Compounds for the treatment of pain and enantiomerically pure compositions thereof

Abstract

This disclosure relates to the use of the monoamine reuptake inhibitor IP2016 (formula (I)) for the treatment of pain. This disclosure also relates to enantiomeric pure compositions of IP2016 and their use as pharmaceuticals.

Description

Technical Field

[0001] This disclosure relates to the use of the monoamine reuptake inhibitor IP2016 (formula (I)) for the treatment of pain. This disclosure also relates to enantiomeric pure compositions of IP2016 and their use as pharmaceuticals. Background Technology

[0002] Treating central nervous system (CNS) disorders with active ingredients is extremely challenging because many complex biological factors can affect treatment outcomes and potential negative side effects.

[0003] The quality of life of subjects was severely impacted when treating pain (particularly neuropathic pain) arising from impairment or injury to the somatosensory system. The induced pain can radiate to adjacent areas and involves peripheral and central sensitization. The prevalence of neuropathic pain is 6.9% to 10%, and it commonly affects people with diabetes. Currently, 200 million people worldwide suffer from neuropathic pain, also known as diabetic polyneuropathy.

[0004] While various treatment options exist, such as anticonvulsants, tricyclic and tetracyclic antidepressants; serotonin reuptake inhibitors and norepinephrine reuptake inhibitors, such as duloxetine; and topical treatments, various drawbacks must be considered when conducting a risk-benefit assessment. Possible side effects include nausea, fatigue, dizziness, excessive sweating, dry mouth, constipation, decreased appetite, insomnia, diarrhea, confusion and tremors, increased intraocular pressure, and increased blood pressure (BP). Furthermore, current treatments have the potential for negative drug interactions.

[0005] In short, poor response to drug therapy results in a large unmet need among patients with neuropathic pain; currently, less than one-third of patients with painful diabetic neuropathy achieve adequate pain relief with existing drug therapies. In the field of amine reuptake inhibitors, the specific receptor activity of the active ingredient can significantly influence its pharmacological characteristics, efficacy, and side effects.

[0006] Therefore, there is a great need for active ingredients that exhibit specific, selective amine reuptake inhibition characteristics to achieve better treatment of CNS conditions (especially pain) and improve poor response to existing treatments. Summary of the Invention

[0007] As stated above, there is a great need for novel compounds and compositions for treating CNS conditions, particularly pain. This disclosure provides a compound for treating pain, such as neuropathic pain.

[0008] In one key aspect, this disclosure provides a compound of formula (I) for use in a method of treating, preventing, or alleviating pain in a subject. (I), or a pharmaceutically acceptable salt thereof.

[0009] The inventors have demonstrated that the compound of formula (I) has analgesic effects in different animal pain models.

[0010] After isolating and separating the enantiomers of compound (I), the inventors found that one of the enantiomers, (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, exhibited enhanced potency and improved receptor activity characteristics in monoamine transporters compared to the other enantiomer. In addition to providing improved inhibitory characteristics in monoamine transporters, the (-) enantiomer was also observed to have a stronger effect on opioid μ receptors compared to the (+) enantiomer.

[0011] Acting on opioid μ receptors and on monoamine transporters acting on serotonin (5-HTT), norepinephrine (NET), and dopamine (DAT) is advantageous in the treatment of pain. Therefore, this paper demonstrates the unexpectedly advantageous properties of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol in the treatment of pain.

[0012] In one aspect, this disclosure provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof. The chiral purity of (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0013] Compared to other medications, such as those used to treat pain, the compounds, compositions, and their medical uses of the present invention can provide additional pharmacodynamic advantages. For example, the compounds can achieve lower toxicity, reduced incidence of treatment-emergent adverse events (TEAEs), improved treatment safety, reduced addiction tendency, or any combination of the foregoing.

[0014] In addition, the compounds and compositions described herein may provide improved pharmacokinetic properties (such as administration, distribution, metabolism and excretion characteristics (ADME)), improved systemic exposure, serum half-life, clearance, or any combination thereof.

[0015] The inventors also demonstrate a method for preparing compositions containing high-purity and larger quantities of isolated IP2016 enantiomers.

[0016] In another aspect, this disclosure provides a method for preparing (+)- or (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol with a chiral purity of 51% or higher, the method comprising: a. Provide a mixture of the following substances: (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol and (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol; b. Treat the mixture with (Boc)₂O to obtain a mixture of enantiomers of the following substances:

[0017] tert-Butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester c. The mixture was separated using chiral liquid chromatography to obtain the following enantiomers: tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester; and d. Under acidic conditions, the isolated enantiomers in step c. are deprotected to obtain enantiomerically pure (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0018] definition As used herein, IP2016 or compound of formula (I) refers to a compound according to the following formula: Compounds of formula (I) or their pharmaceutically acceptable salts. Compounds of formula (I) may also be called: 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0019] As used in this article, "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and cannot overlap. Overlapping means the ability to make specific molecular entities coincide (making the corresponding molecular entities exact copies of each other) simply by translation and rigid rotation.

[0020] Compound of formula (I) can exist in two enantiomers, as shown in scheme 1.

[0021]

[0022] Option 1. The counterpart to IP2016.

[0023] These enantiomers are optically active, meaning they are capable of rotating the plane of polarization of a transmitted plane-polarized beam. Optical rotation is a typical distinguishing feature of systems containing unequal amounts of corresponding enantiomers. Enantiomers that rotate light clockwise under certain conditions (when viewed in the direction facing an oncoming beam) are called right-handed, and their chemical name or formula is indicated by the prefix (+)-; enantiomers that rotate light in the opposite direction are called left-handed, and are indicated by the prefix (-)-.

[0024] Therefore, the enantiomers of IP2016 are referred to in this document as: (+)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, and (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0025] As defined in this paper, "chiral purity" (also abbreviated as "cp", "cp", or "%cp") is a measure of the purity of a chiral substance. It reflects the amount of one enantiomer in a pair of enantiomers relative to the total amount of the two enantiomers. Chiral purity can be calculated as follows:

[0026] As defined in this paper, "enantiomer excess" (also abbreviated as "ee" or "%ee") is a measurement of the purity of a chiral substance. It reflects the degree to which the amount of one enantiomer in a sample containing a pair of enantiomers is greater than that of the other enantiomer in that pair. Enantiomer excess can be calculated as follows:

[0027] Enantiomer excess or chiral purity can be measured or determined using optical techniques such as optical rotation or chiral chromatography to determine the amount of each enantiomer or their relative amounts to each other.

[0028] As used herein, the term "enantiomer purity" refers to a composition in which a particular enantiomer has been enriched to a chiral purity of more than 51%. It encompasses and can be used to refer to compositions containing only one particular enantiomer with a chiral purity of, for example, 51% or higher, 60% or higher, 80% or higher, 90% or higher, 95% or higher, or 98% or higher.

[0029] The compounds of this invention can exist in tautomeric form. Any such tautomer is considered to be within the scope of this invention.

[0030] Furthermore, in compounds of formula I as defined herein, any hydrogen atom can be replaced by deuterium (… 2H) substitution, and any such deuterated compound of formula I containing one or more deuterium atoms in place of a corresponding number of hydrogen atoms is considered to be within the scope of the invention.

[0031] It is known that prodrugs can be produced in the art. Those skilled in the art will know which types of molecular moieties can be introduced into a drug to produce a prodrug. Prodrugs relating to compounds of formula I are considered to be within the scope of this invention.

[0032] "Pharmaceutical acceptable" means that a pharmaceutical composition can be used to prepare a pharmaceutical composition that is generally safe, non-toxic and has no biological or other undesirable properties, and includes pharmaceutical compositions acceptable for veterinary and human use.

[0033] The term "pharmaceutically acceptable salt" for a compound refers to a pharmaceutically acceptable salt as defined herein, and preferably has the desired pharmacological activity of the parent compound. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and trimethylacetic acid; or salts formed when an acidic proton present in the parent compound is replaced by a metal ion such as an alkali metal ion, alkaline earth metal ion, or aluminum ion; or salts formed by coordination with an organic or inorganic base. Acceptable organic bases include, for example, diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, morpholine, and tromethamine. Acceptable inorganic bases include, for example, ammonia, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0034] As used herein, the terms “treatment” or “management” are methods used to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include, but are not limited to, relief or improvement of one or more detectable or undetectable symptoms or conditions, reduction of the severity of a disease or disorder, stabilization (i.e., non-exacerbation) of a disease or disorder, prevention of a disease or disorder, delay or slowing of the progression of a disease or disorder, improvement or mitigation of a disease state, and (partial or complete) relief.

[0035] As used in this article, “neuralgia” includes the neurological component of nociceptive pain.

[0036] As used in this article, “harmful” means the perception or sensation of pain.

[0037] "Abnormal pain" refers to pain caused by stimuli that would not normally cause pain, such as light touch on the skin.

[0038] Hyperalgesia refers to an excessive sensitivity to painful stimuli.

[0039] As used herein, the term “about” when referring to a quantity or percentage should be interpreted as a change of ±10% relative to the value of the quantity or percentage it refers to, such as ±5%. Attached Figure Description

[0040] Figure 1 (A) The time course of paw withdrawal behavior after formalin injection, and (B) the total number of paw withdrawals during the intermediate phase (Int = 6 min to 15 min) and the second phase (P2 = 16 min to 40 min) after formalin administration. (C) The hind paw withdrawal threshold (g) for low-threshold von Frey stimulation; baseline before and after CCI = 17.3 g and 1.4 g, respectively. (D) The duration of hind paw withdrawal (seconds) for high-threshold needle stimulation; baseline before and after CCI = 0 seconds and 14.9 seconds, respectively. All groups n = 8 rats. Data are presented as mean ± standard error. *P < 0.05, ***P < 0.001 compared to the corresponding solvent; +P < 0.05, ++++P < 0.001 compared to the baseline before CCI; one-way ANOVA followed by Dunnett's test. Further experimental details are given in Example 1.

[0041] Figure 2 Analytical chiral HPLC chromatogram of purified isomer 1. Further experimental details are given in Example 4.

[0042] Figure 3 Analytical chiral HPLC chromatogram of purified isomer 2. Further experimental details are given in Example 4.

[0043] Figure 4 Chiral stability of isomer 1 at pH 1. Further experimental details are given in Example 6. Detailed Implementation

[0044] Compounds used to treat pain In one key aspect, this disclosure provides a compound of formula (I) for use in a method of treating, preventing, or alleviating pain in a subject. (I), or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, the compound of formula (I) is 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, the compound of formula (I) is (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or a pharmaceutically acceptable salt thereof.

[0047] In one embodiment, the compound of formula (I) is (+)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the compound is formulated according to formula (Ia). (Ia), or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the compound is according to formula (Ib). (Ib), or a pharmaceutically acceptable salt thereof.

[0050] The inventors have demonstrated that the compound of formula (I) has analgesic effects in different animal pain models.

[0051] In some implementations, pain, treatment methods, and / or subjects are as described elsewhere in this document.

[0052] Enantiomerically pure composition After separating and isolating the enantiomers of the compound of formula (I), the inventors have discovered that one of the enantiomers has increased potency and improved receptor activity characteristics compared with the other enantiomer, and thus has unexpected advantages in the treatment of pain.

[0053] Therefore, in one aspect, this disclosure provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof. The chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0054] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0055] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%. In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%. In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 98%.

[0056] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is 90% to 100%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.

[0057] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is 95% to 100%.

[0058] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is 98% to 100%.

[0059] In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0060] In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is 90% to 100%, such as (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol being 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0061] In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 50%. In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 80%. In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%. In one embodiment, the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%.

[0062] These examples further illustrate how chiral purity can be measured.

[0063] These examples demonstrate that the (-) isomer of IP2016, as determined by optical activity assays, possesses increased potency and improved receptor activity signatures compared to other enantiomers, thus offering unexpected advantages in pain treatment. In addition to providing improved inhibitory signatures in monoamine transporters, the (-) enantiomer was also observed to have a stronger effect on opioid μ receptors compared to the (+) enantiomer.

[0064] Acting on opioid μ receptors and on monoamine transporters acting on serotonin (5-HTT), norepinephrine (NET), and dopamine (DAT) is advantageous in the treatment of pain. Therefore, this paper demonstrates the unexpectedly advantageous properties of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol in the treatment of pain.

[0065] In one aspect, this disclosure provides a composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof. The chiral purity of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0066] In one embodiment, the chiral purity of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 60%.

[0067] In one embodiment, the chiral purity of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%.

[0068] In one embodiment, the chiral purity of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%, such as at least 98%.

[0069] In one aspect, this disclosure provides a composition comprising a compound of formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof. The chiral purity of the compound of formula (Ia) is at least 51%.

[0070] In one embodiment, the chiral purity of the compound of formula (Ia) is at least 60%.

[0071] In one embodiment, the chiral purity of the compound of formula (Ia) is at least 90%.

[0072] In one embodiment, the chiral purity of the compound of formula (Ia) is at least 95%, such as at least 98%.

[0073] In one aspect, this disclosure provides a composition comprising a compound of formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof. The chiral purity of the compound of formula (Ib) is at least 51%.

[0074] In one embodiment, the chiral purity of the compound of formula (Ib) is at least 60%.

[0075] In one embodiment, the chiral purity of the compound of formula (Ib) is at least 90%.

[0076] In one embodiment, the chiral purity of the compound of formula (Ib) is at least 95%, such as at least 98%.

[0077] In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or the compound of formula (Ia), or the compound of formula (Ib) is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0078] In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or the compound of formula (Ia), or the compound of formula (Ib) is 90% to 100%, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% enantiomeric excess.

[0079] In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 50%.

[0080] In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 80%. In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%. In one embodiment, the enantiomeric excess of (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%.

[0081] In one implementation, the enantiomeric excess of formula (Ia) is at least 50%.

[0082] In one embodiment, the enantiomer of formula (Ia) is in excess by at least 80%. In one embodiment, the enantiomer of formula (Ia) is in excess by at least 90%. In one embodiment, the enantiomer of formula (Ia) is in excess by at least 95%.

[0083] In one implementation, the enantiomeric excess of formula (Ib) is at least 50%.

[0084] In one embodiment, the enantiomer of formula (Ib) is in excess by at least 80%. In one embodiment, the enantiomer of formula (Ib) is in excess by at least 90%. In one embodiment, the enantiomer of formula (Ib) is in excess by at least 95%.

[0085] In one embodiment, the composition as described herein comprises one or more pharmaceutically acceptable excipients or diluents. The excipients or diluents may be any pharmaceutically acceptable excipients or diluents known in the art. The excipients or diluents must be "acceptable," meaning compatible with the compound of formula (I) or its enantiomers, with other components of the formulation, and harmless to the subject. The excipients or diluents may be solids or liquids, but are not limited thereto.

[0086] The compositions described herein can be administered and formulated in a variety of oral and parenteral dosage forms. The preparation of these dosage forms can be carried out as is known in the art.

[0087] In one embodiment, the composition as described herein may comprise other therapeutic agents effective in treating pain. These other therapeutic agents effective in treating pain may be any known compound suitable for treating or relieving pain.

[0088] In one aspect, this disclosure provides compositions for methods of treating, preventing, or relieving pain in a subject, as described herein.

[0089] In one embodiment, this disclosure provides a composition for a method of treating, preventing, or relieving pain in a subject, the composition comprising a compound of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0090] In one embodiment, the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is 90% to 100%, such as 95% to 100%, such as 98% to 100%. In some embodiments, the pain, treatment method, and / or the subject are as described elsewhere herein.

[0091] Compound of formula (I), Formula (I), or a pharmaceutically acceptable salt thereof, Use for the preparation of medicines for the treatment, prevention or relief of pain in subjects in need as described herein.

[0092] A method for treating, preventing, or alleviating pain in a subject as described herein, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), Formula (I), Or its pharmaceutically acceptable salt.

[0093] A method for inducing pain relief in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), Formula (I), Or its pharmaceutically acceptable salts, as described herein.

[0094] A method for improving the functionality of a subject suffering from pain, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), Formula (I), Or its pharmaceutically acceptable salts, as described herein.

[0095] In one embodiment, the compound of formula (I) is (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, or a pharmaceutically acceptable salt thereof.

[0096] Any embodiment of a composition comprising a compound of formula (I) described herein (particularly (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol) or a compound of formula (Ib) may be combined with methods for treating, preventing and relieving pain, methods for inducing pain relief or methods for improving pain function, as described herein.

[0097] Treating pain In one implementation, pain is selected from the group consisting of: (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) Chronic or acute secondary headache or orofacial pain.

[0098] In one implementation, chronic or acute primary pain is chronic or acute primary visceral pain, chronic or acute generalized pain, fibromyalgia syndrome, chronic or acute primary musculoskeletal pain, chronic or acute primary headache or orofacial pain, such as migraine, burning mouth syndrome, tension headache, cluster headache or persistent unilateral headache; complex regional pain syndrome (CRPS) or painful cyanosis syndrome.

[0099] In one implementation, chronic or acute cancer-related pain is associated with visceral cancer pain, bone cancer pain, or neurogenic cancer pain.

[0100] In one implementation, chronic or acute cancer-related pain is pain following cancer treatment, such as pain following cancer drug treatment, pain induced by chemotherapy, pain induced by radiation therapy, or pain induced by radiation.

[0101] In one implementation, chronic or acute postoperative pain is postoperative pain following spinal surgery, hernia incision, hysterectomy, amputation, thoracotomy, breast surgery, or arthroplasty.

[0102] In one implementation, chronic or acute post-traumatic pain includes post-burn pain, pain associated with whiplash injury, and pain following musculoskeletal injury.

[0103] In one implementation, chronic or acute secondary musculoskeletal pain is pain caused by persistent inflammation, such as inflammation caused by infection, inflammation caused by crystal deposition, or inflammation caused by autoimmune disorders and autoinflammatory disorders; pain associated with structural changes, such as pain associated with osteoarthritis or vertebral arthropathy; pain caused by neurological disorders, such as pain associated with Parkinson's disease, pain associated with multiple sclerosis, or pain associated with peripheral nerve disorders.

[0104] In one implementation, chronic or acute secondary visceral pain is pain caused by mechanical factors, vascular mechanisms, or persistent inflammation, such as mechanical factors, vascular mechanisms, or persistent inflammation in the head, neck, chest, abdomen, or pelvic region.

[0105] In one implementation, chronic or acute neuropathic pain is central nervous system pain, such as central nervous system pain associated with spinal cord injury, brain injury, post-stroke pain, or multiple sclerosis; peripheral nervous system pain, peripheral nervous system pain following nerve injury, painful polyneuropathy, or painful radiculopathy; or neuropathic orofacial pain.

[0106] In one implementation, chronic or acute secondary headache or orofacial pain is chronic toothache, chronic neurogenic orofacial pain, headache or orofacial pain associated with temporomandibular joint disorder, homeostasis disorder or its nonpharmacological treatment, cranial or cervical vascular disorder, nonvascular intracranial disorder, substance or its withdrawal, or head traumatic injury.

[0107] In one implementation, the pain is neuropathic pain. Neuropathic pain is caused by lesions or diseases of the somatic sensory nervous system. It can be described as a sensation similar to an electric shock, burning, or electric shock. The pain can occur spontaneously without stimulation or be caused by harmful or non-harmful stimuli. The pain can be persistent or intermittent and can be described as a burning, stinging, or cold sensation. Neuropathic pain can originate from several different sources.

[0108] In one implementation, neuropathic pain is acute neuropathic pain. In another implementation, neuropathic pain is chronic neuropathic pain.

[0109] In one implementation, neuropathic pain is caused by alcoholism, diabetes, multiple sclerosis, multiple myeloma, stroke, cancer, cytomegalovirus, trigeminal neuralgia, spinal cord injury, or amputation.

[0110] In one implementation, neuropathic pain is caused by a chronic, progressive neurological disease.

[0111] In one implementation, neuropathic pain is caused by an infection.

[0112] In one implementation, neuropathic pain is caused by injury. In another implementation, neuropathic pain is persistent pain following nerve injury.

[0113] In one implementation, neuropathic pain is caused by a side effect of the medication.

[0114] In one implementation, neuropathic pain is caused by medical procedures such as surgery.

[0115] In one implementation, the neuropathic pain is idiopathic.

[0116] In one implementation, neuropathic pain is the neurological component of nociceptive pain.

[0117] In one implementation, the neuropathic pain is caused by diabetic neuropathy. In another implementation, the diabetes is chronic diabetes.

[0118] In one implementation, neuropathic pain is neuropathic cancer pain.

[0119] In one embodiment, the neuropathic pain is caused by neuropathy that occurs during treatment. In one embodiment, the neuropathy that occurs during treatment is caused by chemotherapy. In one embodiment, the neuropathy that occurs during treatment is caused by radiation therapy. In one embodiment, the neuropathy that occurs during treatment is caused by surgery.

[0120] In one implementation, the pain is trigeminal neuralgia, atypical pain, or hyperalgesia.

[0121] In one implementation, the pain is trigeminal neuralgia.

[0122] In one implementation, the pain is selected from typical trigeminal neuralgia; secondary trigeminal neuralgia, such as that attributed to multiple sclerosis, such as that attributed to space-occupying lesions; and idiopathic trigeminal neuralgia.

[0123] In one implementation, the pain is a painful trigeminal neuropathy, such as that caused by herpes zoster, such as postherpetic neuralgia, such as post-traumatic trigeminal neuropathy, such as idiopathic painful trigeminal neuropathy.

[0124] In one implementation, the pain is postherpetic neuralgia.

[0125] In one implementation, the pain is pain caused by Parkinson's disease.

[0126] In one implementation, the pain is dyspareunia (painful sexual intercourse). In one implementation, the pain is vulvar pain. In one implementation, the pain is vulvar pain or progressive vulvar pain.

[0127] In one implementation, the pain is pain associated with menopausal urogenital syndrome (GSM), or pain associated with vaginal atrophy, vulvovaginal atrophy, urogenital atrophy, or atrophic vaginitis.

[0128] In one embodiment, the compound is capable of inducing a pain reduction of at least 5%, such as at least 10%, such as at least 15%, such as 20%, in the subject.

[0129] In one implementation, pain relief is a subjective measurement of pain.

[0130] In one implementation, pain relief is a measurement of the pain threshold.

[0131] Pain response or relief can be assessed using subjective pain measurements, such as those employing the Visual Analogue Scale (VAS). For example, a 100mm long line could be used, where 0 represents "no pain" and 100 represents "the most intense pain imaginable." Subjects could be asked to mark their VAS by drawing a short vertical line at points they deem appropriate to reflect their pain level.

[0132] Numerical rating scales (NRS) can also be used to assess pain response or relief. For example, an 11-point numerical rating scale ranging from 0 ("no pain") to 10 ("the most severe pain that may be reached") can be used, and subjects can be asked to rate their pain.

[0133] Pain response or relief can also be measured by other subjective measures, such as scoring questionnaire responses using numerical rating scales. For example, the Patient Reported Outcomes (PRO) questionnaire can be used to assess dyspareunia, with questions covering different aspects of pain and assessing responses before, after, and / or during treatment.

[0134] In one implementation, pain is measured using a visual analog scale (VAS), a numerical rating scale (NRS), or a patient-reported outcome (PRO).

[0135] In one implementation, the pain occurs for at least 1 minute, such as at least 5 minutes, such as at least 10 minutes, such as at least 30 minutes, such as at least 1 hour, such as at least 2 hours, such as more than 2 hours.

[0136] In one implementation, the pain occurs for at least one day, such as at least three days or at least one week.

[0137] In one implementation, pain occurs on at least 20% of days, such as at least 30%, at least 40%, or at least 50% of days, within a period of more than one week, such as more than two weeks, such as more than three weeks, such as more than one month, such as more than two months, such as more than three months.

[0138] In one implementation, the subject is given an additional therapeutic agent that is effective in treating pain.

[0139] In one embodiment, the compound is administered in amounts ranging from about 0.01 mg to 100 mg per individual dose.

[0140] In one implementation, the subject is a mammal. In another implementation, the subject is a human.

[0141] In one implementation, the compound is administered orally.

[0142] In one embodiment, the compound is administered parenterally, such as by injection through the skin, mucous membranes, subcutaneous tissue, intramuscular tissue, intraperitoneal cavity, intravenous vein, or intra-arterial system.

[0143] In one embodiment, the compound is formulated in a pharmaceutical composition that also includes a pharmaceutically acceptable diluent, carrier, and / or excipient.

[0144] In one embodiment, the compound is formulated into a solid dosage form, such as tablets, capsules, pills, granules, or powders.

[0145] Preparation method The inventors also demonstrate a method for preparing compositions containing high-purity and larger quantities of isolated IP2016 enantiomers.

[0146] In another aspect, this disclosure provides a method for preparing (+) or (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol with a chiral purity of 51% or higher, the method comprising: a. Provide a mixture of the following substances: (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol and (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol; b. Treat the mixture with (Boc)₂O to obtain a mixture of enantiomers of the following substances:

[0147] tert-Butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester c. The mixture was separated using chiral liquid chromatography to obtain the following enantiomers: tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester; and d. Deprotect the isolated enantiomers from step c. under acidic conditions to obtain enantiomerically pure (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0148] In one embodiment, step b. uses dichloromethane (DCM) as a solvent and is carried out in the presence of diisopropylethylamine (DIPEA).

[0149] In one implementation, step b. is performed between 0°C and 30°C.

[0150] In one embodiment, the mixture from step b. is subjected to liquid-liquid extraction between the organic and aqueous phases prior to step c.

[0151] In one embodiment, the liquid chromatography in step c. includes a stationary phase containing a chiral selective agent. In one embodiment, the chiral selective agent comprises or consists of amylose tris(3-chloro-5-methylphenylcarbamate). Other stationary phases containing suitable chiral selective agents for separation in step c. are known to those skilled in the art.

[0152] In one embodiment, the chiral purity of (+)- or (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0153] (Boc)₂O is di-tert-butyl dicarbonate (CAS: 24424-99-5), as shown below: .

[0154] Those skilled in the art will know the appropriate conditions for deprotecting the protecting group of tert-butyl carboxylate (BOC) as described in step d. In one embodiment, the acidic conditions in step d. are provided by an organic or inorganic acid, such as hydrochloric acid (HCl), trifluoroacetic acid (TFA), or sulfuric acid (H₂SO₄). In one embodiment, the deprotection in step d. is carried out in an organic solvent such as dioxane; or in an aqueous solution. The acid can be dissolved at a suitable concentration (e.g., 4M) to deprotect the tert-butyl carboxylate, but other lower or higher concentrations can be used.

[0155] In one aspect, this disclosure provides a compound according to formula (II): (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0156] In one embodiment, the compound of formula (II) is tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ester.

[0157] In one embodiment, the compound of formula (II) is (+)-tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ester.

[0158] In one embodiment, the compound of formula (II) is (-)-tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid ester.

[0159] entry 1. A compound of formula (I) in a method for treating, preventing, or relieving pain in a subject. Formula (I), or a pharmaceutically acceptable salt thereof.

[0160] 2. The compound for the stated purpose as described in item 1, wherein the compound is 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0161] 3. The compound for the stated purpose as described in item 1, wherein said compound is (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0162] 4. The compound for the stated purpose as described in item 1, wherein the compound is (+)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0163] 5. The compound for the stated purpose as described in item 1, wherein the compound is according to formula (Ia). (Ia), or a pharmaceutically acceptable salt thereof.

[0164] 6. The compound for the stated purpose as described in item 1, wherein the compound is according to formula (Ib). (Ib), or a pharmaceutically acceptable salt thereof.

[0165] 7. The compound for the stated use according to any one of the preceding entries, wherein the pain is selected from the group consisting of: (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) Chronic or acute secondary headache or orofacial pain.

[0166] 8. The compound for the purpose described in item 7, wherein the chronic or acute primary pain is chronic or acute primary visceral pain, chronic or acute generalized pain, fibromyalgia syndrome, chronic or acute primary musculoskeletal pain, chronic or acute primary headache or orofacial pain, such as migraine, burning mouth syndrome, tension headache, cluster headache or persistent unilateral headache; complex regional pain syndrome (CRPS) or painful cyanosis syndrome.

[0167] 9. The compound for the purpose described in item 7, wherein the chronic or acute cancer-related pain is associated with visceral cancer pain, bone cancer pain, or neurogenic cancer pain.

[0168] 10. The compound for the purpose described in item 7, wherein the chronic or acute cancer-related pain is pain following cancer treatment, such as pain following cancer drug treatment, such as chemotherapy-induced painful polyneuropathy, such as pain following radiotherapy, such as radiation-induced painful neuropathy.

[0169] 11. The compound for the purpose described in item 7, wherein the chronic or acute postoperative pain is postoperative pain following spinal surgery, hernia incision, hysterectomy, amputation, thoracotomy, breast surgery, or arthroplasty.

[0170] 12. The compound for the purpose described in item 7, wherein the chronic or acute post-traumatic pain is post-burn pain, whiplash injury-related pain, or musculoskeletal injury-related pain.

[0171] 13. The compound for the use described in item 7, wherein the chronic or acute secondary musculoskeletal pain is pain caused by persistent inflammation, such as inflammation caused by infection, inflammation caused by crystal deposition, or inflammation caused by autoimmune disorders and autoinflammatory disorders; pain associated with structural changes, such as pain associated with osteoarthritis or vertebral arthropathy; pain caused by neurological disorders, such as pain associated with Parkinson's disease, pain associated with multiple sclerosis, or pain associated with peripheral nerve disorders.

[0172] 14. The compound for the purpose described in item 7, wherein the chronic or acute secondary visceral pain is pain caused by mechanical factors, vascular mechanisms, or persistent inflammation, such as mechanical factors, vascular mechanisms, or persistent inflammation in the head, neck, chest, abdomen, or pelvic region.

[0173] 15. The compound for the use described in item 7, wherein the chronic or acute neuropathic pain is central nervous system pain, such as central nervous system pain associated with spinal cord injury, brain injury, post-stroke pain, or multiple sclerosis; peripheral nervous system pain, peripheral nervous system pain following nerve injury, painful polyneuropathy, or painful radiculopathy; or neuropathic orofacial pain.

[0174] 16. The compound for the purpose described in item 7, wherein the chronic or acute secondary headache or orofacial pain is chronic toothache, chronic neurogenic orofacial pain, headache or orofacial pain associated with temporomandibular joint disorder, homeostasis disorder or its nonpharmacological treatment, cranial or cervical vascular disorder, nonvascular intracranial disorder, a substance or its withdrawal, or head traumatic injury.

[0175] 17. The compound for the purpose described in any one of entries 1 to 7 or 15 to 16, wherein the pain is neuropathic pain.

[0176] 18. A compound for the purpose of said use according to any one of entries 1 to 7 or any one of entries 15 to 17, wherein said neuropathic pain is acute neuropathic pain.

[0177] 19. A compound for the purpose of said use according to any one of entries 1 to 7 or any one of entries 15 to 17, wherein said neuropathic pain is chronic neuropathic pain.

[0178] 20. The compound for the purpose according to any one of entries 17 to 19, wherein the neuropathic pain is caused by alcoholism, diabetes, multiple sclerosis, multiple myeloma, stroke, cancer, cytomegalovirus, trigeminal neuralgia, spinal cord injury, or amputation.

[0179] 21. The compound for the use according to any one of items 17 to 19, wherein the neuropathic pain is caused by a chronic progressive neurological disease.

[0180] 22. The compound for the purpose according to any one of entries 17 to 19, wherein the neuropathic pain is caused by an infection.

[0181] 23. The compound for the purpose according to any one of entries 17 to 19, wherein the neuropathic pain is caused by injury.

[0182] 24. The compound for the purpose according to any one of items 17 to 19, wherein the neuropathic pain is persistent pain following nerve injury.

[0183] 25. The compound for the purpose described in any one of entries 17 to 19, wherein the neuropathic pain is caused by a side effect of the drug.

[0184] 26. The compound for the purpose according to any one of entries 17 to 19, wherein the neuropathic pain is caused by a medical procedure such as surgery.

[0185] 27. The compound for the use according to any one of entries 17 to 19, wherein the neuropathic pain is idiopathic.

[0186] 28. The compound for the purpose according to any one of items 17 to 19, wherein the neuropathic pain is the neuropathic component of nociceptive pain.

[0187] 29. The compound for the use according to any one of entries 17 to 19, wherein the neuropathic pain is caused by diabetic neuropathy.

[0188] 30. The compound for the stated use as described in Item 29, wherein the diabetes is chronic diabetes.

[0189] 31. The compound for the purpose according to any one of entries 17 to 19, wherein the neuropathic pain is neuropathic cancer pain.

[0190] 32. The compound for the use according to any one of items 17 to 19, wherein the neuropathic pain is caused by neuropathy that occurs during treatment.

[0191] 33. The compound for the purpose described in item 32, wherein the neuropathy that occurs during the treatment is caused by chemotherapy.

[0192] 34. The compound for the purpose described in item 32, wherein the neuropathy occurring during the treatment is caused by radiation therapy.

[0193] 35. The compound for the purpose described in item 32, wherein the neuropathy that occurs during the treatment is caused by surgery.

[0194] 36. The compound for the purpose according to any one of the preceding entries, wherein the pain is trigeminal neuralgia, atypical pain, or hyperalgesia.

[0195] 37. The compound for the purpose according to any one of the preceding entries, wherein the pain is trigeminal neuralgia.

[0196] 38. The compound for the stated use as described in item 37, wherein the pain is selected from typical trigeminal neuralgia; secondary trigeminal neuralgia, such as that attributed to multiple sclerosis, such as that attributed to space-occupying lesions; and idiopathic trigeminal neuralgia.

[0197] 39. The compound for the purpose described in any one of entries 37 to 38, wherein the pain is painful trigeminal neuropathy, such as that attributable to herpes zoster, such as postherpetic neuralgia, such as post-traumatic trigeminal neuropathy, such as idiopathic painful trigeminal neuropathy.

[0198] 40. The compound for the purpose according to any one of the preceding entries, wherein the pain is postherpetic neuralgia.

[0199] 41. The compound for the purpose according to any one of the preceding entries, wherein the pain is pain caused by Parkinson's disease.

[0200] 42. The compound for the purpose according to any one of the preceding entries, wherein the pain is dyspareunia (painful sexual intercourse).

[0201] 43. The compound for the purpose according to any one of the preceding entries, wherein the pain is vulvar pain.

[0202] 44. The compound for the purpose according to any one of the preceding entries, wherein the pain is vulvar pain or progressive vulvar pain.

[0203] 45. The compound used for the stated purpose according to any one of the preceding entries, wherein the pain is associated with postmenopausal urogenital syndrome (GSM) or with vaginal atrophy, vulvovaginal atrophy, urogenital atrophy, or atrophic vaginitis.

[0204] 46. ​​A compound for the purpose according to any one of the preceding entries, wherein the compound is capable of inducing a pain reduction of at least 5%, such as at least 10%, such as at least 15%, such as 20%, in a subject.

[0205] 47. The compound for the stated purpose as described in item 46, wherein the pain relief is a subjective measurement of pain.

[0206] 48. The compound for the stated purpose as described in item 46, wherein the pain relief is a measurement of the pain threshold.

[0207] 49. The compound for the purpose according to any one of items 46 to 48, wherein the measurement of said pain is performed using a visual analog scale (VAS), a numerical rating scale (NRS), or a patient-reported outcome (PRO).

[0208] 50. The compound for the purpose according to any one of the preceding entries, wherein the pain occurs for at least 1 minute, such as at least 5 minutes, such as at least 10 minutes, such as at least 30 minutes, such as at least 1 hour, such as at least 2 hours, such as more than 2 hours.

[0209] 51. The compound used for the stated purpose according to any one of the preceding entries, wherein the pain occurs for at least one day, such as at least three days, such as at least one week.

[0210] 52. The compound for the use according to any one of the preceding entries, wherein the pain occurs for at least 20% of the days, such as at least 30%, such as at least 40%, or at least 50% of the days, over a period of more than one week, such as more than two weeks, such as more than three weeks, such as more than one month, such as more than two months, such as more than three months.

[0211] 53. The compound for the purpose according to any one of the preceding entries, wherein the subject is given another therapeutic agent that effectively treats the pain.

[0212] 54. The compound for the stated use according to any one of the preceding entries, wherein the compound is administered in an amount of about 0.01 mg to 100 mg per individual dose.

[0213] 55. The compound used for the stated purpose according to any one of the preceding entries, wherein the subject is a mammal.

[0214] 56. The compound for the stated use according to any one of the preceding entries, wherein the subject is a human.

[0215] 57. The compound for the stated use according to any one of the preceding entries, wherein the application of said compound is oral administration.

[0216] 58. The compound for the purpose according to any one of items 1 to 56, wherein the administration of the compound is parenteral, such as by injection into the skin, mucous membrane, subcutaneous, intramuscular, intraperitoneal, intravenous or intra-arterial system.

[0217] 59. A compound for the purpose according to any one of the preceding entries, wherein the compound is formulated in a pharmaceutical composition, the pharmaceutical composition further comprising a pharmaceutically acceptable diluent, a carrier, and / or an excipient.

[0218] 60. The compound for the stated purpose as described in item 59, wherein the compound is formulated into a solid dosage form, such as tablets, capsules, pills, granules or powders.

[0219] 61. A composition comprising a compound of formula (I): (I) or its pharmaceutically acceptable salt. The chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0220] 62. The composition according to item 61, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 60%.

[0221] 63. The composition according to item 61, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%.

[0222] 64. The composition according to item 61, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%, such as at least 98%.

[0223] 65. The composition according to item 61, wherein the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0224] 66. A composition comprising a compound of formula (Ia): (Ia), or a pharmaceutically acceptable salt thereof. The chiral purity of the compound of formula (Ia) is at least 51%.

[0225] 67. The composition according to item 66, wherein the chiral purity of the compound of formula (Ia) is at least 60%.

[0226] 68. The composition according to item 66, wherein the chiral purity of the compound of formula (Ia) is at least 90%.

[0227] 69. The composition according to item 66, wherein the chiral purity of the compound of formula (Ia) is at least 95%, such as at least 98%.

[0228] 70. The composition according to item 66, wherein the enantiomeric excess of the compound of formula (Ia) is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0229] 71. A composition comprising a compound of formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof. The chiral purity of the compound of formula (Ib) is at least 51%.

[0230] 72. The composition according to item 71, wherein the chiral purity of the compound of formula (Ib) is at least 60%.

[0231] 73. The composition according to item 71, wherein the chiral purity of the compound of formula (Ib) is at least 90%.

[0232] 74. The composition according to item 71, wherein the chiral purity of the compound of formula (Ib) is at least 95%, such as at least 98%.

[0233] 75. The composition according to item 71, wherein the enantiomeric excess of the compound of formula (Ib) is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

[0234] 76. The composition according to any one of items 61 to 75, wherein the composition further comprises one or more pharmaceutically acceptable excipients or diluents.

[0235] 77. The composition according to any one of items 61 to 76, wherein the composition is used in a method of treating, preventing or relieving pain in a subject.

[0236] 78. The composition for the said use according to item 77, wherein the pain is the pain according to any one of items 7 to 52.

[0237] 79. A composition for the purpose according to any one of entries 77 to 78, wherein the composition comprises other therapeutic agents that are effective in treating the pain.

[0238] 80. A composition for the said use according to any one of items 77 to 79, wherein the composition comprises one or more pharmaceutically acceptable excipients or diluents.

[0239] 81. A method for preparing (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol with a chiral purity of 51% or higher, said method comprising: a. Provide a mixture of the following substances: (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol and (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol; b. Treat the mixture with (Boc)₂O to obtain a mixture of enantiomers of the following substances:

[0240] tert-Butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester c. The mixture was separated using chiral liquid chromatography to obtain the following enantiomers: tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester; and d. Deprotect the isolated enantiomers from step c. under acidic conditions to obtain enantiomerically pure (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0241] 82. The method according to entry 81, wherein step b. uses DCM as a solvent and is carried out in the presence of diisopropylethylamine (DIPEA).

[0242] 83. The method according to any one of items 81 to 82, wherein step b. is carried out between 0°C and 30°C.

[0243] 84. The method according to any one of items 81 to 8376, wherein prior to step c, the mixture in step b is subjected to liquid-liquid extraction between the organic phase and the aqueous phase.

[0244] 85. The method according to any one of items 81 to 84, wherein the liquid chromatography in step c. comprises a stationary phase containing a chiral selector.

[0245] 86. The method according to any one of items 81 to 85, wherein the chiral selector is amylose tris(3-chloro-5-methylphenylcarbamate) in the form of a chiral selector.

[0246] 87. The method according to any one of entries 81 to 86, wherein the chiral purity of the (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is greater than 60%, such as greater than 90%, such as greater than 95%.

[0247] 88. A compound according to formula (II): (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0248] Item A A1. A compound of formula (I) used in a method for treating, preventing, or relieving pain in a subject. Formula (I), or a pharmaceutically acceptable salt thereof.

[0249] A2. The compound for the stated purpose as described in entry A1, wherein the compound is (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0250] A3. A composition comprising a compound of formula (I): (I) or its pharmaceutically acceptable salt. The chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

[0251] A4. The composition according to entry A3, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%.

[0252] A5. The composition according to any one of entries A3 to A4, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 98%.

[0253] A6. The composition according to any one of items A3 to A5, wherein the composition further comprises one or more pharmaceutically acceptable excipients or diluents.

[0254] A7. The composition according to any one of items A3 to A6, wherein the composition is used in a method of treating, preventing or relieving pain in a subject.

[0255] A8. The compound for the said use according to any one of entries A1 to A2, or the composition for the said use according to entry A7, wherein the pain is selected from the group consisting of: (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) Chronic or acute secondary headache or orofacial pain.

[0256] A9. The compound or composition for the purpose described in entry A8, wherein the pain is neuropathic pain of the subject.

[0257] A10. A compound or composition for the purpose according to any one of entries A8 to A9, wherein the subject is given an additional therapeutic agent for the treatment of pain.

[0258] A11. A compound or composition for the purpose described in any one of entries A8 to A10, wherein the subject is a human.

[0259] A12. A method for preparing (+)- or (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol with a chiral purity of 51% or higher, said method comprising: a. Provide a mixture of the following substances: (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol and (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol; b. Treat the mixture with (Boc)₂O to obtain a mixture of enantiomers of the following substances:

[0260] tert-Butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester c. The mixture was separated using chiral liquid chromatography to obtain the following enantiomers: tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester; and d. Deprotect the isolated enantiomers from step c. under acidic conditions to obtain enantiomerically pure (+)- or (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

[0261] A13. The method according to entry A12, wherein the liquid chromatography in step c. comprises a stationary phase containing a chiral selector.

[0262] A14. The method according to entry A12, wherein the (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol has a chiral purity of more than 60%, such as more than 90%, such as more than 95%.

[0263] A15. A compound according to formula (II): (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0264] Example Example 1: Internal Efficacy Materials and methods This study investigated the role of the racemic mixture of IP2016 in different animal pain models.

[0265] Formalin-induced paw retraction behavior in rats Injection of formalin into the hind paw of rats elicits spontaneous nociceptive behaviors, including paw withdrawal, licking, and biting of the injected paw, reflecting various aspects of sensory and emotional pain processing. Therefore, an automated nociceptive analyzer (Yaksh et al., 2001) was used to assess formalin-induced paw withdrawal behavior in normal, undamaged rats (weighing 180g to 300g) in an unbiased manner. Briefly, a small C-shaped metal band (10mm wide × 27mm long) was placed around the hind paw of the rat to be tested. Each rat (four rats per test phase) was randomly administered IP2016 (3mg / kg, 10mg / kg, 30mg / kg) or the solvent and then placed in a cylindrical acrylic observation chamber (15cm in diameter, 30.5cm in height). The experimental observers were unaware of the experimental treatment. Sixty minutes later, the rats were gently restrained, and formalin (5% saline solution, 50 μl, subcutaneous injection) was injected into the dorsal surface of the hind paw using a 27G needle. They were then returned to their respective observation chambers, each located on a closed detection device consisting of two electromagnetic coils designed to generate an electromagnetic field capable of detecting the movement of a metal strip. The analog signals were then digitized, and software algorithms were applied to distinguish paw retraction from other paw movements. The data were then grouped at 1-minute sampling intervals. Based on the resulting response patterns, three phases of noxious behavior were identified (Munro et al., 2008). The first phase (0 to 5 minutes) can be attributed to direct chemical stimulation of nociceptors, while the intermediate phase (6 to 15 minutes) is associated with the regulation of a monoamine-containing pathway descending from brainstem structures to inhibit nociceptive signaling in the dorsal horn of the spinal cord, and the second phase (16 to 40 minutes) can be attributed to peripheral inflammatory processes and subsequent sensitization of nociceptive spinal cord neurons (Coderre and Bennett, 2010). Raw data from the 1-minute sampling interval were summed for each phase to obtain the total number of withdrawals occurring within that time period. This value was then expressed as a percentage of the solvent response for statistical analysis according to the following equation: Solvent% = (Post-treatment value) / (Sodium value) × 100.

[0266] Chronic constrictive injury procedure Chronic constrictive injury (CCI) was performed on rats (weighing 180g to 220g at the time of surgery) under isoflurane anesthesia as described above (25). The sciatic nerve was exposed at the mid-thigh level near the trifid of the sciatic nerve. Four chromium catgut (4 / 0) sutures (Ethicon, New Brunswick, NJ) were loosely tied around the nerve, spaced 1mm to 2mm apart, so as not to impair vascular supply. The covered muscle was sutured in layers with 4 / 0 synthetic absorbable surgical sutures. The skin was closed and sutured with 4 / 0 silk sutures.

[0267] Routine tests were performed on rats with neurological damage to determine the presence of neurogenic hypersensitivity up to 5 weeks post-surgery, following previously described methods (26). For the low-threshold mechanical hypersensitivity (abnormal pain) test, each rat was removed from its living cage and allowed to acclimatize for 15 minutes in a 15 × 20 cm white Plexiglass test cage placed on an elevated metal grid to contact the plantar surface of the damaged hind paw. A series of calibrated von Frey filaments (lower limit = 0.065 g, upper limit = 19.3 g, Stoelting, Wood Dale IL) were then applied to the hind paw with progressively increasing force for 1 to 2 seconds until the individual filament just began to bend. The filaments were applied 5 times at 1 to 2-second intervals. Fibers that induced reflexive paw retraction in 3 out of 5 applications were considered to represent the threshold level for a response. The presence of high-threshold mechanosensitive hypersensitivity (alcoholism) was determined by pressing the tip of a safety pin onto the sole of the damaged hind paw. The pressure was strong enough to elicit a reflexive withdrawal response in a normal, unoperated animal, but not strong enough to penetrate the skin. A 15-second cutoff time was set for the prolonged withdrawal commonly seen in paws with nerve damage.

[0268] On the day of drug testing, baseline responses to von Frey and needle stimulation were measured in CCI rats. Subsequently, CCI rats were randomly injected with IP2016 (a mixture of enantiomers, 3 mg / kg, 10 mg / kg, and 30 mg / kg) or a solvent, and then returned to the von Frey testing chamber. Observers were unaware of the experimental treatments. The behavioral testing procedure was repeated after 60 minutes to allow for the measurement of efficacy responses following treatment.

[0269] result The results showed that IP2016 produced positive results in pain-related responses in animal models. Figure 1 In the group processed with IP2016, the number of claw retractions in the formalin model was reduced.

[0270] in conclusion Compound (I) has shown positive effects in treating pain in animals.

[0271] Example 2: Purification of IP2016 enantiomers in HCl salt or free salt form.

[0272] Materials and methods Sample material. The racemic mixtures of the two isomers of IP2016 were in the form of HCl salts (7 g).

[0273] Preliminary testing. Attempts were made to separate racemic mixtures in the form of HCl salts using different analytical chiral columns with variations in solvents and additives.

[0274] Free salt test. A racemic mixture of HCl salts was treated with a methanol solution of 7M NH3 to prepare free amines; in this process, 100 mg of HCl salt was placed in a 25 mL RB flask and treated with 10.0 mL of methanol (NH3) at 0 °C with stirring for 3 hours. A clear solution was observed within 10 minutes after the addition of methanol (NH3), and precipitation occurred after 3 hours. The obtained precipitated free amine was filtered and used to separate individual isomers.

[0275] result First, attempts were made to separate the racemic mixture using different analytical chiral columns with varying solvents and additives. Satisfactory separation could not be achieved due to the very poor solubility of the components, or perhaps the nature of the hydrochloride mixture. The peaks were broad and unseparated.

[0276] No separation was detected in the free salt test. No positive results were obtained in either normal-phase or reversed-phase chromatography.

[0277] in conclusion Due to the nature of the mixture, separation of IP2016 enantiomers in hydrochloride or free base form was unsuccessful under different conditions.

[0278] Example 3: Test of IP2016 protection method Materials and methods abbreviation 。 DMAP: 4-Dimethylaminopyridine, DCM: Dichloromethane, THF: Tetrahydrofuran, DIPEA: Diisopropylethylamine.

[0279] The following attempts were made to prepare a salt for the separation of the racemic IP2016: Protected with tert-butyldimethylsilyl chloride (TBDMS-Cl).

[0280]

[0281]

[0282] Protected with fluorenylmethoxycarbonyl chloride (Fmoc-Cl).

[0283]

[0284]

[0285] Protected with benzyl chloroformate (Cbz-Cl).

[0286]

[0287]

[0288] Protected with tert-butyloxycarbonyl anhydride (Boc2O).

[0289]

[0290]

[0291] result Protection with TBDMS-Cl, Fmoc-Cl, and Cbz-Cl was unsuccessful. The conversion yield was extremely low, or the target product could not be formed, when using these reagents.

[0292] Using (Boc)₂O under condition 4.1, even with only 1 equivalent of (Boc)₂O, both the free amine (-NH) and free hydroxyl group (-OH) of IP₂₀₁₆ were protected by Boc in the major product formed. This doubly protected product reacted with an aqueous solution of NaHCO₃, followed by LiOH, in an attempt to achieve selective deprotection at the -OH group, but this was unsuccessful.

[0293] Using (Boc)₂O under conditions 4.2, a single protected compound with protection at the -NH group was obtained in good yield. The product was washed with water and then extracted with DCM. The separated organic layer was washed with brine, dried over Na₂SO₄, and concentrated under vacuum. Silica gel column purification was then performed to give a separated mixture of IP₂₀₁₆ enantiomers. The product was a solid, well soluble in most solvents, and suitable for continuous purification.

[0294] in conclusion Under commonly used amine group protection conditions, several common protecting reagents failed to successfully form the -NH protected derivative of the racemic form of IP2016. Specific conditions for protection with (Boc)₂O were determined.

[0295] Example 4: Chiral separation of IP2016 isomers Materials and methods The protected racemic derivative of Boc (Boc-IP2016) was separated using liquid chromatography (HPLC) on a Chiralpak® IG 5µm 250×20mm column with amylose tris(3-chloro-5-methylphenylcarbamate) as the chiral selector in the stationary phase. The mobile phase was MeOH containing 0.1% diethylamine, in isocratic mode, at a flow rate of 15.0 mL / min. For each injection, 50 mg of the protected isomer mixture was loaded.

[0296] Following preparative chiral separation, the separated isomers were treated with a 4M HCl solution in dioxane at 0°C to 20°C for 12 hours. The precipitate was obtained, filtered, washed with diethyl ether and pentane, dried, and then further characterized.

[0297] Analytical chiral HPLC. Column: CHIRALPAK IG (250 mm × 4.6 mm), 5 μm. Mobile phase: MeOH / diethylamine (100% / 0.1%). Flow rate: 1.0 mL / min. Detection: UV 260 nm.

[0298] Analytical LC-MS. Mobile phase A: 0.1% formic acid aqueous solution. Mobile phase B: acetonitrile:MeOH (50:50). Column: X-BRIDGE C18 (50×4.6mm), 3.5μm. Time / B%: 0 / 30, 4 / 100, 5 / 100, 6 / 30. Flow rate: 1.0 mL / min.

[0299] Optical rotation measurement. Specific rotation was measured at 20°C with methanol as solvent, using an optical path length of 1.00 dm and a wavelength of 589 nm in the MCP 200 instrument.

[0300] result 577 mg of isomer 1 was isolated with a chiral purity of 98.11%, as determined by the percentage of the under-peak area of ​​isomer 1 compared to the total under-peak area of ​​isomers 1 and 2 in the chromatogram of the sample obtained after chiral analytical HPLC. Figure 2 The chromatogram of isomer 1 is shown. The retention time is 12.73 minutes.

[0301] Figure 2 The chromatographic parameters in the data.

[0302]

[0303] 718 mg of isomer 2 was isolated with a chiral purity of 97.15%, as determined by the percentage of the under-peak area of ​​isomer 2 compared to the total under-peak area of ​​isomers 1 and 2 in the chromatogram of the sample obtained after chiral analytical HPLC. Figure 3 The chromatogram of isomer 2 is shown. The retention time is 19.654 minutes.

[0304] Figure 3 The chromatographic parameters in the data.

[0305]

[0306] Table 1. Optical rotation of separated enantiomers.

[0307]

[0308]

[0309] in conclusion The separation of different enantiomers of IP2016 with high enantiomeric purity was achieved.

[0310] Example 5: Receptor Screening Assay Materials and methods Effects on monoamine transporters. Two independent experiments were performed in human embryonic kidney (HEK293, ATCC-CRL-1573) cells stably expressing serotonin transporter (hSERT) and norepinephrine transporter (hNAT). Dopamine transporter (hDAT) was overexpressed in Chinese hamster ovary cells (ATCC-CCL-61). Neurotransmitter transporter assays were performed according to the supplier's instructions (Molecular Devices, San Jose, California, USA). Cells were seeded in 96-well plates, and uptake of fluorescence was measured in each cell line in the presence of specific inhibitors of SERT, NAT, and DAT (i.e., citalopram hydrobromide, nisoxetine, and benzothiophene cyclohexylpiperidine (BTCP)) at a concentration of 1 μM, with 10 serial dilutions (4-fold), each in duplicate. To measure the effects of racemic IP2016 samples, isomer 1, and isomer 2, plated cells were exposed to a compound or solvent at a concentration of 10 μM that was serially diluted 4-fold (10 dilution points, each with double duplicate wells).

[0311] Affinity to opioid μ receptors. Affinity to opioid receptors was determined by measuring the displacement of a specific radioligand with affinity for the opioid receptor by the IP2016 sample, as measured by liquid scintillation counting. The opioid agonist DAMGO (CAS No.: 78123-71-4) was used as a positive control.

[0312] result The results for each isomer on monoamine transporters are shown in Table 2. The racemic compound IP2016 inhibited monoamine transporters in the following order: 5-HTT > NAT = DAT, indicating the greatest effect on serotonin uptake. In contrast, isomer 1 showed a more balanced effect on the three monoamine transporters (5-HTT > NAT > DAT) compared to racemic IP2016, but with lower selectivity for 5-HTT. Isomer 2 was less potent for 5-HTT than both racemic IP2016 and isomer 1, and even less selective for 5-HTT compared to NAT and DAT, suggesting it is a more general monoamine reuptake inhibitor. As can be seen from Table 2, it should be understood that isomer 1 is the most effective of the two stereoisomers for all three monoamine transporters.

[0313] Table 2. IC50 of compounds against serotonin transporter (5-HTT), norepinephrine (NAT), and dopamine transporter (DAT) 50 (nM).

[0314]

[0315] Furthermore, isoform 1 exhibits affinity for opioid μ receptors, of which IC 50 The concentration was 240 nM, thus indicating further potential for pain treatment via this receptor. When tested at the same concentration, isomer 1 was considered to have a greater effect on opioid μ compared to isomer 2.

[0316] in conclusion Compared with isomer 2, isomer 1, corresponding to (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol, showed higher monoamine reuptake inhibition efficacy.

[0317] Isomer 1 showed a significant affinity for the opioid μ receptor and was more effective than isomer 2, indicating further improved properties in pain management via this receptor in addition to monoamine transporters.

[0318] Furthermore, isoform 1 exhibits different receptor-binding characteristics compared to the racemic form in terms of binding to monoaminergic transporters and off-target substances.

[0319] Example 6: Chiral stability of enantiomers of IP2016 Purpose Evaluate the stability of IP2016 enantiomers in aqueous media.

[0320] Materials and methods Isomer 1, with a purity of 98.11%, was used. Isomer 2, with a purity of 97.15%, was used.

[0321] Stability was assessed at a total of 5 pH values: 1, 2, 3, 5, and 7.

[0322] On day 1 of the overall stability study, different test samples were prepared. The deprotected isomer was dissolved in pure water, and the pH was adjusted to a specific value using dilute HCl solution. Racemic mixtures were also measured, as these were also suitable for monitoring retention time differences in chiral stability measurements. The solutions were then transferred to sealed HPLC vials. Measurements began immediately.

[0323] Then, incubation was performed in HPLC vials throughout the entire study (18 days). One set was kept at room temperature, while another set of identical HPLC vials was kept cooled at 4°C and measured after 4 hours. Additionally, freshly weighed standards were prepared: immediately before the first measurement on day 1, freshly weighed individual isomers and racemic mixtures were taken to detect potential changes in the samples already dissolved in solution compared to the pH-adjusted test samples. On day 1 of the overall stability study, the following samples were prepared: Test sample: Isomer 1 (dissolved in pure water and adjusted to pH 1, pH 2, pH 3, pH 5 and pH 7 respectively) Isomer 2 (dissolved in pure water and adjusted to pH 1, pH 2, pH 3, pH 5 and pH 7 respectively) Original racemic material Standard sample: Weigh fresh immediately before measurement. Isomer 1 (dissolves in pure water, pH not adjusted) Isomer 2 (dissolves in pure water, pH not adjusted) A mixture of isomer 1 and isomer 2 (dissolved in pure water, pH not adjusted). Original racemic material (adjusted to pH 1, pH 2, pH 3, pH 5 and pH 7 respectively) On each measurement day, each test sample and standard were measured by LC in MeOH / water (95% / 5%), 10 mM ammonium bicarbonate. Additionally, measurements were performed using the 0.1% DIEA (diisopropylethylamine) method. Stability studies were conducted for 18 days.

[0324] During projects using these compounds, their chiral stability was continuously monitored by applying stress conditions such as temperature, solvent, and acidic pH.

[0325] Analytical chiral LC method.

[0326] Method 1: Column: CHIRALPAK IG-3, 5 μm RP, 150 × 4.6 mm. Mobile phase: MeOH / water (95% / 5%), 10 mM ammonium bicarbonate. Flow rate: 1.0 mL / min. UV: 295 nm.

[0327] Method 2: Column: CHIRALPAK IG, 5 μm, 250 × 4.6 mm. Mobile phase: MeOH / DIEA (100% / 0.1%). Flow rate: 1.0 mL / min. UV: 295 nm.

[0328] result The results showed that the isomers were stable for at least 2 weeks in water at room temperature and pH 1, 2, 3, 5 and 7, and their chirality did not change significantly, even under stress conditions. Figure 4 The isomer purity of isomer 1 is shown, calculated using the area of ​​the corresponding chiral analytical HPLC peak at pH 1.

[0329] The results showed that the isomer was stable for at least one week at room temperature and in an organic solvent (dioxane), and its chirality did not change significantly, even under stress conditions (30°C).

[0330] in conclusion The separated enantiomers of IP2016 exhibit good chiral stability under different conditions (including stress conditions).

[0331] Example 7: Stereochemical Configuration Study Purpose Structural studies were conducted on the absolute configuration of the enantiomer of IP2016.

[0332] Materials and methods As described in Example 4, enantiomers of IP2016 were isolated to obtain isomer 1 and isomer 2. Each isolated enantiomer was derivatized to its (R) and (S) configurations using Mosher's reagent (3,3,3-trifluoro-2-methoxy-2-phenyl-propionic acid, MTPA).

[0333] Therefore, the following four forms were generated: Isomer 1 (R)-MTPA Isomer 1 (S)-MTPA Isomer 2 (R)-MTPA Isomer 2 (S)-MTPA In addition, a portion of the reaction products between approximately 7 mg of a mixture of racemic IP2016 derivatized with MTPA was investigated.

[0334] All NMR spectra were recorded on a JEOL ECZ spectrometer operating at 400 MHz (9.4 T) and 300 K.

[0335] All spectra were obtained using [the method described]. 1 A broadband probe with an H-type decoupling coil. Recording is achieved using a 45° excitation pulse and eight additional scans. 1 1H NMR spectrum. Spectral width 15 ppm (limited from 7.5 kHz to 6.0 kHz), digital resolution 0.22 Hz.

[0336] Heteronuclear correlation spectrum (13C-hsqc) is obtained by analyzing 1k complex data points (f2, 1 H dimension) and f1 13 The data was recorded using a matrix consisting of 1024 increments (1024 data points) along the C dimension. The spectral width was 10 ppm in f2 (limited from 5 kHz to 4 kHz) and 140 ppm (14.1 kHz) in f1. Eight additional scans were performed, with a repetition time of 0.95 seconds for each increment, resulting in a total of 16192 scans. The experiment lasted for 4 hours.

[0337] Homonuclear correlation spectrum (cosy) is obtained by analyzing 2k complex data points (f2, 1 The data was recorded using a matrix consisting of H-dimensional data and 1024 increments (512 complex data points in f1). The spectral width was 10 ppm in f2 (limited from 5 kHz to 4 kHz) and f1 (4 kHz). Eight additional scans were performed, with a repetition time of 2 seconds for each increment, resulting in a total of 8096 scans. The experiment lasted 4.5 hours.

[0338] Homonuclear NOE spectra (noesy) are obtained by analyzing 2k complex data points (f2, 1 The data was recorded using a matrix consisting of H-dimensional data and 1024 increments (512 complex data points in f1). The spectral width was 10 ppm in f2 (limited from 5 kHz to 4 kHz) and f1 (4 kHz). Eight additional scans were performed, with a repetition time of 3.5 seconds for each increment, resulting in a total of 8096 scans. The experiment lasted for 8 hours.

[0339] After baseline processing and correction using a 5th-order polynomial and automatic signal threshold detection, a total of 184 integration regions were manually defined and numerically integrated using Bruker Topspin 4.3.0 software. The sensitivity limit was evaluated through 12 integration regions in the signal-free portion of the spectrum, with the variance (in digital resolution) set to 1. Five times the variance was then added to all integrations used to calculate the specified correlations for the upper and lower distances, and subtracted from the variance. Distance calibration for each of the four substances was obtained using three (or two in the case of the cisamide of MCC13997) homoproton pairs spaced 1.8 Å apart. (4 or 6 integrations) All distances assumed theoretical R0. -6 The distances are calculated based on dependencies. Table 3 only lists non-trivial distances.

[0340] Heteronuclear long-range correlation spectrum (HMBC) is obtained by analyzing 4k complex data points (f2, 1 The data was recorded using a matrix consisting of H-dimensional data and 1024 increments (512 complex data points in f1). The spectral width was 8 ppm in f2 (limited from 4 kHz to 3.2 kHz) and 110 ppm in f1 (11 kHz, optimized for folding at 125 ppm). Twenty-four additional scans were performed, with a repetition time of 3.5 seconds per increment, resulting in a total of 24,576 scans. The experiment lasted 15 hours.

[0341] Different conformational combinations of each isomer of IP2016 and the (R)-isomer of Mosher salt were modeled using the free software AVOGADRO (Hanwell et al.) and force field MFF94 (Halgren et al.).

[0342] result Because amine and alcohol derivatives of Mosher salt (MTPA, 3,3,3-trifluoro-2-methoxy-2-phenyl-propionic acid) can induce the production of 1 The chemical shift difference of H-NMR has led to its extensive literature review on its application in the determination of absolute configuration (Latypov et al.; Seco et al.; Hoye et al.), and it has been verified by X-ray crystal structure (Ichikawa et al.).

[0343] NMR analysis was performed on the mixture of diastereomers obtained by (R)-MTPA derivatization of the racemic IP2016, and the obtained attribution results were compared with the spectra of optically pure diastereomers obtained by (R)-MTPA or (S)-MTPA derivatization of the separated enantiomers of IP2016.

[0344] The diastereomers formed by the reaction of IP2016 enantiomers with (R)-MTPA are described below: 2-((1S,5R)-8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol Mosher salt derivative:

[0345] Name: (2R)-3,3,3-trifluoro-1-[(1S,5R)-3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-2-methoxy-2-phenyl-prop-1-one Abbreviation: (1S,5R)-(R)MTPA 2-((1R,5S)-8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol Mosher salt derivative:

[0346] Name: (2R)-3,3,3-trifluoro-1-[(1R,5S)-3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]-2-methoxy-2-phenyl-prop-1-one Abbreviation: (1R,5S)-(R)MTPA Each IP2016 isomer of the MTPA secondary amide exhibits two stable conformations, resulting in a major (higher content) and minor (lower content) rotational isomer for each diastereomer. These rotational isomers can be based on... 13 The chemical shift differences in C-NMR and the correlation of signals in NOESY spectra are used to specify the relationship, similar to the accepted rules for -Pro amide bonds in peptides (London et al.; Dorman et al.; Grathwohl et al.; Siemion et al.).

[0347] 4 combinations: (1R,5S)-(R)MTPA, the main rotational isomer (1R,5S)-(R)MTPA, minor rotational isomer (1S,5R)-(R)MTPA, major rotatory isomers and (1S,5R)-(R)MTPA, minor rotational isomer; Modeling was performed using the free software AVOGADRO and the force field MMFF94. First, the optimal conformation was searched for by randomizing the orientation of the rotational bonds, and the results were further optimized using force field calculations. Next, the two main conformations of the amide bonds in each rotational isomer were fixed by constraining the torsion angle, and the above procedure was repeated (repeatedly using the MMFF94 force field for conformation search and optimization).

[0348] The results are in excellent agreement with the preference for amide rotational isomers. Based on the MTPA-derived model of the IP2016 isomer, the orientation of the benzene ring of the MTPA residues should induce a characteristic reduction in the chemical shift of protons located within the anisotropic cone (Günther et al.). The anisotropic cone of the benzene ring is inversely proportional to the square of the distance, and based on the kinematic mean of the benzene ring, an induced shielding effect greater than 0.2 ppm (the difference in chemical shift between protons) can be observed for distances up to 8 Å.

[0349] For the major rotational isomer, the anisotropic cone points to the H2 proton in (1R,5S)-(R)MTPA and the H7 proton in (1S,5R)-(R)MTPA. For the minor rotational isomer, the anisotropic cone points to the H6 proton in (1R,5S)-(R)MTPA and the H4 proton in (1S,5R)-(R)MTPA. Therefore, the protons are expected to have lower chemical shifts in each corresponding conformation.

[0350] As can be seen from Table 3, for the major rotational isomers, the proton at the H2 position has a lower chemical shift in isomer 1 (R)-MTPA (bold), while the proton at the H7 position has a lower chemical shift in isomer 2 (R)-MTPA (underlined).

[0351] For minor rotational isomers, the proton at the H6 position has a lower chemical shift in isomer 1 (R)-MTPA(*), while the proton at the H4 position has a lower chemical shift in isomer 2 (R)-MTPA(**).

[0352] Table 3. Selected protons in isomer 1 (R)-MTPA and isomer 2 (R)-MTPA 1 H-NMR shift.

[0353]

[0354] Therefore, based on the expected anisotropic shielding effect of the phenyl groups in MTPA, the experimentally measured chemical shift differences provide the following stereochemical allocation for each IP2016 enantiomer:

[0355] in conclusion The absolute configuration of the IP2016 enantiomer was specified based on the explanation of the differences in chemical shifts caused by the anisotropy of phenyl residues in the MTPA derivative.

[0356] References Hanwell, MD; Curtis, DE; Lonie, DC; Vandermeersch, T.;Zurek, E.; Hutchison, GR Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. Journal of Cheminformatics 2012, 4 (1),17. DOI: 10.1186 / 1758-2946-4-17. Halgren, TA Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. Journal of ComputationalChemistry 1996, 17 (5-6), 490-519. DOI: https: / / doi.org / 10.1002 / (SICI)1096-987X(199604)17:5 / 6<490::AID-JCC1>3.0.CO;2-P. Latypov, S. K.; Galiullina, N. F.; Aganov, A. V.; Kataev, V. E.;Riguera, R. Determination of the absolute stereochemistry of alcohols andamines by NMR of the group directly linked to the chiral derivatizingreagent. Tetrahedron 2001, 57 (11), 2231-2236. DOI: https: / / doi.org / 10.1016 / S0040-4020(01)00056-4. Seco, J. M.; Quiñoá, E.; Riguera, R. The Assignment of AbsoluteConfiguration by NMR. Chemical Reviews 2004, 104 (1), 17-118. DOI: 10.1021 / cr000665j. Hoye, T. R.; Jeffrey, C. S.; Shao, F. Mosher ester analysis for thedetermination of absolute configuration of stereogenic (chiral) carbinolcarbons. Nature Protocols 2007, 2 (10), 2451-2458. DOI:10.1038 / nprot.2007.354. Ichikawa, A.; Ono, H.; Mikata, Y. Characteristic Conformation ofMosher’s Amide Elucidated Using the Cambridge Structural Database. Molecules2015, 20 (7), 12880-12900. LONDON, RE QUANTITATIVE EVALUATION OF γ-TURN CONFORMATION INPROLINE CONTAINING PEPTIDES USING13 C NMR International Journal of Peptideand Protein Research 1979, 14 (5), 377-387. DOI: https: / / doi.org / 10.1111 / j.1399-3011.1979.tb01948.x. Dorman, DE; Bovey, FA Carbon-13 magnetic resonance spectroscopy. Spectrum of proline in oligopeptides. The Journal of Organic Chemistry 1973, 38 (13), 2379-2383. DOI: 10.1021 / jo00953a021. Grathwohl, C.; Wüthrich, K. NMR studies of the rates of proline cis–trans isomerization in oligopeptides. Biopolymers 1981, 20 (12), 2623-2633.DOI: https: / / doi.org / 10.1002 / bip.1981.360201209. Siemion, IZ; Wieland, T.; Pook, KH. Influence of the distance of the proline carbonyl from the β- and γ-carbon on the position of the 13C-NMR signals. Angewandte Chemie 1975, 87 (19), 712-714. DOI:10.1002 / anie.197507021. Günther, H. NMR spectroscopy: basic principles, concepts and applications in chemistry; John Wiley & Sons, 2013.

Claims

1. A composition comprising a compound of formula (I): (I) or its pharmaceutically acceptable salt. The chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 51%.

2. The composition according to claim 1, wherein the (-)2-(8-azabicyclo[ 3.2.1] Oct-2-en-3-yl)benzo[b]thiophene-5-ol has a chiral purity of at least 60%.

3. The composition according to claim 1, wherein the (-)2-(8-azabicyclo[ 3.2.1] Oct-2-en-3-yl)benzo[b]thiophene-5-ol has a chiral purity of at least 90%.

4. The composition according to claim 1, wherein the chiral purity of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 95%, such as at least 98%.

5. The composition according to claim 1, wherein the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

6. The composition according to claim 1, wherein the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 50%.

7. The composition according to claim 1, wherein the enantiomeric excess of (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol is at least 90%.

8. The composition according to claim 1, wherein the compound of formula (I) is a compound of formula (Ib): (Ib), or a pharmaceutically acceptable salt thereof. The chiral purity of the compound of formula (Ib) is at least 51%.

9. The composition according to claim 6, wherein the chiral purity of the compound of formula (Ib) is at least 60%.

10. The composition according to claim 6, wherein the chiral purity of the compound of formula (Ib) is at least 90%.

11. The composition according to claim 6, wherein the chiral purity of the compound of formula (Ib) is at least 95%, such as at least 98%.

12. The composition according to claim 6, wherein the enantiomeric excess of the compound of formula (Ib) is at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or at least 98%.

13. The composition according to claim 1, wherein the enantiomeric excess of the compound of formula (Ib) is at least 50%.

14. The composition according to claim 1, wherein the enantiomeric excess of the compound of formula (Ib) is at least 90%.

15. The composition according to any one of claims 1 to 14, wherein the composition further comprises one or more pharmaceutically acceptable excipients or diluents.

16. The composition according to any one of claims 1 to 15, wherein the composition comprises other therapeutic agents that are effective in treating pain.

17. The composition according to any one of claims 1 to 16, wherein the composition is used in a method of treating, preventing or relieving pain in a subject.

18. A compound used in a method of treating, preventing or relieving pain in a subject, wherein the compound is (-)-2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

19. The composition of claim 17, or the compound of claim 18 for the said use, wherein the pain is selected from the group consisting of: (i) Chronic or acute primary pain, (ii) Chronic or acute cancer-related pain, (iii) Chronic or acute postoperative pain, (iv) Chronic or acute post-traumatic pain, (v) Chronic or acute secondary musculoskeletal pain, (vi) Chronic or acute secondary visceral pain, (vii) Chronic or acute neuropathic pain, and (viii) Chronic or acute secondary headache or orofacial pain.

20. The composition or compound for the purpose according to claim 19, wherein the chronic or acute primary pain is chronic or acute primary visceral pain, chronic or acute generalized pain, fibromyalgia syndrome, chronic or acute primary musculoskeletal pain, chronic or acute primary headache or orofacial pain, such as migraine, burning mouth syndrome, tension headache, cluster headache or persistent unilateral headache; complex regional pain syndrome (CRPS) or painful cyanosis syndrome.

21. The composition or compound for the purpose according to claim 19, wherein the chronic or acute cancer-related pain is associated with visceral cancer pain, bone cancer pain, or neurogenic cancer pain.

22. The composition or compound for the use according to claim 19, wherein the chronic or acute cancer-related pain is post-cancer treatment pain, such as post-cancer drug treatment pain, such as chemotherapy-induced painful polyneuropathy, such as post-radiation pain, such as radiation-induced painful neuropathy.

23. The composition or compound for the purpose according to claim 19, wherein the chronic or acute postoperative pain is postoperative pain following spinal surgery, hernia incision, hysterectomy, amputation, thoracotomy, breast surgery, or arthroplasty.

24. The composition or compound for the purpose according to claim 19, wherein the chronic or acute post-traumatic pain is post-burn pain, whiplash injury-related pain, or musculoskeletal injury-related pain.

25. The composition or compound of claim 19 for the stated use, wherein the chronic or acute secondary musculoskeletal pain is pain caused by persistent inflammation, such as inflammation caused by infection, inflammation caused by crystal deposition, or inflammation caused by autoimmune disorders and autoinflammatory disorders; pain associated with structural changes, such as pain associated with osteoarthritis or vertebral arthropathy; pain caused by neurological disorders, such as pain associated with Parkinson's disease, pain associated with multiple sclerosis, or pain associated with peripheral nerve disorders.

26. The composition or compound of claim 19 for the stated use, wherein the chronic or acute secondary visceral pain is pain caused by mechanical factors, vascular mechanisms, or persistent inflammation, such as mechanical factors, vascular mechanisms, or persistent inflammation in the head, neck, chest, abdomen, or pelvic region.

27. The composition or compound of claim 19 for the stated use, wherein the chronic or acute neuropathic pain is central nervous system pain, such as central nervous system pain associated with spinal cord injury, brain injury, post-stroke pain, or multiple sclerosis; peripheral nervous system pain, peripheral nervous system pain following nerve injury, painful polyneuropathy, or painful radiculopathy; or neuropathic orofacial pain.

28. The composition or compound for the use of claim 19, wherein the chronic or acute secondary headache or orofacial pain is chronic toothache, chronic neurogenic orofacial pain, headache or orofacial pain associated with temporomandibular joint disorder, homeostasis disorder or its nonpharmacological treatment, cranial or cervical vascular disorder, nonvascular intracranial disorder, a substance or its withdrawal, or head traumatic injury.

29. The composition or compound for the said use according to any one of claims 19 and 27 to 28, wherein the pain is neuropathic pain.

30. The composition or compound for the said use according to any one of claims 19 and 27 to 29, wherein the neuropathic pain is acute neuropathic pain.

31. The composition or compound for the said use according to any one of claims 19 and 27 to 29, wherein the neuropathic pain is chronic neuropathic pain.

32. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by alcoholism, diabetes, multiple sclerosis, multiple myeloma, stroke, cancer, cytomegalovirus, trigeminal neuralgia, spinal cord injury, or amputation.

33. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by a chronic progressive neurological disease.

34. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by an infection.

35. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by injury.

36. The composition or compound for the use according to any one of claims 29 to 31, wherein the neuropathic pain is persistent pain following nerve injury.

37. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by a side effect of the drug.

38. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by a medical procedure such as surgery.

39. The composition or compound for the said use according to any one of claims 29 to 31, wherein the neuropathic pain is idiopathic.

40. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is the neuropathic component of nociceptive pain.

41. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by diabetic neuropathy.

42. The composition or compound for the said use according to claim 41, wherein the diabetes is chronic diabetes.

43. The composition or compound for the said use according to any one of claims 29 to 31, wherein the neuropathic pain is neuropathic cancer pain.

44. The composition or compound for the purpose according to any one of claims 29 to 31, wherein the neuropathic pain is caused by neuropathy that occurs during treatment.

45. The composition or compound for the said use according to claim 44, wherein, The neuropathy that occurred during the treatment was caused by chemotherapy.

46. ​​The composition or compound for the said use according to claim 44, wherein, The neuropathy that occurred during the treatment was caused by radiotherapy.

47. The composition or compound for the said use according to claim 44, wherein, The neuropathy that occurred during the treatment was caused by the surgery.

48. The composition or compound for the said use according to any one of claims 19 to 47, wherein the pain is trigeminal neuralgia, atypical pain, or hyperalgesia.

49. The composition or compound for the purpose according to any one of claims 19 to 48, wherein the pain is trigeminal neuralgia.

50. The composition or compound for the use according to claim 49, wherein the pain is selected from typical trigeminal neuralgia; secondary trigeminal neuralgia, such as that attributed to multiple sclerosis, such as that attributed to space-occupying lesions; and idiopathic trigeminal neuralgia.

51. The composition or compound for the use according to any one of claims 49 to 50, wherein the pain is painful trigeminal neuropathy, such as that attributable to herpes zoster, such as postherpetic neuralgia, such as post-traumatic trigeminal neuropathy, such as idiopathic painful trigeminal neuropathy.

52. The composition or compound for the purpose according to any one of claims 19 to 51, wherein the pain is postherpetic neuralgia.

53. The composition or compound for the said use according to any one of claims 19 to 52, wherein the pain is pain caused by Parkinson's disease.

54. The composition or compound for the said use according to any one of claims 19 to 53, wherein the pain is dyspareunia (painful sexual intercourse).

55. The composition or compound for the purpose according to any one of claims 19 to 54, wherein the pain is vulvar pain.

56. The composition or compound for the purpose according to any one of claims 19 to 55, wherein the pain is vulvar pain or progressive vulvar pain.

57. The composition or compound for the use according to any one of claims 19 to 56, wherein the pain is associated with menopausal urogenital syndrome (GSM) or with vaginal atrophy, vulvovaginal atrophy, urogenital atrophy, or atrophic vaginitis.

58. The composition or compound for the purpose according to any one of claims 19 to 57, wherein the composition or compound is capable of inducing a pain reduction of at least 5%, such as at least 10%, such as at least 15%, such as 20%, in the subject.

59. The composition or compound for the purpose according to claim 58, wherein the pain relief is a subjective measurement of pain.

60. The composition or compound for the said use according to claim 58, wherein the pain relief is a measurement of the pain threshold.

61. The composition or compound for the said use according to any one of claims 58 to 54, wherein the measurement of said pain is performed using a visual analog scale (VAS), a numerical rating scale (NRS), or a patient-reported outcome (PRO).

62. The composition or compound for the purpose according to any one of claims 19 to 61, wherein the pain occurs for at least 1 minute, such as at least 5 minutes, such as at least 10 minutes, such as at least 30 minutes, such as at least 1 hour, such as at least 2 hours, such as more than 2 hours.

63. The composition or compound for the said use according to any one of claims 19 to 62, wherein the pain occurs for at least one day, such as at least three days, such as at least one week.

64. The composition or compound for the said use according to any one of claims 19 to 63, wherein the pain occurs for at least 20% of the days, such as at least 30%, such as at least 40%, or at least 50% of the days, over a period of more than one week, such as more than two weeks, such as more than three weeks, such as more than one month, such as more than two months, such as more than three months.

65. The composition or compound for the purpose according to any one of claims 19 to 64, wherein the subject is given an additional therapeutic agent that effectively treats the pain.

66. The composition or compound for the purpose according to any one of claims 19 to 65, wherein the compound is administered in an amount of about 0.01 mg to 100 mg per individual dose.

67. The composition or compound for the said use according to any one of claims 19 to 66, wherein the subject is a mammal.

68. The composition or compound for the said use according to any one of claims 19 to 67, wherein the subject is a human.

69. The composition or compound for the said use according to any one of claims 19 to 68, wherein the administration of said composition or compound is oral administration.

70. The composition or compound for the said use according to any one of claims 19 to 68, wherein the administration of said composition or compound is parenteral, such as by injection into the skin, mucous membrane, subcutaneous, intramuscular, intraperitoneal, intravenous or intra-arterial system.

71. The composition or compound for the said use according to any one of claims 19 to 70, wherein the composition or compound further comprises a pharmaceutically acceptable diluent, a carrier, and / or an excipient.

72. The composition or compound for the said use according to claim 71, wherein, The composition or compound is formulated into a solid dosage form, such as tablets, capsules, pills, granules or powders.

73. The composition or compound for the said use according to any one of claims 19 to 72, wherein the composition comprises other therapeutic agents that are effective in treating the pain.

74. A method for preparing (+) or (-)2-(8-azabicyclo[] with a chiral purity of 51% or higher. 3.2.1] A method for oct-2-en-3-yl)benzo[b]thiophene-5-ol, said method comprising: a. Provide a mixture of the following substances: (+)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol and (-)2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol; b. Treat the mixture with (Boc)₂O to obtain a mixture of enantiomers of the following substances: tert-Butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester c. The mixture was separated using chiral liquid chromatography to obtain the following enantiomers: tert-butyl 3-(5-hydroxybenzo[b]thiophen-2-yl)-8-azabicyclo[3.2.1]oct-2-en-8-carboxylic acid ester; and d. Deprotect the isolated enantiomers from step c. under acidic conditions to obtain enantiomerically pure (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol.

75. The method of claim 74, wherein step b. is carried out using DCM as a solvent in the presence of diisopropylethylamine (DIPEA).

76. The method according to any one of claims 74 to 75, wherein step b. is performed between 0°C and 30°C.

77. The method according to any one of claims 74 to 76, wherein prior to step c, the mixture in step b is subjected to liquid-liquid extraction between the organic phase and the aqueous phase.

78. The method according to any one of claims 74 to 77, wherein the liquid chromatography in step c. comprises a stationary phase containing a chiral selector.

79. The method according to any one of claims 74 to 78, wherein the chiral selector is amylose tris(3-chloro-5-methylphenylcarbamate) in the form of a chiral selector.

80. The method according to any one of claims 74 to 79, wherein the acidic conditions in step d. are provided by an organic or inorganic acid, such as hydrochloric acid (HCl), trifluoroacetic acid (TFA), or sulfuric acid (H2SO4).

81. The method according to any one of claims 74 to 80, wherein the deprotection in step d. is carried out in an organic solvent such as dioxane; or in an aqueous solution.

82. The method according to any one of claims 74 to 81, wherein the (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol has a chiral purity of more than 60%, such as more than 90%, such as more than 95%.

83. The method according to any one of claims 74 to 82, wherein the chiral purity of the (+) or (-) 2-(8-azabicyclo[3.2.1]oct-2-en-3-yl)benzo[b]thiophene-5-ol exceeds 90%.

84. A compound according to formula (II): (II), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

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