula 5:

[0258] (5);

[0259] deprotecting the compound of Formula 5 via a deprotecting agent, to obtain a compound of Formula 6:

[0260] (6);

[0261] oxidizing the compound of Formula 6 with an oxidizing agent, to obtain a compound of Formula 7:

[0262] (7);

[0263] reacting the compound of Formula 7 with a second mixture comprising propargyl chloride and a metallating agent, to obtain a compound of Formula 8:

[0264] (8);

[0265] reacting the compound of Formula 8 with a third mixture comprising a compound of Formula 9:

[0266] (9),

[0267] CuI, Nal, and a second base, to obtain a compound of Formula 10:

[0268] (10), and

[0269] partially hydrogenating the compound of Formula 10 using a hydrogenating agent, to obtain the compound of Formula 12.

[0270] In some aspects, the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl.

[0271] In some aspects, the first base is imidazole.

[0272] In some aspects, the metalating agent is n-BuLi or EtMgBr.

[0273] In some aspects, the deprotecting agent is DDQ, n-Bu4NF, or Et3N*HF.

[0274] In some aspects, the oxidizing agent is Dess-Martin periodinane, pyridinium dichromate, oxalyl chloride-DMSO, or 2-iodoxybenzoic acid (IBX).

[0275] In some aspects, the second base is K2CO3.

[0276] In some aspects, the hydrogenating agent is Lindlar catalyst.

[0277] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 4, or an enantiomer thereof:

[0278] (4).

[0279] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 5, or an enantiomer thereof:

[0280] (5).

[0281] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 6, or an enantiomer thereof:

[0282] (6).

[0283] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 7, or an enantiomer thereof:

[0284] (7).

[0285] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 8, or an enantiomer thereof:

[0286] (8).

[0287] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 10, or an enantiomer thereof:

[0288] (10).

[0289] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of any one of Formulae 11, 12, 13, or 14, which can be used in the treatment of pain or in the manufacture of a medicament for the treatment of pain.

[0290] According to yet another aspect of the present disclosure, which can be used in combination with any other aspect described herein, there is provided a compound of any one of Formulae 11, 12, 13, or 14, which can be used in the treatment of inflammation, cancer, diabetes, analgesia, cardiovascular disease, fibrosis, calcium-mediated diseases, and the like.

[0291] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method of treating, ameliorating, or preventing pain in a subject, the method comprising:

[0292] administering to the subject a compound of Formula 11:

[0293] (11),

[0294] or a pharmaceutically acceptable salt thereof.

[0295] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method of treating, ameliorating, or preventing pain in a subject, the method comprising:

[0296] administering to the subject a compound of Formula 12:

[0297] (12),

[0298] or a pharmaceutically acceptable salt thereof.

[0299] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a method of treating, ameliorating, or preventing pain in a subject, the method comprising:

[0300] administering to the subject a compound of Formula 11:

[0301] (11),

[0302] or a pharmaceutically acceptable salt thereof, and a compound of Formula 12:

[0303] (12),

[0304] or a pharmaceutically acceptable salt thereof.

[0305] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided an analgesic composition for treating, ameliorating or preventing pain in a subject, the composition comprising:

[0306] a compound of Formula 11:

[0307] (11),

[0308] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0309] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided an analgesic composition for treating, ameliorating or preventing pain in a subject, the composition comprising:

[0310] a compound of Formula 12:

[0311] (12),

[0312] or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0313] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 11:

[0314] (11),

[0315] use of a compound of Formula 11, or a pharmaceutically acceptable salt thereof, for treating, ameliorating or preventing pain in a subject, wherein the compound or pharmaceutically acceptable salt thereof is for administration to the subject.

[0316] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 12:

[0317] (12),

[0318] use of a compound of Formula 12, or a pharmaceutically acceptable salt thereof, for treating, ameliorating or preventing pain in a subject, wherein the compound or pharmaceutically acceptable salt thereof is for administration to the subject.

[0319] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 11:

[0320] (11),

[0321] or a pharmaceutically acceptable salt thereof, for use in treating, ameliorating, or preventing pain in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is for administration to the subject.

[0322] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 12:

[0323] (12),

[0324] or a pharmaceutically acceptable salt thereof, for use in treating, ameliorating, or preventing pain in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is for administration to the subject.

[0325] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 11:

[0326] (11),

[0327] or a pharmaceutically acceptable salt thereof, for use in treating, ameliorating, or preventing pain in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is for administration to the subject.

[0328] According to another aspect of the present disclosure, which can be used alone or in combination with any other aspect described herein, there is provided a compound of Formula 12:

[0329] (12),

[0330] or a pharmaceutically acceptable salt thereof, for use in treating, ameliorating, or preventing pain in a subject, wherein the compound or a pharmaceutically acceptable salt thereof is for administration to the subject.

[0331] Other aspects and features of the present 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. The foregoing summary is not necessarily descriptive of all aspects of the disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0332] Embodiments and aspects of the present disclosure will now be described in greater detail, with reference to the drawings, in which:

[0333] Figure 1 is a general scheme depicting the synthesis of compounds 11 and 12;

[0334] Figure 2 is a general scheme depicting the synthesis of compounds of Formula XI and XII;

[0335] Figure 3This describes a general scheme for the synthesis of compounds having formulas 13 and 14;

[0336] Figure 4 This is a graph depicting the effects of PBT-3 (11) and PBT-4 (12) on the plantar mechanical pain threshold in surgical model rats; n=6, mean ± SEM, *p<0.05, **p<0.01, ***p<0.001; and

[0337] Figure 5 A mixture of enantiomers of PBT-3 and PBT-4, each forming an enantiomer, is depicted. Detailed Implementation

[0338] One or more exemplary embodiments and aspects have been described by way of example. This document describes compositions, preparation methods and approaches related to hydroxyepoxygen analogs, and their uses. It should be understood that the embodiments, aspects, and examples are provided for illustrative purposes to those skilled in the art and are not intended to be limiting in any way. All references to embodiments, examples, aspects, chemical formulas, compounds, compositions, solutions, mixtures, etc., are intended to be illustrative and not limiting.

[0339] Definitions

[0340] The term "compound" will be understood to refer to a compound, and in some embodiments, to the extent of its stability, to any of its hydrates or solvates. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, which may be an organic or inorganic solvent.

[0341] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). The compounds disclosed herein are limited to stable compounds encompassed by the compounds described herein or their pharmaceutically acceptable salts.

[0342] As used herein, the term "composition" is intended to cover a specified amount of the specified compound, and any form directly or indirectly produced by a combination of the specified amounts of the specified compound. This term is also intended to cover forms comprising a pharmaceutically acceptable salt of compound 11 or 12 or the aforementioned compounds and one or more pharmaceutically acceptable carriers or excipients. Therefore, the compositions of this disclosure cover any composition prepared by mixing the compounds of this disclosure with one or more pharmaceutically acceptable carriers or excipients. "Pharmaceutically acceptable" means that the carrier or excipient is compatible with the compounds disclosed herein and with other components of the composition.

[0343] The compounds disclosed herein can be used in the form of pharmaceutically acceptable salts. Those skilled in the art will recognize those instances where the compounds of this disclosure can form salts. Examples of such compounds are described herein by reference to possible salts. This reference is for illustrative purposes only. Pharmaceutically acceptable salts can be used with compounds intended for the treatment of patients. However, non-pharmaceutical salts can be used to prepare intermediate compounds.

[0344] The term "pharmaceutically acceptable salt" refers to a salt (including internal salts, such as zwitterions) that has similar efficacy to the parent compound and is biologically or otherwise desirable (e.g., neither toxic nor harmful to its recipient). Therefore, one embodiment of this disclosure provides a pharmaceutically acceptable salt of the compounds of this disclosure. As used herein, the term "salt" means any of the following: an acidic salt formed with an inorganic acid and / or an organic acid, and a basic salt formed with an inorganic base and / or an organic base. Salts of the compounds of this disclosure can be formed by methods known to those skilled in the art, such as by reacting the compounds of this disclosure with a certain amount of an acid or base (such as an equal amount) in a medium (such as a medium in which the salt precipitates) or in an aqueous medium, followed by lyophilization.

[0345] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates (also referred to as “besylates”), bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (also referred to as “mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluenesulfonates (also referred to as “tosylates”), and the like. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids which 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 of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J of Pharmaceutics (1986) 33 201-217; 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 its website).

[0346] 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 dicyclohexyl amines, t-butyl amines, choline, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, and butyl chlorides, bromides, and iodides; methyl, ethyl, and butyl sulfates, for example), long chain halides (for example, decyl, lauryl, and stearyl chlorides, bromides, and iodides; decyl, lauryl, and stearyl sulfates, for example), aralkyl halides (for example, benzyl and phenethyl bromides), and others.

[0347] 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). Furthermore, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters can be used to alter the solubility or hydrolytic properties of the compound.

[0348] Unless explicitly stated to the contrary, all ranges referenced herein are inclusive; that is, a range includes the values ​​at its upper and lower limits, and all values ​​in between. As an example, temperature ranges, percentages, equivalent ranges, etc., as described herein include the upper and lower limits of the range, and any values ​​within a continuous interval therebetween. Numerical values ​​provided herein, and the use of the term "about," can include variations of +1%, 2%, 3%, 4%, 5%, 10%, +15%, and 20%, and their numerical equivalents.

[0349] The compounds disclosed herein, and pharmaceutically acceptable salts of the aforementioned compounds, can be administered by contacting the active agent with the site of action of the agent. The compounds can be administered as a single therapeutic agent or in combination with a therapeutic agent via conventional methods suitable for use in combination with a drug. The compounds can be administered alone, but may also be administered with a drug carrier selected based on the chosen route of administration and standard pharmaceutical practice.

[0350] A composition comprising a pharmaceutically acceptable salt of a compound disclosed herein or a compound thereof, and one or more pharmaceutically acceptable carriers or excipients. The composition may be prepared and packaged in bulk form, wherein a therapeutically effective amount of the disclosed compound may be extracted and then administered to a subject, such as as a powder or syrup.

[0351] Alternatively, the composition may be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt of the aforementioned compound.

[0352] The compounds disclosed herein and pharmaceutically acceptable carriers or excipients can be formulated into dosage forms suitable for administration to a subject via the desired route of administration. For example, dosage forms may include those suitable for: (1) oral administration, such as tablets, capsules, sacs, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, capsules, and flat capsules; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution.

[0353] Suitable pharmaceutically acceptable carriers or excipients will vary depending on the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients can be chosen for their particular function that can be performed in the composition. For example, certain pharmaceutically acceptable carriers or excipients can be chosen because they are able to facilitate the production of a uniform dosage form. Certain pharmaceutically acceptable carriers or excipients can be chosen because they are able to facilitate the production of a stable dosage form. Certain pharmaceutically acceptable carriers or excipients can be chosen because they are able to facilitate the carrying or transport of a compound disclosed herein from one organ or portion of the body to another organ or portion of the body after it has been administered to a subject. Certain pharmaceutically acceptable carriers or excipients can be chosen because they are able to improve patient compliance.

[0354] 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, emulsifying agents, sweeteners, flavoring agents, taste-masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.

[0355] The skilled artisan has the knowledge and skill in the art to select the appropriate amounts of suitable pharmaceutically acceptable carriers and excipients for use in the compositions of the present disclosure. In addition, the skilled artisan has access to a number of resources that describe pharmaceutically acceptable carriers and excipients and can be used to select 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 (American Pharmaceutical Association and Pharmaceutical Press). The compositions of the present disclosure are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Company).

[0356] As used herein, the term "treating" a disease or disorder can include: preventing the disease or disorder, i.e., causing the clinical symptoms of the disease or disorder not to develop in a subject that can be exposed to or predisposed to the disease or disorder but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting the development of the disease or its clinical symptoms; relieving the disease, i.e., causing the regression of the disease or its clinical symptoms.

[0357] An "effective amount" when used in connection with the compositions 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 is not limited to, treating, ameliorating, or preventing pain in a subject. An "effective amount" when used in connection with one or more agents disclosed herein is the total amount of the one or more agents that can be used to treat, ameliorate, or prevent pain.

[0358] The term "about" means the recited numerical indication plus or minus 10% of that recited numerical indication.

[0359] As used herein, unless otherwise indicated, "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups with one to ten carbon atoms. For example, "Ci-C 10 alkyl" specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. 10 defined as including groups that have a linear, branched, or cyclic arrangement with one, two, three, four, five, six, seven, eight, nine, or ten carbon atoms. For example, "Ci-C 10 alkyl" specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.

[0360] The term "alkenyl" if not specified as to the number of carbon atoms refers to straight or branched chain nonaromatic hydrocarbon groups containing 2 to 10 carbon atoms and at least one carbon-carbon double bond. Thus, "C2-C6 alkenyl" means an alkenyl group having 2 to 6 carbon atoms. Alkenyl groups include ethenyl, propenyl, butenyl, and cyclohexenyl. As described above for alkyl groups, the straight chain, branched, or cyclic portions of the alkenyl groups can contain the double bond and can be substituted if a substituted alkenyl group is indicated.

[0361] The term "alkynyl" if not specified as to the number of carbon atoms refers to straight or branched chain nonaromatic hydrocarbon groups containing 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Thus, "C2-C6 alkynyl" means an alkynyl group having 2 to 6 carbon atoms and at least one triple bond. Alkynyl groups include ethynyl, propynyl, butynyl, and cyclohexynyl. As described above for alkyl groups, the straight chain, branched, or cyclic portions of the alkynyl groups can contain the triple bond and can be substituted if a substituted alkynyl group is indicated.

[0362] As used herein, "ring" is intended to mean any stable monocyclic or bicyclic carbocyclic ring having at least three and up to 12 atoms in each ring. Examples of such elements include cycloalkanes, cycloalkenes, and cycloalkynes.

[0363] As used herein, "heterocycle" is intended to mean any stable monocyclic or bicyclic carbon ring having 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 heterocyclic alkanes, heterocyclic alkenes, and heterocyclic alkynes.

[0364] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring having up to 12 atoms in each ring, at least one of which is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl. In the event the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.

[0365] As used herein, the term "heteroaryl" denotes a stable monocyclic, bicyclic, or tricyclic ring having up to 10 atoms in each ring, at least one of which is aromatic and contains 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: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinoly, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, oxazolyl, and tetrahydroquinoline. In the event the heteroaryl substituent is bicyclic and one ring is non-aromatic or does not contain a heteroatom, it is understood that attachment is via the aromatic ring or via the heteroatom-containing ring, respectively. If the heteroaryl contains a nitrogen atom, it is understood that the corresponding N-oxides are also encompassed by this definition.

[0366] As understood by one of skill in the art, "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo, and iodo.

[0367] As understood by one of skill in the art, the term "carbohydrate group" as used herein refers to any suitable carbohydrate group such as, but not limited to, a glucose, galactose, glucosamine, or galactosamine moiety.

[0368] The compounds of the present application can have asymmetric centers, chiral axes and chiral planes of symmetry (as described in E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pp. 1119-1190), and can exist as racemates, racemic mixtures, and as individual diastereomers, all of which are intended to be within the scope of the present application, unless otherwise indicated. In addition, the compounds disclosed herein can exist as tautomers, and both tautomeric forms are intended to be covered by the scope of the present application, even though only one tautomeric structure is depicted.

[0369] Embodiments of the present disclosure

[0370] Disclosed herein are synthetic methods and processes for preparing cyclopropyl analogs (PBTs) of hydroxyoxyphenyls. For example, provided is the synthesis of a compound of general formula I:

[0371]

[0372] Formula (I)

[0373] wherein:

[0374] X is O, CH2, NH, S, N-C1-C6alkyl, (CH2) n or (CH2) m Y1, wherein n = 2, 3 or 4; Y1is S, NH or O, and m is 1, 2 or 3;

[0375] R2is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3or PO3H;

[0376] R3is C4-C 10 alkyl, C4-C10alkenyl or C4-C 10 alkynyl;

[0377] R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, saturated or unsaturated C1-C4alcohol, 6-membered aryl or Y2-R1; wherein aryl is optionally -(CH2) n- phenyl, wherein n is 1 to 9, wherein Y2is C1-C10alkyl, C2-C10alkenyl, or C2-C10alkynyl, and said Y2is optionally substituted with -OH and / or halogen, wherein R1is OH, halogen, N3, NH2, COOR4, or CONHR4, wherein R4is H, C1-C6alkyl, 5- to 6-membered cycloalkyl, 5- to 6-membered aryl, carbohydrate group; in some cases, R4is CH3, H, or C1-C6alkyl which can be substituted with COOH or 5- to 6-membered heterocycle; and 10 alkyl; and

[0378] A dashed line (— ) is a single, double, or triple bond.

[0379] In some embodiments, the compound of Formula I has the following structure:

[0380] X is CH2;

[0381] R2is OH, H, halogen, C1-C6alkyl, CH2OH, N3, NH2, SH, CH2N3, or PO3H;

[0382] R3is C4-C 10 alkyl, C4-C 10 alkenyl, or C4-C 10 alkynyl;

[0383] R5is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, or Y2-R1, wherein Y2is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, Y2is optionally substituted with -OH and / or halogen;

[0384] R1is COOR4or CONHR4, wherein R4is H, CH3, 5- to 6-membered aryl, carbohydrate; and

[0385] A dashed line (— ) is a single, double, or triple bond.

[0386] In some aspects, the compound of Formula I has the following structure:

[0387] X is CH2;

[0388] R2is OH;

[0389] R3is C4-C 10 alkenyl;

[0390] Y2-R1, wherein Y2is C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10alkynyl, Y2is optionally substituted with -OH and / or halo;

[0391] R1is COOR4, wherein R4is C1-C 10 alkyl; and

[0392] The dashed line (— ) is a double bond.

[0393] Exemplary synthetic schemes for compounds of Formula I, such as PBT-3, PBT-4, PCA-3, and PCA-4, are shown in Figure 1 , Figure 2 and Figure 3 .

[0394] As shown therein, commercially available trans-dimethyl 1,2-cyclopropanedicarboxylate 1 (B0) [CAS 826-35-7] can be a source of the cyclopropane moiety of compounds 11, 12, XI, and XII. Trans-dimethyl 1,2-cyclopropanedicarboxylate 1 can be a mixture of enantiomers, such as a racemic mixture.

[0395] In Step 1, reduction of compound 1 (B0) can be performed with a suitable reducing agent, such as lithium aluminum hydride, diisobutylaluminum hydride (DIBAL-H), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), lithium borohydride, lithium triethylborohydride, or diborane-dimethyl sulfide complex, to give trans-cyclopropane-1,2-diyl dimethanol 2 (B1).

[0396] In Step 2, the one hydroxyl group in compound 2 (B1) can be protected with a suitable protecting group. While p-methoxybenzyl is described as the protecting group, other groups can be used, such as tert-butyldimethylsilyl-, tert-butyldiphenylsilyl-, and the like. Protection of compound 2 with p-methoxybenzyl gives trans-(2-{[(4-methoxybenzyl)oxy]methyl}cyclopropyl)methanol 3 (B2).

[0397] In Step 3, the hydroxyl group in compound 3 (B2) is exchanged for an iodine moiety by treatment with I2in the presence of PPh3and imidazole, or by obtaining the corresponding p-toluenesulfonate and treatment with sodium iodide, or by obtaining the mesylate with sodium iodide, to give trans-1-({[2-(iodomethyl)cyclopropyl]methoxy}methyl)-4-methoxybenzene 4 (B3). Those skilled in the art will appreciate that the p-toluenesulfonate or mesylate is an example of a suitable leaving group for the subsequent substitution reaction.

[0398] In Step 4, iodide 4 (B3) is treated with 1-heptyne in THF-HMPA using n-BuLi or EtMgBr as the metallating agent to give trans-1-methoxy-4-{[(2-oct-2-yn-1- ylcyclopropyl)methoxy]methyl}benzene 5 (B4).

[0399] In Step 5, compound 5 (B4) is treated with a suitable deprotection agent such as DDQ to cleave the p-methoxybenzyl group or n-Bu4NF or Et3N*HF to cleave the t- butyldimethylsilyl or t-butyldiphenylsilyl group. Deprotection 5 provides intermediate trans-(2-oct-2-yn-1- ylcyclopropyl)methanol 6 (M3).

[0400] 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 give trans-(1R,2R)-2-oct-2-yn-1- ylcyclopropanecarboxaldehyde 7 (M4).

[0401] In Step 7, aldehyde 7 (M4) is treated with propargyl chloride in Et20 or THF using n-BuLi or EtMgBr as the metallating agent to give (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.

[0402] In Step 8, compound 8 (M5) is reacted with methyl hexynoate 9 or other alkyl esters (including ethyl, t-butyl, benzyl-, etc.) (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 to give precursors (10S*)- and (10R*)-10-hydroxy-10-[(1R*,2R*)-2-oct-2-yn-1- ylcyclopropyl]dec-5,8-diynoate methyl ester 10 (M6) with a 3:5 ratio of epimers at C10 (trans: cis diastereomeric ratio of the hydroxyl and cyclopropyl stereocenters).

[0403] 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 give: (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8- dienoic acid methyl ester 11 (PBT-3) (minor product, less polar) and (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-dienoic acid methyl ester 12 (PBT-4) (major product, more polar).

[0404] In step 10, hydrolysis of compound 11 (PBT-3) and compound 12 (PBT-4) in MeOH-H2O is carried out under suitable conditions such as basic conditions to give the corresponding free acids (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-dienoic acid 13 (PCA-3) and (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-dienoic acid 14 (PCA-4). Figure 3

[0405] ​Compounds 11 and 12 can be purified using one or more suitable purification techniques such as silica gel column chromatography followed by additional purification by preparative RP-HPLC. The target compounds can be obtained in a diastereomeric ratio of 3:5 (compound 11 : compound 12) as clear oils. The same ratio between the more and less polar epimers is obtained for the natural HxB3 methyl ester when a similar condensation of the appropriate aldehyde with the Li derivative of the terminal acetylene is used (Vasiljeva et al., Tetrahedron 49: 1993, 4099). Therefore, the same relative configuration is expected for the less and more polar PBT-3 and PBT-4. NMR spectra of the individual PBT-3 and PBT-4 methyl esters show some differences between the epimers: the coupling constant J10,11 of the more polar epimer (d, J = 7.8 Hz) is larger than that of the less polar epimer (d, J = 7.3 Hz), and the proton at C11 of the cyclopropyl group has a smaller chemical shift (0.68 ppm) for the more polar epimer than for the less polar epimer (0.81 ppm). These data are consistent with the data described for a, b-cyclopropylmethanol systems (Descotes et al., Tetrahedron 29: 2931-2935, 1973).

[0406] Although Figure 1 and Figure 2 depicts purification / isolation of epimers 11 and 12 after step 9, one skilled in the art will appreciate that the hydroxyl epimers can be isolated at an earlier step, such as step 8. The epimers 11 and 12 can be isolated as free hydroxyl groups, or as one skilled in the art will appreciate, the hydroxyl group can first be coupled to a chiral resolving agent known in the art. Coupling to a chiral resolving agent can improve resolution of the epimers compared to uncoupled epimers.

[0407] As one skilled in the art will appreciate, Figures 1-3 The synthetic method depicted in Scheme 1 is an example of a suitable method of synthesizing compounds of Formula I. Modifications known in the art can be made to the synthetic procedure described above to obtain different compounds of Formula I. For example:

[0408] In embodiments where X is O: the epoxide derivative of compound 1 can be obtained by epoxidation of the trans double bond, or alternatively, the trans double bond derivative of compound 1 where the cycloalkane is a double bond is subsequently converted to an epoxide, such as prior to step 9;

[0409] In embodiments where X is NH: the synthesis of analogous aziridine intermediates is known in the art, for example: Tetrahedron, 2011, Vol. 67, Issue 14, pp. 2570-2578, which is incorporated by reference.

[0410] In embodiments where X is N-Ci-C6alkyl: the NH in the aziridine intermediate as discussed above can be alkylated;

[0411] In embodiments where X is S: the epoxide intermediate as discussed above can be treated with KSCN;

[0412] In embodiments where R2is halogen: procedures known in the art can be used to substitute the -OH of R2-OH with Cl, Br or I;

[0413] In embodiments where R2is N3: embodiments where R2= Br or I can be treated with sodium azide;

[0414] In embodiments where R2is NH2: embodiments where R2is azide can be reduced using PPh3or other methods known in the art;

[0415] In embodiments where R2is SH: embodiments where R2= OH can be treated with Lawessons reagent;

[0416] In embodiments where R2is PO3H: embodiments where R2= OH can be phosphorylated with corresponding reagents known in the art, such as triisopropyl phosphate, followed by removal of the isopropyl moieties;

[0417] In embodiments where R3is C4-C 10 alkenyl: the corresponding terminal alkyne can be used; 10 In embodiments where R3is C4-C

[0418] In embodiments where R3is C4-C 10 alkenyl: the corresponding terminal alkyne can be used;

[0419] In embodiments where R3is C4-C 10 alkynyl: the corresponding terminal alkyne can be used;

[0420] In embodiments where R5is Ci-C6alkyl: aldehyde 7 (M4) can be treated with the corresponding Grignard reagent derived from an alkyl halide;

[0421] In embodiments where R5is C2-C6alkenyl: aldehyde 7 (M4) can be treated with the corresponding lithiated terminal acetylene, followed by reduction of the triple bond moiety to a double bond;

[0422] In embodiments where R5is C2-C6alkynyl: aldehyde 7 (M4) can be treated with the corresponding lithiated terminal acetylene;

[0423] In embodiments where R5is a saturated or unsaturated C1-C4alcohol: the ester groups of PBT-3 (11) and PBT-4 (12) can be reduced to alcohols using a suitable reducing agent;

[0424] In embodiments where R5is a 6-membered aryl: aldehyde 7 (M4) can be treated with the corresponding lithiated C6aryl;

[0425] In embodiments where R5is Y2-R1; where aryl is -(CH2) n - phenyl, where n is 1 to 9, where Y2is C1-C 10 alkyl, C2-C 10 alkenyl, or C2-C 10 alkynyl: such compounds can be obtained by treating aldehyde 7 (M4) with the corresponding lithiated alkyl, alkenyl, or alkynyl halide;

[0426] In embodiments where R5is Y2substituted with -OH and / or halogen: aldehyde 7 (M4) can be treated with the corresponding lithiated compound, optionally with a protected OH group (e.g., an OSiMe2tBu protecting group or other group), and the halogen can be obtained by exchanging OH with Cl, Br, or I using methods known in the art;

[0427] In embodiments where R1is OH, halogen, N3, NH2, COOR4, or CONHR4: aldehyde 7 (M4) can be treated with the corresponding lithiated compound, optionally with a protected OH group (OSiMe2tBu, etc.), followed by substitution of OH with halogen, N3, or NH2; for COOR4: esterification using PBT-3 and PBT-4 can be used; for COONH4, amidation of PCA-3 and PCA-4 with the corresponding alkyl amine or aryl amine (including carbohydrate amines such as glucosamine or galactosamine) can be used; and

[0428] In embodiments where the dashed line (— ) is a single bond: one or more of the triple bonds of compound 10 (M6) can be fully hydrogenated to single bonds.

[0429] The compounds, compositions, and methods of the present application can be used to treat or prevent pain. In some embodiments, the compounds of the compositions described herein are 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 to the subject a compound of Formula 11, or a pharmaceutically acceptable salt thereof.

[0430] In one embodiment, there is provided a method of treating, ameliorating or preventing pain in a subject, the method comprising administering to the subject a compound of Formula 12, or a pharmaceutically acceptable salt thereof.

[0431] In one embodiment, there is provided a method of treating, ameliorating or preventing pain in a subject, the method comprising administering to the subject a compound of Formula 11, or a pharmaceutically acceptable salt thereof, and a compound of Formula 12, or a pharmaceutically acceptable salt thereof.

[0432] In one embodiment, there is provided an analgesic composition for use in treating, ameliorating or preventing pain in a subject, the composition comprising a compound of Formula 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0433] In one embodiment, there is provided an analgesic composition for use in treating, ameliorating or preventing pain in a subject, the composition comprising a compound of Formula 12, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0434] The present disclosure will be further illustrated in the following examples.

[0435] Examples

[0436] Example 1 : Synthesis of compounds 11 and 12

[0437] Instruments and reagents

[0438] Purification of PBT-3 (11) and PBT-4 (12) was performed by preparative HPLC using a CN-3 column 4.6 x 250 mm (Inertsil ™ GC analysis of tBDMS derivatives of PBT-3 (11) and PBT-4 (12) was performed on an Agilent 7890B gas chromatograph using an Agilent HP column (30 m x 0.32 mm x 0.25 pm). 1 H-NMR spectra were obtained on a Bruker-AM400 (500 MHz) spectrometer (Bruker, Karlsruhe, Germany) in CDC13 with Me4Si as internal standard (δ = 0). LCMS (ESI) analysis of PBT-3 (11) and PBT-4 (12) was performed on an Agilent Ultivo instrument.

[0439] Trans-(2-{[(4-methoxybenzyl)oxy]methyl}cyclopropyl)methanol (3, PBT-B2)

[0440] To a mixture of DMF (350 g) and PBT-B1 (2, 51.6 g, 506 mmol) in a 2000 mL three necked flask was added 60% NaH (16.2 g, 405 mmol) in portions at 40-45 °C. After the addition was complete, the mixture was stirred at 55-60 °C for 1 hour, then cooled to 20-30 °C, and added NaI (1.5 g, 10 mmol) followed by TBAB (1.5 g, 4.7 mmol). To the prepared mixture was added PMB-Cl (63.4 g, 406 mmol) dropwise, and the mixture was stirred at 20-30 °C for 2 hours. The mixture was quenched with 100 g of NH4Cl (aqueous solution), evaporated at 60 °C and 0.5 mm Hg to remove DMF, diluted with water (200 g), extracted with dichloromethane (2 x 330 g). The combined organic phase was washed with water (200 g) and saturated brine (200 g), and dried over MgSO4. The solvent was evaporated, and the red-brown oily residue (113 g) was purified by silica gel eluted with 20% EtOAc in hexanes to give PBT-B2 (3, 46.4 g) with an overall yield of 41.3% for two steps.

[0441] 1 H-NMR (400 MHz, CDCl3, ppm): 0.42-0.49 (m, 2H, cyclopropyl-H), 0.95-1.02 (m, 2H, H 2 +H 3 ), 2.17 (br.s, 1H, OH), 3.21 (m, 1H, H 4 ), 3.35 (m, 2H, H 1 ), 3.45 (m, 1H, H 1' ), 3.79 (s, 3H, OCH3), 4.45 (s, 2H, Ar-CH2), 6.86 (d, 2H, Ar-H), 7.24 (d, 2H, Ar-H).

[0442] Trans-1-({[2-(iodomethyl)cyclopropyl]methoxy}methyl)-4-methoxybenzene (4, PBT-B3)

[0443] PPh3 (141.6 g, 508 mmol) and imidazole (36.8 g, 541 mmol) were dissolved into 1200 mL CH2Cl2cooled to below 8 °C and I2(137 g, 539 mmol) was added in portions keeping the temperature below 30 °C. The mixture was cooled to -5 °C - 0 °C and a solution of PBT-B2 (3, 80.0 g, 360 mmol) in 400 mL CH2Cl2was added dropwise. The mixture was stirred at 10 °C - 15 °C for 1 hour and quenched with water (320 g). The organic layer was separated and washed with water and saturated brine, dried over MgSO4and evaporated. The residue (274 g) was passed through silica gel eluting with 10% EtOAc in hexanes. The filtrate was evaporated to give 117.0 g of PBT-B3 (4) as an oil, 97.87% yield.

[0444] 1 H-NMR (400 MHz, CDCl3, ppm): 0.52 and 0.76 (m, 2H, cyclopropyl-H), 1.04-1.27 (m, 2H, H 2 +H 3 ), 2.17 (br.s, 1H, OH), 3.21 (m, 1H, H 1 ), 3.06-3.11 (t, 1H, H 4 ), 3.18-3.35 (m, 3H, H 1 +H 4 ), 3.79 (s, 3H, OCH3), 4.45 (s, 2H, Ar-CH2), 6.86 (d, 2H, Ar-H), 7.23 (d, 2H, Ar-H).

[0445] Trans-1-methoxy-4-{[(2-oct-2-yn-1-ylcyclopropyl)methoxy]methyl}benzene (PBT-B4, 5)

[0446] A solution of 1-heptine [CAS 628-71-7] (84.7 g, 882 mmol) in THF (1190 mL) was cooled to -60°C under nitrogen. To this solution was added dropwise a 2.5 M solution of n-BuLi in hexanes (350 mL, 875 mmol) below -50°C. After stirring for 30 minutes, a mixture of HMPA / THF [189 g HMPA + 250 ml THF] was added and the mixture was stirred at -50°C for 30 minutes. To the mixture was added a solution of PBT-B3 (4, 117.0 g, 352 mmol) in 300 mL THF and the mixture was stirred at -30°C for 0.5 hours and then at 10-20°C for 4 hours. The mixture was quenched with saturated NH4Cl solution (500 g) at -5-0°C. The organic layer was washed with saturated NH4Cl (500 g) and saturated brine (300 g), dried over MgSO4 and evaporated to give PBT-B4 (5, 105.8 g, quantitative) as an oil which was used in the next step without further purification.

[0447] Trans-(2-oct-2-yn-1-ylcyclopropyl)methanol (PBT-M3, 6)

[0448] To a mixture of PBT-B4 (5, 105.8 g, 353 mmol) in CH2Cl2(1000 mL) and water (50 mL) was added DDQ (120 g, 1892 mmol) and the mixture was stirred for 0.5-1.0 hours. The mixture was filtered off. The filtrate was washed with saturated NaHCO3(2 x 525 g), saturated NaHSO3(2 x 525 g) and saturated brine (400 g), dried over MgSO4 and evaporated. The crude brown-black oil was purified by column chromatography on silica gel eluting with EtOAc-hexanes to give 32.5 g of M3 (6) in a total yield of 50% from B2 to M3 (iodination, Csp 3 -coupling, deprotection).

[0449] 1 H-NMR (400 MHz, CDC13, ppm): 0.40-0.55 (dt, 2H, cyclopropyl-H), 0.73-0.85 (m, 2H, H 2 +H 3 ), 0.90 (t, 3H, H 11 ), 1.33 (m, 4H, H 9 +H 10 ), 1.48 (quintet, 2H, H 8 ), 2.14 (tt, 2H, H 7 ), 2.19 and 2.23 (dt, 1H, H4 ), 2.32 and 2.35 (dt, 1H, H 4' ), 3.46 (m, 2H,H 1 )。

[0450] Trans-(1R,2R)-2-oct-2-yn-1-ylcyclopropanecarboxaldehyde (PBT-M4, 7)

[0451] To a solution of PBT-M3 (6, 10.0 g, 55.5 mmol) in CH2Cl2(200 mL) was added Dess-Martin periodinane (35.3 g, 83.3 mmol) in portions at 10-20 °C under stirring over 60 min. Then water (1 g) was added and the mixture was stirred at ambient temperature for 1 h. The mixture was concentrated under vacuum at 40 °C to remove CH2Cl2. Then the residue was diluted with MTBE (200 mL) and stirred for 30 min. The mixture was filtered and the filtrate was evaporated at 70 °C to remove MTBE and AcOH formed as by-products. M4 (7) was obtained as a light yellow oil (10.2 g, quantitative) which was used in the next step without further purification.

[0452] (1S*)- and (1R*)-4-chloro-1-[(1R*,2R*)-2-oct-2-yn-1-ylcyclopropyl]but-2-yn-1-ol (PBT-M5, 8)

[0453] A solution of propargyl chloride [CAS 624-65-7] (12.4 g, 166 mmol) in 300 mL Et2O was cooled to -60 °C. A 2.5 M n-BuLi solution in hexanes (66 mL, 165 mmol) was added dropwise at a temperature below -50 °C and the mixture was stirred at -50 °C for 30 min. Then a 20 mL Et2O solution of PBT-M4 (7, 9.89 g, 55.6 mmol) was added dropwise and the mixture was stirred at -50 °C for 30 min. The mixture was quenched with water and warmed to ambient temperature for 10 min. The organic layer was separated, dried over MgSO4and evaporated. The light yellow oil was purified by silica gel column chromatography eluted with EtOAc in hexanes to give 9.6 g of M5 (8) with an overall yield of 68.5% for the two steps (oxidation, aldehyde addition) from M3 to M5.

[0454] Note: Intermediate M5 is not stable at room temperature. It is stable when stored at -20 °C.

[0455] 1 H-NMR (400 MHz, CDC13, ppm): 0.57-0.69 (m, 2H, cyclopropyl-H), 0.90 (t, 3H, J = 7.1 Hz, H 14 ), 1.03, 1.09 (m, 1H, H 5), 1.19 (m, 1H, H 6 ), 1.32 (m, 4H, H 12 +H 13 ), 1.48 (quintet, 2H, J=7.2Hz, H 11 ), 1.89 (d, 1H, J=6.4Hz, OH), 2.13 (tt, 2H, J=2.4 and 7.2Hz, H 10 ), 2.22-2.40 (m, 2H, H7), 4.15 (t, 2H, J=2.3Hz, H 1 ), 4.28 (m, 0.3H, H 4 ), 4.35 (m, 0.7H, H 4' ).

[0456] (10S*)- and (10R*)-10-hydroxy-10-[(1R*,2R*)-2-oct-2-yn-1-ylcyclopropyl]dec-5,8-diyne acid methyl ester (PBT-M6, 10) (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-diene acid methyl ester (PBT-3, 11) and (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-diene acid methyl ester (PBT-4, 12)

[0457] A suspension of anhydrous CuI (9.0 g, 47.3 mmol), NaI (14.2 g, 94.6 mmol), and K₂CO₃ (13.1 g, 94.9 mmol) in 120 mL of DMF was supplemented with a solution of methyl 5-hexynate [CAS 77758-51-1] (9, 6.6 g, 52.3 mmol) in 30 mL of DMF and a solution of propargyl chloride PBT-M5 (8, 12.0 g, 47.6 mmol) in 30 mL of DMF. The mixture was stirred at 15 °C–25 °C for 16 hours, and then an aqueous solution of NH₄Cl (360 mL) was added. The mixture was extracted with MTBE (360 mL), the organic phase was washed with NH4Cl aqueous solution (2 × 180 mL), dried over MgSO4, and the residue was purified by silica gel column chromatography by elution with 16% EtOAc in hexane to give a yellow oily triyne (PBT-M6, 10) (12.2 g, 75.0%). 1 H-NMR analysis showed that the diastereomer ratio was 3:5 (trans:cis diastereomer ratio of the hydroxyl and cyclopropyl stereocenters).

[0458] Note: Intermediate M6 is unstable even when stored at -20°C. M6 should be used as soon as possible.

[0459] 1 ¹H-NMR (400MHz, CDCl₃, ppm): 0.57–0.64 (m, 2H, cyclopropyl-H), 0.90 (t, 3H, J=7.0Hz, H₂). 20), 1.00-1.22 (m, 2H, H 11 +H 12 ), 1.33 (m, 4H, H 18 +H 19 ), 1.48 (quintet, 2H, H) 17 ), 1.82 (quintet, 2H, H) 3 ), 2.13-2.25 (m, 6H, H 4 +H 13 +H 16 ), 2.44 (t, 2H, H 2 ), 3.15-3.30 (m, 2H, H) 7 ), 3.68 (s, 3H, COOMe), 4.26 (dt, 0.4H, H 10 ), 4.32 (dt,0.65H, H 10' ).

[0460] Figure 5 (5Z,8Z,10S*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-diene acid (PCA-3, 13) and (5Z,8Z,10R*)-10-hydroxy-10-{(1R*,2R*)-2-[(2Z)-oct-2-en-1-yl]cyclopropyl}dec-5,8-diene acid (PCA-4, 14) Example 2 - Study of the biological activity of PBT-3

[0461] A solution of triyne M6 (10, 10 g, 29.2 mmol) in 200 mL of cyclohexane was added to a mixture of hydrogen-presaturated lindra catalyst (10 g) and quinoline (50 g) in 300 mL of cyclohexane. The resulting mixture was stirred with an H2 balloon for 2 hours. The poisoned catalyst was filtered off, and the filtrate was added to a fresh portion of hydrogen-presaturated lindra catalyst (10 g) and quinoline (10 g) in 100 mL of cyclohexane. During this procedure, the reaction mixture was analyzed by GC, and hydrogenation was carried out until the contents of PBT-3 (11) and PBT-4 (12) in the reaction mixture reached 80%. The catalyst was filtered off, and the filtrate was washed with 5% HCl aqueous solution to remove quinoline, dried with MgSO4, and evaporated. The residue was purified by silica gel column chromatography, eluting with a 15% EtOAc hexane solution to obtain two crude epimers, PBT-3 (11, less polar, 4.0 g, 39.2%) and PBT-4 (12, more polar, 6.0 g, 58.8%). The crude PBT-3 (11) and PBT-4 (12) were purified by preparative RP-HPLC to obtain PBT-3 (11, 2.9 g, 29%) and PBT-4 (12, 4.9 g, 48%). Mice As shown, diastereomeric pure PBT-3 and PBT-4 were obtained, which are mixtures of enantiomers.

[0462] PBT-3 (11) 1H-NMR (400 MHz, CDC13, ppm): 0.34 (dt, IH, J = 4.8, 8.4 Hz, cyclopropyl-H), 0.43 (dt, IH, J = 8.4, 5.0 Hz, cyclopropyl-H), 0.75-0.85 (m, 2H, H 11 +H 12 ), 0.88 (t, 3H, J = 7.0 Hz, H 20 ), 1.24-1.38 (m, 4H, H 18 +H 19 ), 1.63-1.77 (m, 4H, H 3 +H 17 ), 1.92-2.15 (m, 6H, H 4 +H 13 +H 16 ), 2.31 (t, 2H, J = 7.5 Hz, H 2 ), 2.70-2.88 (m, 2H, H 7 ), 3.66 (s, 3H, COOMe), 3.96 (ddd, IH, J = 1.0, 7.3 and 7.3 Hz, H 10 ), 5.33-5.43 (m, 6H, olefinic).

[0463] MS (ESI, pos) for PBT-3 (11): 331.3 [M-OH] + , 371.3 [M+Na] + .

[0464] MS (ESI, pos) for PBT-4 (12): 1 H-NMR (400 MHz, CDC13, ppm): 0.39 (dt, IH, J = 4.8 and 8.1 Hz, cyclopropyl-H), 0.53 (dt, IH, J = 4.8 and 8.5 Hz, cyclopropyl-H), 0.68 (m, IH, H 11 ), 0.83 (m, IH, H 12 ), 0.87 (t, 3H, J = 6.8 Hz, H 20 ), 1.26-1.36 (m, 6H, H 17 +H 18 +H 19 ), 1.70 (quintet, 2H, J = 7.5 Hz, H 3 ), 1.90-2.12 (m, 6H, H4 +H 13 +H 16 ), 2.32 (t, 2H, J=7.5Hz, H 2 ),2.75 (m, 2H, H 7 ), 3.67 (s, 3H, COOMe), 3.95 (ddd, 1H, J=1.0, 7.8 and 7.8Hz, H 10 ), 5.36-5.50 (m, 6H, olefinic H).

[0465] MS (ESI, pos) of PBT-4 (12): 331.3 [M-OH] + 371.3 [M+Na] + .

[0466] Drugs Mechanical sensitivity (von Frey) test Carrageenan hypersensitivity

[0467] Add 10 mL of 0.1 N NaOH to a 10 mL solution of PBT-3 (11) (350 mg, 1.0 mmol) or PBT-4 (12) (350 mg, 1.0 mmol) in MeOH and incubate the solution at ambient temperature for 5 hours. Evaporate the MeOH, extract the aqueous solution with Et2O (2×), and discard the Et2O extract. Acidify the aqueous layer to pH 3 with 0.1 N HCl, extract with EtOAc, and dry and evaporate the combined organic extracts with Na2SO4 to give two epimers of PCA-3 and PCA-4 (330 mg, 98%).

[0468] MS (ESI, pos): 335.2. [M+H] for PCA-3 (13). + MS (ESI, pos): 335.2. [M+H] for PCA-4 (14) +

[0469] Table 1 : Summary of the results of the von Frey test

[0470] Example 3: Study of the analgesic activity of PBT-4 and comparative study between PBT-3 and PBT-4

[0471] Experiments were performed on naive adult (7-8 weeks old) C57B1 / 6 / N female mice obtained from Charles River (Saint Constant, Quebec, Canada). All mice were housed in groups of four in ventilated cages (5 x 7 x 14 inches) in closed circuit ventilated cages (Techniplast Easy Flow #BOX110EFUL) upon arrival. All mice were maintained in a temperature-controlled environment (20°C ± 1°C) with a 12:12 hour light:dark cycle. Compressed cotton nesting pads and corrugated paper bedding were provided in each cage as an environmental enrichment source. All mice had ad libitum access to food (Harlan Teklad 8604) and water. Procedures followed the standards of animal care set forth by the Canadian Council on Animal Care (CCAC) and approved by the Laboratory Animal Sciences Biosciences Committee at the University of Toronto.

[0472] Figures 1-3

[0473] 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 μΐ) was added to each sample prior to injection into mice. Morphine and ketorolac were administered intraperitoneally (10 ml / kg volume), while PBT-3 (11) was administered subcutaneously (20 μΐ) into the left hind paw.

[0474] Figure 5

[0475] All mice were habituated to the test chamber for at least 60 minutes prior to the start of testing. For the von Frey test, mice were randomly assigned to drug and dose, and the experimenter was blind to drug and dose. Dixon's up-and-down method was used (PMID: 7990513). Mice were placed on a perforated metal floor (holes 5 mm in diameter placed 7 mm apart) within a small Plexiglas chamber (9 x 5 x 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; in the range of forces from ≈ 0.15 g to ≈ 1.3 g) was applied to the plantar surface of the hind paw until the fiber bent, and then held for 3 seconds. For all baseline measurements, the threshold force required to elicit a paw withdrawal (median 50% paw withdrawal) was determined twice on each hind paw (and averaged) with a minimum of 20 minutes between consecutive measurements. After drug administration, 1 measurement was made on each hind paw at the indicated time points.

[0476] Table 2: Grouping of the animals and doses

[0477] Lambda carrageenan (2%; 20 mg / mL; Sigma Aldrich, Oakville, ON) was suspended in saline by sonication and injected subcutaneously into the plantar surface of the left hind paw using a 100 μL microsyringe with a 30 gauge needle in a volume of 20 μL. The mechanical sensitivity of both hind paws of the mice was tested using the von Frey test before carrageenan injection and 3 hours after carrageenan injection. All drugs were injected immediately after the post-carrageenan (3 hours) test, and post-drug measurements were made after 30 minutes, 60 minutes, and 120 minutes.

[0478] Establishment of the animal model

[0479]

[0480] These results show that the PBT compounds described in this specification show dose-dependent analgesic activity. The activity of PBT-3 at 30 minutes after drug administration at a dose of 10 mg / kg (Table 1) is comparable to that of ketorolac, and is about 75% of the activity shown by morphine at half the dose. Since PBTs have shown no toxicity or demonstrable side effects in animal models of cancer and pulmonary fibrosis, these studies of analgesia will be beneficial to the in vivo effects of the compounds, and can allow them to replace or reduce the dose of conventional drugs in other diseases, to prevent their many known side effects.

[0481] Measurement of the mechanical pain threshold

[0482] This example investigates whether PBT-4 also has an analgesic effect and compares it to the analgesic effect of PBT-3. PBT-3 is a mixture of enantiomers having the trans configuration of the cyclopropyl moiety and the adjacent hydroxyl group, while PBT-4 is a mixture of enantiomers having the cis configuration of the cyclopropyl moiety and the adjacent hydroxyl group. PBT-4 is the C10 epimer of PBT-3. While PBT-3 has been shown to have an analgesic effect in the von Frey test (Example 1), it is not known whether PBT-4 also has an analgesic effect. Statistical method The synthesis of PBT-4 is shown below, and shows only one enantiomer of each cis and trans product, but it will be understood that both enantiomers can be present, unless otherwise indicated, e.g. as shown in Results of the experiment .

[0483] This experiment was designed to investigate whether PBT-4 also has an analgesic effect and to compare it to the analgesic effect of PBT-3 (Table 1). The results here show that the analgesic effect of PBT-4 (10 mg / kg) is similar in potency to that of PBT-3, and that their analgesic effects in this model can last for more than 12 hours.

[0484] 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 entire plantaris muscle was elevated and cut longitudinally, leaving the origin and insertion points intact (surgery took about 5 minutes). The skin was then sutured and the wound was disinfected. A stainless steel needle stimulated a point on the plantar surface of the rat's right hind paw (not less than 5 mm from the surgical incision). The mechanical paw withdrawal threshold (PWT) of the rat's hind paw was recorded at measurement times of 2, 4, 6, 8, 10 and 12 hours after modeling. The PBT-3 and PBT-4 groups (n=6 for each group) were administered once by tail vein 30 minutes before modeling was established, at a dose of 10 mg / kg and a volume of 5 mL / kg. A sham surgery group and vehicle group (n=6 for each group) were also included. This information is summarized in Table 2 below.

[0485] Experimental animals: SPF grade SD rats, n=24, body weight 210 g - 220 g, male.

[0486] Experimental instruments: Electronic Von Frey - Italy Ugo Basile Ugo 38450

[0487] Figure 4

[0488]

[0489] Figure 4

[0490] After the SD rats were acclimated, the rats were anesthetized with isoflurane inhalation. A 10% povidone-iodine solution was applied to the plantar surface of the right hind paw, and a 1 cm long line was made along the plantar proximal 0.5 cm to the distal toes. An incision was made at the bottom of the foot, and the plantaris muscle was elevated and cut longitudinally. The origin and insertion points of the muscle were left intact. The skin was sutured after hemostasis and the wound was disinfected. The procedure lasted 5-10 minutes. The blank group was not subjected to surgical modeling treatment. The PBT-3 and PBT-4 groups were administered once by tail vein 30 minutes before modeling was established, at a dose of 10 mg / kg and a volume of 5 mL / kg.

[0491] References

[0492] During the measurement, a stainless steel needle stimulates a certain point on the plantar surface of the rat's right hind paw from underneath the metal mesh (not less than 5 mm from the surgical incision). After the stainless steel needle contacts the skin of the plantar surface, the stimulating force continues to increase. When the rat feels pain, the right hind limb is lifted, and the plantar skin is separated from the stainless steel needle. At this time, the value displayed by the measuring instrument is the mechanical stimulation paw withdrawal threshold (PWT) of the rat's hind paw. The measurement time is 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours after modeling.

[0493] P.M. Demin

[0494] The experiment uses IBM SPSS 26.0 software for statistical analysis. Single factor ANOVA is used to analyze the differences between groups. When the variance is equal, LSD t-test is used for comparison between groups. When the variance is not uniform, Dunnett T3 test is used for comparison between groups. The experimental data is measured using "mean ± SEM", and P < 0.05 means that there is a statistically significant difference.

[0495] P.M. Demin

[0496] The results of the mechanical pain threshold measurement show that after the operation modeling, the mechanical pain threshold of the model (or vehicle) group is significantly lower than that of the blank group. Compared with the model group, the mechanical pain threshold of the PBT-3 group and the PBT-4 10 mg / kg group is significantly increased 2-12 hours after the operation, and the drug effect is stable. The mechanical pain threshold of the PBT-4 10 mg / kg group is similar to that of the PBT-3 10 mg / kg group, and there is no significant difference between them, and relative to the sham operation group (16%) and the vehicle group (42%), p < 0.001 (see ​ ).

[0497] The in vivo biological experiments in this paper show that both PBT-3 and PBT-4 have equivalent analgesic effects in the induction of painful surgical modeling. Although the drugs are administered intravenously through the tail vein, it is important to note that the analgesic effect lasts at least up to 12 hours (end of the experiment), as ​ shown. Another pain model (the carrageenan model of Example 2) shows that the analgesic effect of PBT-3 is about half that of morphine when administered at a dose of 10 mg / kg to the plantar region of the hind paw. Therefore, these drugs are effective as long-acting analgesics, which can be due to their incorporation into the lipid pool, followed by gradual and slow release into the circulation.

[0498] ​

[0499] 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.

[0500] 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.

[0501] Pace-Asciak et al. (1990) Biolog. Oxidation Systems, Eds C.C. Reddy et al., Academic Press, New York, 725-735.

[0502] 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.

[0503] 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.

[0504] 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.

[0505] 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.

[0506] 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.

[0507] 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.

[0508] 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. 6126-6130 D. 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.

[0509] 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.

[0510] C. R. Pace-Asciak. The hepoxilins and some analogues: a review of their biology. British J. Pharmacol., 2009, V. 158, P. 972-981.

[0511] 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

[0512] 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.

[0513] 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.

[0514] Jin Lee, Tae-Hun Kim, Yoon-Joo Ko, Jin-Byung Park, Deok-Kun Oh. Highly efficient 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.

[0515] 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.

[0516] ​, C.R. Pace-Asciak. Synthesis of racemic 11,12-cyclopropylanalogs of hepoxilins A3 and B3. Tetrahedron Lett., 1993, V. 34, P. 4305-4308.

[0517] ​ , 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.

[0518] All references cited are hereby incorporated by reference. In the event of a conflict between information in any reference and this disclosure, and in the event of a conflict between any reference cited and any reference incorporated by reference and this disclosure, the present disclosure will control.

[0519] What has been described is merely illustrative of the principles of the present disclosure. Numerous modifications and variations are possible in light of the above teachings without departing from the scope of the appended claims.

Claims

1. A method for preparing compounds having formula III: (III) The method includes: Compounds having formula 2: (2)， Coupled with a suitable protecting group (PG).

2. The method according to claim 1, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

3. A method for preparing a compound having formula 3: (3)， The method includes: Compounds having formula 2: (2)， Coupling with p-methoxybenzyl chloride.

4. A method for preparing compounds having formula IV: (IV), The method includes: Compounds having formula (III): (III), It reacts with: i) I2, PPh3 and bases; ii) toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide.

5. The method according to claim 4, wherein the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

6. A method for preparing a compound having Formula 4: (4)， The method includes: Compounds having formula (3): (3)， It reacts with: i) I2, PPh3 and bases; ii) p-toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide.

7. The method according to claim 6, wherein the base is imidazole, triethylamine, diisopropylethylamine, or pyridine.

8. A method for preparing compounds having formula V: (V)， The method includes: 1-Heptaneyne was reacted with a metallizing agent to obtain the first mixture; as well as Compounds having formula (IV): (IV), It reacts with the first mixture.

9. The method according to claim 8, wherein the metallizing agent is n-BuLi or EtMgBr.

10. A method for preparing a compound having Formula 5: (5)， The method includes: 1-Heptaneyne was reacted with a metallizing agent to obtain the first mixture; as well as Compounds having formula (4): (4)， It reacts with the first mixture.

11. The method of claim 10, wherein the metallizing agent is n-BuLi or EtMgBr.

12. A method for preparing a compound having Formula 6: (6)， The method includes: Compounds having formula V via deprotection agents: (V)， Perform deprotection.

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

14. A method for preparing a compound having Formula 6: (6)， The method includes: Compounds having formula 5 via DDQ: (5)， Perform deprotection.

15. A method for preparing a compound having Formula 7: (7)， The method includes: Using an oxidizing agent to oxidize compounds having formula 6: (6)， Oxidation.

16. The method of claim 15, wherein the oxidant is Dysmartin periodide, pyridinium dichromate, oxaloyl chloride-DMSO, or 2-iodobenzoic acid (IBX).

17. A method for preparing a compound having Formula 8: (8)， The method includes: Compounds having formula 7: (7)， It reacts with a second mixture containing propargyl chloride and a metallizing agent.

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

19. A method for preparing a compound having formula X: (X)， Compounds having formula 8: (8)， Compounds containing formula IX: (IX)、 A third mixture of CuI, NaI, and alkali reacts.

20. The method according to claim 19, wherein the base is K2CO3.

21. A method for preparing a compound having Formula 10: (10)， Compounds having formula 8: (8)， With compounds containing formula 9: (9)、 A third mixture of CuI, NaI, and alkali reacts.

22. The method according to claim 21, wherein the base is K2CO3.

23. A method for preparing compounds having formula XI: (XI), The method includes: Using a hydrogenating agent to make a compound having formula X: (X)， Partial hydrogenation.

24. The method of claim 23, wherein the hydrogenating agent is a lindra catalyst.

25. A method for preparing a compound having the formula XII: (XII), The method includes: Using a hydrogenating agent to make a compound having formula X: (X)， Partial hydrogenation.

26. The method of claim 25, wherein the hydrogenating agent is a lindra catalyst.

27. A method for preparing a compound having Formula 11: (11)， The method includes: Using a hydrogenating agent to make a compound having formula 10: (10)， Partial hydrogenation.

28. The method of claim 27, wherein the hydrogenating agent is a lindra catalyst.

29. A method for preparing a compound having Formula 12: (12)， The method includes: Using a hydrogenating agent to make a compound having formula 10: (10)， Partial hydrogenation.

30. The method of claim 29, wherein the hydrogenating agent is a lindra catalyst.

31. A method for preparing a compound having Formula 13: (13)， The method includes: Compounds having formula 11 are made under alkaline conditions: (11)， hydrolysis.

32. The method according to claim 31, wherein the alkaline conditions comprise methanol / water and alkali.

33. The method according to claim 32, wherein the base is sodium hydroxide, lithium hydroxide or potassium hydroxide.

34. A method for preparing a compound having Formula 14: (14)， The method includes: Compounds having formula 12 are produced under alkaline conditions: (12)， hydrolysis.

35. The method of claim 34, wherein the alkaline conditions comprise methanol / water and alkali.

36. The method according to claim 35, wherein the base is sodium hydroxide, lithium hydroxide, or potassium hydroxide.

37. A method for preparing compounds having formula XI: (XI), The method includes: Compounds having formula 2: (2)， Coupled with a suitable protecting group (PG), a compound having formula III is obtained: (III); The compound having formula (III) is reacted with: i) I2, PPh3 and a first base; ii) p-toluenesulfonyl chloride and sodium iodide; or iii) methanesulfonyl chloride and sodium iodide to give the compound having formula (IV): (IV); The compound having formula (IV) is reacted with a first mixture comprising 1-heptyne and a metallizing agent to give a compound having formula V: (V)； Deprotecting the compound having formula V with a deprotecting agent yields a compound having formula 6: (6)； The compound having formula 6 is oxidized with an oxidizing agent to obtain a compound having formula 7: (7)； The compound having formula 7 is reacted with a second mixture comprising propargyl chloride and a metallizing agent to give a compound having formula 8: (8)； Make the compound having formula 8 and the compound containing formula IX: (IX)、 The reaction of CuI, NaI, and the second base in a third mixture yields a compound with formula X: (X); and The compound having formula X is partially hydrogenated using a hydrogenating agent to obtain the compound having formula XI.

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

39. The method according to any one of claims 37 to 38, wherein the first base is imidazole.

40. The method according to any one of claims 37 to 39, wherein the metallizing agent is n-BuLi or EtMgBr.

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

42. The method according to any one of claims 37 to 41, wherein the oxidant is Dysmartin periodoalkane, pyridinium dichromate, oxaloyl chloride-DMSO, or 2-iodobenzoic acid (IBX).

43. The method according to any one of claims 37 to 42, wherein the second base is K2CO3.

44. The method according to any one of claims 37 to 43, wherein the hydrogenating agent is a lindra catalyst.

45. A method for preparing a compound having the formula XII: (XII), The method includes: Compounds having formula 2: (2)， Coupled with a suitable protecting group (PG), a compound having formula III is obtained: (III); The compound having formula (III) is reacted with: i) I2, PPh3 and a first base; or ii) toluenesulfonyl chloride and sodium iodide to give the compound having formula (IV): (IV); The compound having formula (IV) is reacted with a first mixture comprising 1-heptyne and a metallizing agent to give a compound having formula V: (V)； Deprotecting the compound having formula V with a deprotecting agent yields a compound having formula 6: (6)； The compound having formula 6 is oxidized with an oxidizing agent to obtain a compound having formula 7: (7)； The compound having formula 7 is reacted with a second mixture comprising propargyl chloride and a metallizing agent to give a compound having formula 8: (8)； Make the compound having formula 8 and the compound containing formula IX: (IX)、 The reaction of CuI, NaI, and the second base in a third mixture yields a compound with formula X: (X); and The compound having formula X is partially hydrogenated using a hydrogenating agent to obtain the compound having formula XII.

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

47. The method according to any one of claims 45 to 46, wherein the first base is imidazole.

48. The method according to any one of claims 45 to 47, wherein the metallizing agent is n-BuLi or EtMgBr.

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

50. The method according to any one of claims 45 to 49, wherein the oxidant is Dysmartin periodide, pyridinium dichromate, oxaloyl chloride-DMSO, or 2-iodobenzoic acid (IBX).

51. The method according to any one of claims 45 to 50, wherein the second base is K2CO3.

52. The method according to any one of claims 45 to 51, wherein the hydrogenating agent is a lindra catalyst.

53. A method for preparing a compound having Formula 11: (11)， The method includes: Compounds having formula 2: (2)， Coupling with p-methoxybenzyl chloride yields a compound having formula 3: (3)； The compound having formula 3 is reacted with: i) I2, PPh3 and a first base; or ii) toluenesulfonyl chloride and sodium iodide to give the compound having formula 4: (4)； The compound having formula 4 is reacted with a first mixture comprising 1-heptyne and a metallizing agent to give a compound having formula 5: (5)； The compound having formula 5 was deprotected using a deprotecting agent to obtain a compound having formula 6: (6)； The compound having formula 6 is oxidized with an oxidizing agent to obtain a compound having formula 7: (7)； The compound having formula 7 is reacted with a second mixture comprising propargyl chloride and a metallizing agent to give a compound having formula 8: (8)； The compound having formula 8 is combined with the compound containing formula 9: (9)、 The reaction of CuI, NaI, and the second base in a third mixture yields a compound having Formula 10: (10), and The compound having formula 10 is partially hydrogenated using a hydrogenating agent to obtain the compound having formula 11.

54. The method according to claim 53, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

55. The method according to any one of claims 53 to 54, wherein the first base is imidazole.

56. The method according to any one of claims 53 to 55, wherein the metallizing agent is n-BuLi or EtMgBr.

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

58. The method according to any one of claims 53 to 57, wherein the oxidant is Dysmartin periodoalkane, pyridinium dichromate, oxaloyl chloride-DMSO, or 2-iodobenzoic acid (IBX).

59. The method according to any one of claims 53 to 58, wherein the second base is K2CO3.

60. The method according to any one of claims 53 to 59, wherein the hydrogenating agent is a lindra catalyst.

61. A method for preparing a compound having Formula 12: (12)， The method includes: Compounds having formula 2: (2)， Coupling with p-methoxybenzyl chloride yields a compound having formula 3: (3)； The compound having formula 3 is reacted with: i) I2, PPh3 and a first base; or ii) toluenesulfonyl chloride and sodium iodide to give the compound having formula 4: (4)； The compound having formula 4 is reacted with a first mixture comprising 1-heptyne and a metallizing agent to give a compound having formula 5: (5)； The compound having formula 5 was deprotected using a deprotecting agent to obtain a compound having formula 6: (6)； The compound having formula 6 is oxidized with an oxidizing agent to obtain a compound having formula 7: (7)； The compound having formula 7 is reacted with a second mixture comprising propargyl chloride and a metallizing agent to give a compound having formula 8: (8)； The compound having formula 8 is combined with the compound containing formula 9: (9)、 The reaction of CuI, NaI, and the second base in a third mixture yields a compound having Formula 10: (10), and The compound having formula 10 is partially hydrogenated using a hydrogenating agent to obtain the compound having formula 12.

62. The method according to claim 61, wherein the protecting group is p-methoxybenzyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

63. The method according to any one of claims 61 to 62, wherein the first base is imidazole.

64. The method according to any one of claims 61 to 63, wherein the metallizing agent is n-BuLi or EtMgBr.

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

66. The method according to any one of claims 61 to 65, wherein the oxidant is Dysmartin periodide, pyridinium dichromate, oxaloyl chloride-DMSO, or 2-iodobenzoic acid (IBX).

67. The method according to any one of claims 61 to 66, wherein the second base is K2CO3.

68. The method according to any one of claims 61 to 67, wherein the hydrogenating agent is a lindra catalyst.

69. A method for treating, improving, or preventing pain in a subject, the method comprising: The subject was given a compound having formula 11: (11)， Or its pharmaceutically acceptable salt.

70. A method for treating, improving, or preventing pain in a subject, the method comprising: The subject was given a compound having formula 12: (12)， Or its pharmaceutically acceptable salt.

71. An analgesic composition for treating, improving, or preventing pain in a subject, said composition comprising: Compounds having Formula 11: (11)， Or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

72. An analgesic composition for treating, improving, or preventing pain in a subject, said composition comprising: Compounds having Formula 12: (12)， Or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

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