Methods for preparation and dose regimens for use of SSTR4 agonists and salts thereof

Abstract

To provide methods for the preparation of SSTR4 agonist compounds, and dose regimens for the use of pharmaceutically acceptable salts and / or hydrates thereof.SOLUTION: The present invention provides methods for preparing SSTR4 agonist compounds through a diasteromerically selective cyclization reaction without the need for a separate epimerization step. As one example of SSTR4 agonist compounds, (1R,5S,6r)-N-(2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide is illustrated. The present invention also provides novel intermediates for preparing SSTR4 agonist compounds. The present invention also provides dose regimens for the treatment of pain and / or neuropathic pain, such as diabetic peripheral neuropathy, central neuropathy, or mixed neuropathy.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention is directed to a method for the preparation of an SSTR4 agonist. Kind Code: A1 Abstract: The present invention is directed to a method for the preparation of a salt of an STR4 agonist.

[0002] The present invention also relates to a method for treating chronic lower back pain, osteoarthritis pain, and / or diabetic neuropathy, diabetes mellitus, and the like. Peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, SS in the treatment of neuropathic pain, such as central neuropathy and / or mixed neuropathy Use of TR4 agonists and pharma- ceutically acceptable salts and / or hydrates thereof Regarding dosage regimens. [Background technology]

[0003] Somatostatin or somatotropin-release inhibitory factor Serotinyltransferase (SRIF) is a cyclic peptide found in humans. It is widely produced in the human body. It acts both systemically and locally to stimulate the secretion of various hormones, growth factors, and neurotransmitters. The effect of somatostatin is to inhibit G protein complexes, of which there are five known subtypes. These are mediated by a family of receptors, which are divided into two subfamilies: The first subfamily includes SSTR2, SSTR3, and SSTR5. The second subfamily includes SSTR1 and SSTR4.

[0004] Somatostatin regulates processes such as cell proliferation, glucose homeostasis, inflammation, and pain. In this embodiment, somatostatin or somatostatin peptide phospholipase A is involved in the regulation of the Other members of the family mediate nociceptive and inflammatory processes through the SSTR4 pathway. It is thought to inhibit

[0005] WO 2014 / 184275 discloses an SSTR4 agonist and Certain 3-azabicyclo[3.1]cyclopentadiene ( ... However, sufficient ene 3-Azabicyclo[3.1.0]hexafluorophosphate with enantiomeric and diastereomeric purity It can be difficult to synthesize 6-carboxamide derivatives. Although routes to synthesis are known, many of the steps used in previous synthetic routes are impractical and and / or may be too expensive to utilize on a commercial scale.

[0006] Therefore, an alternative method for preparing a specific SSTR4 agonist in sufficient purity for commercial scale is Therefore, the present invention provides a method for the preparation of (1R,5S,6r)-N-(2 -Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3 - Certain SSTRs such as azabicyclo[3.1.0]hexane-6-carboxamide For the preparation of compound 4, and its pharma- ceutically acceptable salts, solvates, and / or hydrates. This method is intended to

[0007] Diabetic neuropathy is a common complication of diabetic microvascular disease. Approximately 40% of people with diabetic microvascular disease experience diabetic neuropathy, and approximately 80% of people with diabetic neuropathy experience diabetic microvascular disease. Patients with this condition develop peripheral polyneuropathy.

[0008] Symptoms of diabetic peripheral neuropathy include hyperalgesia, paresthesia, and deep, aching pain. Symptoms of diabetic peripheral neuropathy (DPNP) include shallow sleep , associated with poor mobility, depression, and quality of life.

[0009] Unfortunately, there are limited treatment options for DPNP. The three approved drugs are pregabalin, duloxetine, and tapentadol. Pregabalin and duloxetine have each been studied in multiple placebo-controlled clinical trials. Both drugs have demonstrated efficacy in clinical trials, but both require titration to minimize adverse reactions. Tapentadol is an opioid mu receptor agonist and has the same effects as other opioids. Gabapentin, a selective analgesic, has the same pharmacological limitations and adverse reaction profile as other selective analgesics. Other class II drugs, including serotonin norepinephrine reuptake inhibitors, tricyclic antidepressants, and anticonvulsants A number of drugs are in clinical use in an off-label manner. However, all these drugs Dose-limiting toxicities of agents prevent patients from tolerating therapeutic doses and lead to subtherapeutic doses in the clinic. This results in increased doses and further reduces the effectiveness of these drugs. In addition, 50% of patients Only one patient continued therapy after 3 months.

[0010] Suboptimal dosing and poor tolerability profiles of non-opioid analgesics may contribute to the management of DPNP. Opioids are used as a last resort to treat Although effective against acute pain, they offer little clinical benefit in chronic pain. There is evidence to suggest that this is not the case, not to mention the potential for reduced efficacy due to resistance. .

[0011] Additionally, opioid compounds are known to provide relief from pain symptoms, but The effects of oid compounds also include hallucinations, nausea, dizziness, sedation, constipation, urinary retention, dependence, and addiction. As many as 25% of patients receiving opioid pain treatments Even in the short term, a person can develop a dependency on opioid compounds. In fact, opioid addiction can be On October 26, 2017, US President Donald Trump announced A Public Health Emergency has been declared. To provide relief from pain symptoms without the potential for the development of addiction and / or dependence, Long-term research into the development of non-opioid compounds and dosing regimens for non-opioid compounds There is a long-standing unmet need. Summary of the Invention

[0012] Thus, the present invention provides a method for treating neuropathic pain and / or diabetes using non-opioid compounds. The present invention relates to a drug regimen for the treatment of pain, such as pathopathic neuropathy and / or mixed neuropathy. do.

[0013] Methods for the preparation of certain SSTR4 compounds are disclosed in International Publication No. WO 2014 / 184275. No. 2021 / 233427, and No. 2022 / 012534. However, these compounds have been produced on a laboratory scale, with synthetic procedures that are impractical on a commercial scale. In these previous preparations, the synthetic route may include: (1) palladium and / or The costly catalyst containing rhodium and / or the hydrogenation catalyst used to carry out the reduction step are (2) Diazides that require epimerization after cyclization of the heterocycle using aluminum lithium Both (1) and (2) resulted in a mixture of stereomers. and preferably has trace amounts of Pd, Rh, Li, Al, and / or lower activity. An additional purification step may be added to remove the unwanted diastereomer.

[0014] Pd, Pt, Mo, Rh, Fe, Ni, Cr, W, or combinations of these Using a transition metal catalyst and / or an aluminum hydride salt such as lithium aluminum hydride For example, (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Certain SSTR4 such as azabicyclo[3.1.0]hexane-6-carboxamide Novel routes to the compounds and their salts are disclosed herein. Additionally, the disclosed methods includes a cyclization step involving treatment with a (2-haloethyl)diphenylsulfonium salt, leads to a single diastereomeric intermediate without the need for a subsequent epimerization step. Finally, the disclosed methods are more cost-effective than previously disclosed routes, such as fewer than 8 or between 4 and 7 total steps. It has fewer total steps.

[0015] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo and (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridinyl) (2-phenyl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexa phenylalanine-6-carboxamide L-tartrate sesquihydrate and its pharma- ceutical acceptable salts. and / or hydrate thereof to treat pain in a patient in need of such treatment. Also disclosed herein is a method for producing (1R,5S,6r)-N-(2-methyl-1-((3-methyl) ethylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1. 0]Hexane-6-carboxamide, and (1R,5S,6r)-N-(2-methyl- 1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.2.1] Chloro[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate, The administration of a pharma- ceutically acceptable salt and / or hydrate of and / or diabetic neuropathy, diabetic peripheral neuropathy pain, polyneuropathy, distal sensory polyneuropathy Neuropathic pain, including neuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy Also disclosed herein are methods for treating pain in a patient in need thereof.

[0016] The non-opioid compound (1R,5S,6r)-N-(2-methyl-1-((3-methyl)- ethylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1. 0]Hexane-6-carboxamide is an SSTR4 agonist compound. (1R,5 S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane 1,2-diphenyl-3-azabicyclo[3.1.0]hexane-6-carboxamide, and (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) )Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Pharmaceutically acceptable salts and / or hydrates thereof, such as voxamide L-tartrate sesquihydrate. The subject is a patient with chronic low back pain, osteoarthritis pain, and / or diabetic neuropathy, diabetic peripheral nerve pain, and / or Transcranial pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy and / or for certain pain conditions, such as neuropathic pain, including mixed neuropathy. Thus, disclosed herein are potential first-in-class treatments for , chronic lower back pain, osteoarthritis pain, and / or diabetic neuropathy, diabetic peripheral neuropathy Pain from pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and For the treatment of certain pain conditions, such as neuropathic pain, including mixed neuropathy and / or It is a dosing regimen with proven clinical efficacy for [Brief description of the drawings]

[0017] [Figure 1] FIG. 1 shows the mean change in mean pain intensity in a Phase 2 study for the treatment of diabetic peripheral neuropathy with (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate salt sesquihydrate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Chronic low back pain, osteoarthritis pain, and / or diabetic neuropathy, diabetic peripheral neuropathy Pain from pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and SSTR4 agonists in the treatment of neuropathic pain, including pain in patients with rheumatoid arthritis and / or mixed neuropathy Dosage regimes for the use of the compounds, as well as pharma- ceutically acceptable salts and / or hydrates thereof Disclosed herein are methods for producing such a compound.

[0019] In addition, certain SSTR4 agonist compounds, as well as (1R,5S,6r)-N-( 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate Also described herein are capsule compositions containing pharma- ceutically acceptable salts and / or hydrates thereof, such as will be disclosed.

[0020] In addition, certain SSTR4 agonist compounds, as well as 1R,5S,6r)-N-(2 -Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3 -azabicyclo[3.1.0]hexane-6-carboxamide and its pharma- ceutically acceptable derivatives Also disclosed herein are methods for the preparation of the salts and / or hydrates thereof.

[0021] Also, diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, Neuropathies, such as peripheral neuropathy, central neuropathy, and / or mixed neuropathy (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridinyl)) Lysine-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]he The dosage regimen for the use of xan-6-carboxamide L-tartrate sesquihydrate is also described herein. Disclosed in the specification.

[0022] Also provided is a method of treating pain in a patient in need thereof, comprising administering to the patient: A dose of about 25 mg to about 1400 mg per dose of the formula:

[0023] [ka] or a pharma- ceutically acceptable salt and / or hydrate thereof. , methods are also disclosed herein.

[0024] Also provided is a method of treating pain in a patient in need thereof, comprising administering to the patient: A dose of about 25 mg to about 1400 mg per dose of the formula:

[0025] [ka] Also disclosed herein are methods that include administering a compound of the formula:

[0026] Also provided are methods for treating neuropathic pain in a patient in need of such treatment. administering to a patient a dose of about 50 mg to about 600 mg per dose of a compound of the formula:

[0027] [ka] Also disclosed herein are methods that include administering a compound of the formula:

[0028] Also provided is a method of treating pain in a patient in need thereof, comprising administering to the patient: A dose of about 25 mg to about 1400 mg per dose of the formula:

[0029] [ka] Also disclosed herein are methods that include administering a compound of the formula:

[0030] Also provided is a method of treating pain in a patient in need of such treatment, comprising: A patient is administered a dose of about 50 mg to about 600 mg of a compound of the formula:

[0031] [ka] Also disclosed herein are methods that include administering a compound of the formula:

[0032] Also, the present invention relates to an SSTR4 agonist compound, and a pharma- ceutically acceptable salt thereof and / or a Also disclosed herein is a novel method for preparing hydrates on a commercial scale.

[0033] Also, the formula:

[0034] [ka] Also disclosed herein is a capsule composition comprising the compound of formula (I) or a hydrate thereof. Also, the formula:

[0035] [ka] Also disclosed herein is a method for preparing a compound of the formula: The method comprises reacting a compound of the formula:

[0036] [ka] (wherein R is C1-C6 alkyl), formula:

[0037] [ka] where X is a halogen and A is an anion, ,formula:

[0038] [ka] and obtaining an intermediate compound of the formula: The intermediate compound

[0039] [ka] Mixed with

[0040] [ka] and

[0041] [ka] and removing the tosyl functionality from to obtain the compound.

[0042] Also included herein is the (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate Products containing any of the compounds are disclosed herein.

[0043] Detailed Description of the Invention SSTR4 agonists The disclosed methods can be used to prepare compounds of formula I. Methods also include for preparing salts, solvates, hydrates, and / or combinations thereof of Formula I. It can also be used for

[0044] [ka]

[0045] Formula I. SSTR4 agonists, (1R,5S,6r)-N-(2-methyl-1-((3 -Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3. 1.0]Hexane-6-carboxamide The disclosed methods can be used to prepare compounds of formula II. The method also includes the steps of preparing solvates, hydrates, and / or combinations thereof of Formula II. It can be used for this purpose.

[0046] [ka]

[0047] Formula II. Tartrate salt of SSTR4 agonist, (1R,5S,6r)-N-(2-methyl -1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabi Cyclo[3.1.0]hexane-6-carboxamide tartrate The disclosed methods can be used to prepare compounds of formula III. The methods described herein also include preparing solvates, hydrates, and / or combinations thereof of formula III. It can be used to

[0048] [ka]

[0049] Formula III. L-tartrate salt of SSTR4 agonist, (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate. The disclosed methods can be used to prepare compounds of formula IV.

[0050] [ka]

[0051] Formula IV. (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine-2 -yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6 -Carboxamide L-tartrate sesquihydrate

[0052] method Methods for preparing SSTR4 agonist compounds are disclosed herein. Methods for preparing 4 agonist compounds include, as further discussed herein, SSTR4 agonist compounds, their pharma- ceutically acceptable salts, and / or solvates / water thereof The disclosed method can be used in commercial scale production of hydrates. More preferably, the reaction is carried out using a batch processing methodology. In one embodiment, the batch is In one embodiment, the batch is produced in a process scale of at least 1 kilogram. In one embodiment, a batch of at least 10 kilograms is produced. In one embodiment, the batch is produced in at least 100 kilograms.

[0053] formula:

[0054] [ka] or a pharma- ceutically acceptable salt, solvate, or The method for preparing the hydrate comprises the steps of:

[0055] (a) tert-butyl tosylcarbamate is reacted with a suitable C1-C6 alkyl 4-halobuta This may include mixing with a 2-enoate.

[0056] Step (a) of the method for preparing an SSTR4 agonist compound comprises the steps of: In a polar aprotic solvent, tert-butyl tosylcarbamate is reacted with a suitable C1-C6 aryl group. and mixing with an alkyl 4-halobut-2-enoate compound, wherein X is a halogen leaving group such as Cl, Br, or I.

[0057] [ka]

[0058] Formula V. Step (a) of the method for preparing an SSTR4 agonist compound The components of step (a) are reacted in a polar aprotic solvent at about 10° C. to about 25° C., about 15° C. to about 2 The components in step (a) may be combined at a temperature of 5° C. or 20° C. to 25° C. The temperature of the mixture is raised to about 25° C. to about 50° C., about 25° C. to about 40° C., or about 30° C. The product mixture of step (a) can be filtered, and the collected residue can be treated with a polar aprotic It can be washed with a solvent to give the product in solution.

[0059] Suitable polar aprotic solvents are well known to those skilled in the art of organic synthesis design. Rotonic solvents include, inter alia, acetonitrile, acetone, dimethylsulfoxide, Examples include N,N-dimethylformamide and tetrahydrofuran.

[0060] In another embodiment, the method comprises reacting tert-butyl ether in acetonitrile as shown in formula VI. -Butyl tosyl carbamate mixed with (E) methyl 4-bromobut-2-enoate compound Methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylfuran This can include obtaining a phenyl)sulfonamido)but-2-enoate.

[0061] [ka]

[0062] Formula VI. Step (a) of the method for preparing an SSTR4 agonist compound In another embodiment, step (a) comprises:

[0063] [ka] Mixed with

[0064] [ka] This can include obtaining:

[0065] Further components to step (a) include a base such as potassium carbonate, and / or potassium iodide. Salts such as ammonium phosphate may be mentioned.

[0066] (b) C1-C6 alkyl(E)-4-((N-(tert-butoxycarbonyl)- Mix 4-methylphenyl)sulfonamido)but-2-enoate with acid

[0067] Step (b) of the process for preparing an SSTR4 agonist compound comprises preparing a compound represented by formula VII: In a polar aprotic solvent, the product produced in step (a), C1-C6 alkyl ( E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfone The method can include mixing the amide)but-2-enoate with a suitable acid.

[0068] [ka]

[0069] Formula VII. Step (b) of the method for preparing an SSTR4 agonist compound The components of step (b) are reacted in a polar aprotic solvent at about 10° C. to about 25° C., about 15° C. to about 2 The ingredients in step (b) can be combined at a temperature of 5° C. or 20° C. to 25° C. The temperature of the mixture is about 40°C to about 75°C, about 40°C to about 60°C, or about 55°C to about 60°C. The reaction solution may be allowed to rise to at least 4 hours, at least 10 hours, or The elevated temperature can be maintained for at least 12 hours.

[0070] After heating the mixture of the components of step (b) to a high temperature, the solution is concentrated to remove the remaining polar aprotic The solvent can be exchanged for toluene and / or ethyl acetate.

[0071] Polar aprotic solvents allow the product to be purified without any further purification steps other than filtration of by-products. The solvent may be the same as in step (a) so that the cations remain in solution for a period of time, or the solvent may be a different solvent. The solvent may be a polar aprotic solvent.

[0072] A suitable acid in step (b) is a tertiary amine which is reacted with a tert-butyl ester to form the tertiary amine. The acid may be any acid that can be used to form a secondary amine. Suitable acids include Examples of suitable acids include trifluoroacetic acid, hydrochloric acid, sulfuric acid, and hydrofluoric acid, among other acids.

[0073] In another embodiment, step (b) is carried out in acetonitrile, as shown in formula VIII: Methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl) Sulfonamide) but-2-enoate is mixed with trifluoroacetic acid to give methyl (E)- to obtain 4-((4-methylphenyl)sulfonamido)but-2-enoate It is possible.

[0074] [ka]

[0075] Formula VIII. Step (b) of the method for preparing an SSTR4 agonist In another embodiment, step (b) comprises:

[0076] [ka] Mix with trifluoroacetic acid,

[0077] [ka] This can include obtaining:

[0078] Step (c) C1-C6 alkyl(E)-4-((4-methylphenyl)sulfonamide ) but-2-enoate is mixed with a sulfonium salt

[0079] Step (c) of the process for preparing an SSTR4 agonist compound comprises preparing a compound represented by formula IX: , in a suitable heterocyclic solvent, the product produced in step (b), C1-C6 alkyl(E)- 4-((4-methylphenyl)sulfonamido)but-2-enoate, The intermediate compound, (1R,5S)-3-(p-tolylsulfonyl)-3-aza This can include obtaining bicyclo[3.1.0]hexane-6-carboxylic acid.

[0080] [ka]

[0081] Formula IX. Step (c) of the method for preparing an SSTR4 agonist The ingredients of step (c) can be combined at a temperature between -10°C and 10°C or at about 0°C. Phonium salts and C1-C6 alkyl(E)-4-((4-methylphenyl)sulfonamido In addition to but-2-enoate, potassium fluoride and / or potassium hydroxide are added. The temperature of the solution is gradually or stepwise increased to 30° C. over a period of about 10 hours to about 30 hours. It can be raised step by step.

[0082] Suitable heterocyclic solvents include, inter alia, tetrahydrofuran, furan, 2-methyl-tetrahydrofuran, Contains hydrofuran.

[0083] After increasing the temperature of the solution, a base such as lithium hydroxide can be added at the elevated temperature. The reaction can be allowed to proceed for an additional period of time. The additional period of time can range from about 8 hours to about 24 hours. The time may be from about 12 hours to about 18 hours, or about 16 hours.

[0084] The intermediate compound, (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3 1.0]Hexane-6-carboxylic acid can be prepared by conventional synthetic organic chemistry separation techniques well known to those skilled in the art. can be used to separate it from the solution.

[0085] The sulfonium salt used in step (c) can be represented by the formula X, where X is , Cl, Br, or I, and A is any suitable leaving group known to those skilled in the art. It is an anion.

[0086] [ka]

[0087] Formula X. Sulfonium salt for step (c) The sulfonium salt used in step (c) may also be represented by formula XI:

[0088] [ka]

[0089] Formula XI. Formula X. Sulfonium salt for step (c) In another embodiment, step (c) comprises preparing methyl(E)-4-( (4-Methylphenyl)sulfonamido)but-2-enoate to 2-(bromoethyl) Mix with diphenylsulfonium triflate to form the intermediate compound (1R,5S)-3 -(p-Tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxone This can include obtaining an acid.

[0090] [ka]

[0091] Formula XII. Step (c) of the process for preparing an SSTR4 agonist In another embodiment, step (c) comprises:

[0092] [ka] and mixed with the intermediate compound

[0093] [ka] or a salt or solvate thereof.

[0094] Step (d) (1R,5S)-3-(p-tolylsulfonyl)-3-azabicyclo[3. 1.0]Hexane-6-carboxylic acid to 2-methyl-1-((3-methylpyridine-2-isopropyl) Mix with 2-(oxy)propan-2-amine Step (d) of the process for preparing an SSTR4 agonist compound is represented by formula XIII: As shown in FIG. 1, the intermediate compound (1R,5S)-3-(p-tolylsulfonyl) 2-methyl-1-azabicyclo[3.1.0]hexane-6-carboxylic acid ((3-methylpyridin-2-yl)oxy)propan-2-amine It is possible to do so.

[0095] [ka]

[0096] Formula XIII. Step (d) of the method for preparing an SSTR4 agonist 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine The intermediate compound is reacted with a suitable reagent such as oxalyl chloride or thionyl chloride prior to the addition of to generate the acid chloride in situ and convert the -OH functionality to -Cl under synthetic conditions well known to those skilled in the art. can be replaced with

[0097] The acid chloride thus produced can be reacted with 2-methyl- In combination with 1-((3-methylpyridin-2-yl)oxy)propan-2-amine It is possible to do so.

[0098] The solution temperature can be increased to about 15° C. to about 25° C. after about 2 to about 4 hours.

[0099] In another embodiment, step (d) comprises reacting the intermediate compound with

[0100] [ka] Mixed with

[0101] [ka] This can include obtaining:

[0102] Step (e) ((1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine -2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1. 0]Hexane-6-carboxamide mixed with potassium diphenylphosphine Step (e) of the process for preparing an SSTR4 agonist compound is as shown in formula XIV The product produced in step (d), ((1R,5S,6r)-N-(2-methyl-1- ((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3- Azabicyclo[3.1.0]hexane-6-carboxamide was reacted with potassium diphenylphos The method may include mixing the fins.

[0103] [ka]

[0104] Formula XIV. Step (e) of the method for preparing an SSTR4 agonist ((1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl )Oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexa The amine-6-carboxamide is dissolved in a suitable solvent such as methyl tert-butyl ether. The temperature can be about -100°C to about -50°C, about -80°C to about -55°C, or about The temperature can be reduced to -70℃ to about -60℃. The mudiphenylphosphine can be added dropwise.

[0105] After all of the potassium diphenylphosphine has been added, reduce the temperature of the solution by at least The mixture may then be maintained for at least 4 hours, at least 6 hours, or at least 8 hours. The temperature of the solution is raised to about 15°C to about 25°C, and the SSTR agonist compound, (1S,5R) -N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3 -azabicyclo[3.1.0]hexane-6-carboxamide can be prepared by the reaction of a typical It can be isolated from the solution using a variety of methods.

[0106] In another embodiment, step (e) comprises:

[0107] [ka] Mix with potassium diphenylphosphine to obtain SSTR4 agonist compound. may include.

[0108] Salts of SSTR4 agonist compounds Methods for preparing pharma- ceutically acceptable salts of SSTR4 agonist compounds are also described herein. A method for preparing a pharma- ceutically acceptable salt of an SSTR4 agonist compound is disclosed. The method includes (1) a disclosed method for preparing an SSTR4 agonist compound, and (2) (i) reaction with an acid, (ii) a salt metathesis reaction, and / or (iii) a SSTR4 ligand. via other reactions which may result in the formation of pharma- ceutically acceptable salts of the nisto compounds; This can include producing a pharma- ceutically acceptable salt of the SSTR4 agonist.

[0109] Suitable pharma- ceutically acceptable salts of the SSTR4 agonist compounds include adipate, bromide, , chloride, besylate, esylate, mesylate, tosylate, phosphate, succinate, Sulfate, citrate, tartrate, L-tartrate, malate, and / or L-malate Other suitable salts include (1S,5R,6r)-N-[1 ,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[1,2-diphenyl ether] Chloro[3.1.0]hexane-6-carboxamide tartrate, (1S,5R,6r)-N -[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-a Zabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, and / or (1 R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy) )propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Other suitable salts include the salts shown in Formulae II to IV. The L-tartrate salt is also known as the (2R,3R)-2,3-dihydroxysuccinate salt. It can be known.

[0110] intermediate compound Also, the present invention relates to an SSTR4 agonist compound, a pharma- ceutically acceptable salt thereof, or a water and / or solvates thereof produced during the disclosed methods for the preparation of Novel intermediate compounds are also disclosed herein. Suitable intermediates may be used at any time during the disclosed process. The preferred intermediates can be isolated as pure compounds. or can be produced only in solution.

[0111] SSTR4 agonist compounds, or pharma- ceutically acceptable salts or hydrates thereof, and / or solvates thereof, the intermediates of formula XV, The pharma- ceutically acceptable salts thereof, their hydrates, and / or their solvates are listed below. In the formula, Y is H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether or a combination thereof, R1 and R2 are independently H, OH , NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof wherein the phenyl functional group is substituted with one or more R' groups, each R' group being independently H, OH, NH2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or and combinations thereof. In one embodiment, Y is OH, Cl, Br, I, or NH 2R1, R2 can be H, and R' can be CH3 in the para position.

[0112] [ka]

[0113] Formula XV. intermediate compound In one embodiment, the intermediate compound is represented by formula XVI: and / or a solvate thereof, wherein Y is H, OH, NH 2Cl, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof R1 and R2 are independently H, OH, NH2Cl, Br, I, C1-C6 ar The phenyl functionality may be one alkyl, one C1-C6 ether, or a combination thereof. or more R', each R' group being independently selected from H, OH, NH2Cl, Br, I , C1-C6 alkyl, C1-C6 ether, or a combination thereof. In one embodiment, Y can be OH, Cl, Br, I, or NH2R1, and R2 can be H; R' can be a CH3 in the para position.

[0114] [ka]

[0115] Formula XVI. intermediate compound In one embodiment, the intermediate compound is represented by formula XVII, or a pharma- ceutically acceptable salt thereof, Y may be H, OH, NH2C, l, Br, I, C1-C6 alkyl, C1-C6 ether, or a combination thereof. In one embodiment, Y can be OH, NH2Cl, Br, or I.

[0116] [ka]

[0117] Formula XVI. intermediate compound In one embodiment, the intermediate compound is also represented by the formula XVIII or a pharma- ceutically acceptable salt thereof, and / or a solvate thereof.

[0118] [ka]

[0119] Formula XVIII. intermediate compound The intermediate compounds described herein are SSTR4 agonist compounds, or pharma- ceutically acceptable derivatives thereof. The compounds can be used to prepare the salts, hydrates and / or solvates thereof. The intercalation compound may be an SSTR4 antagonist, as described herein and illustrated in Formula VIII. The amide-carboxylic acid coupler as in step (d) of the process for preparing the aniline compound We have developed a stable scaffold for producing various SSTR4 agonist compounds through a ring-pulling reaction. provide.

[0120] composition In addition, the compound of formula I to IV, or a pharma- ceutically acceptable salt or hydrate thereof, can be used in the method of the present invention. The present invention also provides pharmaceutical compositions comprising the compound of the present invention together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. In some embodiments, the composition further comprises one or more therapeutic agents. .

[0121] In some embodiments, the pharmaceutical composition is a tablet composition. The active ingredients include, among others, microcrystalline cellulose, croscarmellose sodium, fumarate, and cetearyl alcohol. Sodium stearyl malate is an example.

[0122] The tablet composition may contain from about 25 mg to about 1400 mg, from about 50 mg to about 600 mg, or from about 50 mg to about 200 mg of an SSTR4 agonist, or a hydrate or a pharma- ceutically acceptable salt thereof. The compound may contain salts.

[0123] In some embodiments, the pharmaceutical composition is a capsule composition. In this case, the capsule composition does not contain any inactive ingredients and contains an SSTR4 agonist compound or In some embodiments, the compound may include a hydrate or a pharma- ceutically acceptable salt of The capsule composition may include one or more pharma- ceutically acceptable carriers, diluents, or excipients. In some embodiments, the capsule composition can include, among other suitable inactive ingredients, , microcrystalline cellulose, silicon dioxide, colloidal silicon dioxide.

[0124] The capsule composition contains from about 25 mg to about 1400 mg, from about 50 mg to about 600 mg, or 50 mg to about 200 mg of an SSTR4 agonist, or a hydrate or pharma- ceutically acceptable salt thereof The capsule composition may be placed in a suitable capsule, such as a gelatin capsule. The capsules are available in sizes 000, 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 020, 021, 022, 023, 024, It can be 0, 0, 1, or 2.

[0125] In some embodiments, the pharmaceutical composition is an aqueous composition.

[0126] Treatment method Also provided is a method of treating pain in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound of formula I-IV, or a pharma- ceutically acceptable salt or hydrate thereof , including administering the composition in combination with one or more pharma- ceutically acceptable carriers, diluents, or excipients. , methods are also disclosed herein.

[0127] Also provided is a method of treating pain in a patient, comprising administering to a patient in need of such treatment , about 25 mg to about 1400 mg of a compound of formula III, i.e., (1R,5S,6r)- N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl l)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, is a compound of formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-((3-methyl) ethylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1. 0]Hexane-6-carboxamide L-tartrate sesquihydrate is used in the manufacture of one or more pharma- ceutical Also disclosed herein are methods comprising administering the compound to a subject in the presence of an acceptable carrier, diluent, or excipient. In some embodiments, the method of treating pain in a patient comprises administering to said patient a therapeutically effective amount of a first amount of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg of a compound of formula III, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) )Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Voxamide L-tartrate, or the compound of formula IV, i.e., (1R,5S,6r)-N-( 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate In some embodiments, the compound of formula III, That is, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine-2- 2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- Carboxamide L-tartrate, or formula IV, i.e. (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate In some embodiments, the first dose can be repeated. For example, the first amount may be 400 mg and the second amount may be 250 mg. and the second amount may be 400 mg or 600 mg.

[0128] In some embodiments, the method of treating pain comprises administering to a patient in need of such treatment , about 50 mg to about 600 mg of a compound of formula III, i.e., (1R,5S,6r)-N- (2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl) -3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or Compound IV, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methyl) Pyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0] Hexane-6-carboxamide L-tartrate sesquihydrate is administered twice daily. It is possible to do so.

[0129] In some embodiments, the method of treating pain comprises administering to a patient in need of such treatment , about 50mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500m g, or about 600 mg of a compound of formula III, i.e., (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of formula IV The compound, namely (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridinyl) (2-phenyl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexa 2. The drug is intended to be administered twice daily. can be done.

[0130] Also provided is a method of treating chronic back pain, including chronic lower back pain, in a patient, comprising administering to said patient a therapeutically effective amount of A patient in need of such treatment is administered an effective amount of a compound of Formula I-IV, or a pharma- ceutical acceptable salt or salt thereof. or a hydrate thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. Also disclosed herein are methods comprising administering

[0131] Also provided is a method of treating chronic back pain, including chronic lower back pain, in a patient, comprising administering to said patient a therapeutically effective amount of A patient in need of treatment is administered about 25 mg to about 1400 mg of a compound of formula III, i.e., 1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy) 3-Azabicyclo[3.1.0]hexane-6-carboxamide mido-L-tartrate, or the compound of formula IV, i.e., (1R,5S,6r)-N-(2-methyl-L-tartrate) 1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-a Zabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate, including administering together with one or more pharma- ceutically acceptable carriers, diluents, or excipients; Also disclosed herein are methods for treating chronic pain, including chronic low back pain, in a patient. The method of treating chronic back pain comprises administering to a patient in need of such treatment a first amount of SSTR4. Approximately 50 mg, approximately 100 mg, approximately 200 mg, approximately 300 mg, approximately 400 mg of agonist, About 500 mg, or about 600 mg, of a compound of formula III, i.e., (1R,5S,6r) -N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane-2- yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-((3 -Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3. 1.0]Hexane-6-carboxamide L-tartrate sesquihydrate In some embodiments, an additional amount of a compound of formula III, i.e., (1R,5S, 6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane -2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartar or formula IV, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methyl)-2-propanediol; ethylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1. 0]Hexane-6-carboxamide L-tartrate sesquihydrate can be administered in one day. In some embodiments, the first amount can be repeated or a different amount can be added. For example, the first amount can be 400 mg and the second amount can be 4 00mg or 600mg.

[0132] In some embodiments, the method for treating chronic back pain, including chronic lower back pain, comprises administering to a patient in need of such treatment. A patient is administered about 50 mg to about 600 mg of a compound of formula III, i.e., (1R,5S, 6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane -2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartar or a compound of formula IV, i.e., (1R,5S,6r)-N-(2-methyl-1-( (3-Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[ 3.1.0] Hexane-6-carboxamide L-tartrate sesquihydrate, administered twice daily This may include:

[0133] In some embodiments, the method of treating chronic back pain, including chronic lower back pain, comprises administering to said subject a therapeutically effective amount of For patients who need treatment, about 50 mg, about 100 mg, about 200 mg, about 300 mg, and about 4 00 mg, about 500 mg, or about 600 mg of a compound of formula III, i.e., (1R,5S ,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane (2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-alcohol The tartrate, or the compound of formula IV, i.e. (1R,5S,6r)-N-(2-methyl-1- ((3-Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo [3.1.0] Hexane-6-carboxamide L-tartrate sesquihydrate, administered twice daily This may include providing.

[0134] Also provided is a method of treating neuropathic pain in a patient in need of such treatment. and administering to a patient having a condition in need thereof an effective amount of a compound of formula I-IV, or a pharma- ceutically acceptable salt thereof, The hydrates may be administered together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. Also disclosed herein are methods for treating neuropathic pain, comprising: Diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy neuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy.

[0135] In addition, the efficacy and safety of diabetic neuropathy, diabetic peripheral neuropathic pain, and polyneuropathy in patients Distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy 20. A method for treating neuropathic pain comprising administering to a patient in need of such treatment about 25 mg to about 1400 mg of a compound of formula III, i.e., (1R,5S,6r)-N-( 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or formula I Compound V, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methylpi Lysine-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]he xan-6-carboxamide L-tartrate sesquihydrate is administered in the presence of one or more pharma- ceutically acceptable salts of Also disclosed herein are methods comprising administering the composition to a subject in the presence of a carrier, diluent, or excipient. In some embodiments, the patient is treated with diabetic neuropathy, polyneuropathy, distal neuropathy, or Neuropathic polyneuropathy, peripheral neuropathy, diabetic peripheral neuropathy pain, central neuropathy, and / or The method of treating neuropathic pain, including mixed neuropathy, comprises administering to a patient in need of such treatment a first amount of about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg of a compound of formula III, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) )Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Voxamide L-tartrate, or the compound of formula IV, i.e., (1R,5S,6r)-N-( 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)- 3-Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate In some embodiments, the compound of formula III, That is, (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine-2- 2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- Carboxamide L-tartrate, or formula IV, i.e. (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate In some embodiments, the first dose can be repeated. For example, the first amount may be 400 mg and the second amount may be 250 mg. and the second amount may be 400 mg or 600 mg.

[0136] In some embodiments, the present invention relates to treatment of diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, and the like. Neuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy The method for treating neuropathic pain, including neuropathic pain disorders, provides about 5 0 mg to about 600 mg of a compound of formula III, i.e., (1R,5S,6r)-N-(2- Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3- Azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of formula IV The compound, namely (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridinyl) (2-phenyl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexa 2. The drug is intended to be administered twice daily. can be done.

[0137] In some embodiments, the present invention relates to treatment of diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, and the like. Neuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy The method for treating neuropathic pain, including neuropathic pain disorders, provides about 5 0mg, about 100mg, about 200mg, about 300mg, about 400mg, about 500mg, or about 600 mg of the compound of formula III, i.e., (1R,5S,6r)-N-(2-methyl- -1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabi Cyclo[3.1.0]hexane-6-carboxamide L-tartrate, or a compound of formula IV (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine-2 -yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6 - Carboxamide L-tartrate sesquihydrate may be administered twice daily. do.

[0138] Also provided is a method of treating pain associated with osteoarthritis in a patient, comprising administering to said patient a A patient in need of treatment is administered an effective amount of a compound of Formula I-IV, or a pharma- ceutically acceptable salt thereof. or a hydrate thereof, together with one or more pharma- ceutically acceptable carriers, diluents, or excipients. Also disclosed herein are methods comprising administering to

[0139] Also provided is a method of treating osteoarthritis pain in a patient in need of such treatment. A patient in need thereof is administered about 25 mg to about 1400 mg of a compound of formula III, i.e., (1R, 5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L -tartrate, or a compound of formula IV, i.e. (1R,5S,6r)-N-(2-methyl- 1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.2.1] Chloro[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate, Also disclosed herein are methods of mixing the compound with a pharma- ceutically acceptable carrier, diluent, or excipient as described above. In some embodiments, the method is for treating osteoarthritis pain in a patient. The method comprises administering to a patient in need of such treatment about 50% of a first amount of an SSTR4 agonist. mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 600 mg The compound of formula III, i.e., (1R,5S,6r)-N-(2-methyl-1-((3- Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1 0.0]hexane-6-carboxamide L-tartrate, or a compound of formula IV, i.e., ( 1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy) 3-Azabicyclo[3.1.0]hexane-6-carboxamide In some embodiments, the method may include administering mid-L-tartrate sesquihydrate. Then, a further amount of the compound of formula III, i.e., (1R,5S,6r)-N-(2-methyl-1- ((3-Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo [3.1.0] Hexane-6-carboxamide L-tartrate, or the compound of formula IV, i.e., 1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy) 3-Azabicyclo[3.1.0]hexane-6-carboxamide Mido-L-tartrate sesquihydrate can be administered in one day. can repeat the first amount or can administer a different amount. For example, The first amount may be 400 mg and the second amount may be 400 mg or 600 mg. That's fine.

[0140] In some embodiments, the method of treating osteoarthritis pain comprises administering to a subject in need of such treatment. A patient in need thereof is administered about 50 mg to about 600 mg of a compound of formula III, i.e., (1R,5S ,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane (2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-alcohol The tartrate, or the compound of formula IV, i.e. (1R,5S,6r)-N-(2-methyl-1- ((3-Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo [3.1.0] Hexane-6-carboxamide L-tartrate sesquihydrate, administered twice daily This may include providing.

[0141] In some embodiments, the method of treating osteoarthritis pain comprises administering to a subject in need of such treatment. For patients who need it, about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg g, about 500 mg, or about 600 mg of a compound of formula III, i.e., (1R,5S,6r )-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane-2 -yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate or formula IV, i.e. (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridine) Lysine-2-yl)oxy)propan-2-yl)-3-azabicyclo[3.1.0]he 100 mg of xanthene-6-carboxamide L-tartrate sesquihydrate, administered twice daily It is possible.

[0142] Also provided is a compound of formula I-IV, or a pharma- ceutically acceptable salt or salt thereof, for use in therapy. Additionally disclosed herein are compounds of formula I-II for use in treating pain. Also disclosed herein is a compound of formula IV, or a pharma- ceutically acceptable salt or hydrate thereof. Also provided is a compound of formula I-IV, or a combination thereof, for use in the treatment of chronic back pain, including chronic lower back pain. Also provided herein are pharma- ceutically acceptable salts or hydrates of the formula: A compound of formula I-IV, or a pharma- ceutically acceptable salt or salt thereof, for use in the treatment of Hydrates are also disclosed herein. In some embodiments, the neuropathic pain is caused by diabetic Neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral Peripheral neuropathy, central neuropathy, and / or mixed neuropathy. A compound of formula I-IV, or a pharma- ceutically acceptable salt thereof, for use in the treatment of pain associated with The salts and hydrates are also disclosed herein.

[0143] Also, about 25 mg to about 1400 mg of a compound of formula I-IV or its analogues in the treatment of pain. Also disclosed herein is the use of a pharma- ceutically acceptable salt or hydrate of About 25 mg to about 1400 mg of a compound of formula I-IV or its The use of pharma- ceutically acceptable salts or hydrates is also disclosed herein. In a treatment, about 25 mg to about 1400 mg of a compound of Formula I-IV or a pharma- ceutically acceptable salt thereof. Also disclosed herein are uses of salts or hydrates thereof. Pathological pain includes diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, distal These are sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy. Also, from about 25 mg to about 1400 mg of formula I in the treatment of pain associated with osteoarthritis. Also disclosed herein are the uses of compounds of formula (I) to (IV) or pharma- ceutically acceptable salts or hydrates thereof. can be.

[0144] Also, in the treatment of pain, about 50 mg to about 600 mg of a compound of formula I-IV or The use of pharma- ceutically acceptable salts or hydrates is also disclosed herein. About 50 mg to about 600 mg of a compound of formula I-IV or a pharmaceutical composition thereof in the treatment of chronic back pain. The use of a therapeutically acceptable salt or hydrate thereof is also disclosed herein. About 50 mg to about 600 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof. Use of the salts or hydrates is also disclosed herein. Pain may be caused by diabetic neuropathy, diabetic peripheral neuropathic pain, polyneuropathy, or distal sensory polyneuropathy. Neuropathy is a neuropathic disorder characterized by a neuropathic, peripheral, central, and / or mixed neuropathic disorder. About 50 mg to about 600 mg of a compound of formula I-IV in the treatment of pain associated with osteoarthritis. The use of the compounds or their pharma- ceutically acceptable salts or hydrates is also disclosed herein.

[0145] Also, about 600 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof in the treatment of pain. The use of the salt or hydrate thereof is also disclosed herein. In the treatment of pain, about 600 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof or The use of about 600 mg or a hydrate thereof in the treatment of neuropathic pain is also disclosed herein. The use of mg of a compound of formula I-IV or a pharma- ceutically acceptable salt or hydrate thereof is also contemplated herein. In some embodiments, the neuropathic pain is caused by diabetic neuropathy, diabetic neuropathy, Peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, Central neuropathy and / or mixed neuropathy. About 600 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt or hydrate thereof The use of is also disclosed herein.

[0146] Also, about 400 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof in the treatment of pain. The use of the salt or hydrate thereof is also disclosed herein. In the treatment of pain, about 400 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof or The use of about 400 mg or a hydrate thereof in the treatment of neuropathic pain is also disclosed herein. The use of mg of a compound of formula I-IV or a pharma- ceutically acceptable salt or hydrate thereof is also contemplated herein. In some embodiments, the neuropathic pain is caused by diabetic neuropathy, diabetic neuropathy, Peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, Central neuropathy and / or mixed neuropathy. About 400 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt or hydrate thereof The use of is also disclosed herein.

[0147] Also, about 200 mg of a compound of formula I-IV or a pharma- ceutical acceptable salt thereof in the treatment of pain. The use of the tolerable salts or hydrates thereof is also disclosed herein. About 200 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof in the treatment of vertebral pain. Also disclosed herein is the use of about 20 The use of 0.0 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt or hydrate thereof is also disclosed herein. In some embodiments, the neuropathic pain is caused by diabetic neuropathy, diabetes mellitus, Diabetic peripheral neuropathic pain, polyneuropathy, distal sensory polyneuropathy, peripheral neuropathy, Central neuropathy and / or mixed neuropathy. Pain associated with osteoarthritis. In the treatment, about 200 mg of a compound of formula I-IV or a pharma- ceutically acceptable salt thereof or The use of the hydrates is also disclosed herein.

[0148] Additionally, it is used for the treatment of pain, chronic back pain (including chronic lower back pain), neuropathic pain, and osteoarthritis. A compound of formula I-IV or a compound thereof for the manufacture of a medicament for treating a disease or condition selected from the group consisting of pain associated with The use of a pharma- ceutically acceptable salt or hydrate of is also disclosed herein. In terms of form, neuropathic pain can be classified as diabetic neuropathy, diabetic peripheral neuropathic pain, multiple Neuropathy, distal sensory polyneuropathy, peripheral neuropathy, central neuropathy, and / or mixed neuropathy It is a menstrual disorder.

[0149] In some embodiments, the first amount or effective amount of the SSTR4 agonist comprises at least Once a day, 1 to 4 times a day, at least twice a day, once a day, twice a day, every 24 hours, 12 It may be administered hourly, every 8 hours, every 6 hours, or every 4 hours.

[0150] Patients who require treatment for diabetic neuropathy are those who meet one or more of the following characteristics: Any patient with a visual analog score of 40 or greater but less than 95 before starting treatment may be included. Participant-reported or visual analog scale (VAS) pain values Pain Catastrophic Factors (PCF) Trophizing Scale score of 30 or less, less than 40 kg / m2 (borderline a body mass index (BMI) of 0.01 mg / kg / day, including a BMI of 0.01 mg / kg / day, For example, the Michigan Neuropathy Screening Institute ment Part B 3 or more uses of neuropathy secondary to peripheral neuropathy Patients with symmetrical foot pain for days and a history and current diagnosis of type 1 or type 2 diabetes mellitus and / or stability as indicated by a glycosylated hemoglobin level of 11 or less prior to initiating treatment. The patient had stable glycemic control.

[0151] definition As used herein, in the context of this disclosure (especially in the context of the claims), The terms "a," "an," "the," and similar terms are used herein unless otherwise defined in this specification. Unless otherwise clearly contradicted by context, both the singular and plural forms are used. should be interpreted as a bar.

[0152] As used herein, the term "hydrate" refers to a compound or a salt thereof that contains water. a solid adduct of the compound or its salt, wherein water molecules are incorporated into the crystal lattice of the compound or its salt. As used herein, the term "sesquihydrate" refers to a solid adduct of the compound or a hydrate of a salt thereof, the stoichiometric ratio of water to the compound or salt thereof being 1.5:1. Refers to Japanese things.

[0153] As used herein, the term "treat" or "treating" refers to any inhibiting, slowing, halting, or reversing the progression or severity of a condition or disorder This includes making the person do so.

[0154] As used herein, the term "patient" refers to a mouse, guinea pig, rat, "Patient" refers to a mammal, such as a mammal, animal, mammalian subject, or human. It is understood that the preferred patient is a human.

[0155] As used herein, the term "effective amount" refers to a single or multiple dose administered to a patient. and refers to the amount or dosage of the compound of the present invention that provides the desired effect in the patient being diagnosed or treated. vinegar.

[0156] The effective amount can be readily determined by one of skill in the art using known techniques. In making this decision, several factors are taken into consideration, including but not limited to: the species of the individual; their size, age, and general health; any particular disease or disorder associated with them; the extent or involvement or severity of the disorder; the response of the individual patient; the particular compound administered; formula; bioavailability characteristics of the administered preparation; selected dosing regimen; use of concomitant medications; as well as other relevant circumstances.

[0157] Thus, the terms "treatment" and "treating" refer to the treatment of an existing disorder and / or It is intended to refer to any method that can slow, interrupt, arrest, control, or halt the progression of the condition. Although it is expected, it is not necessary to demonstrate complete elimination of all symptoms.

[0158] A "pharmaceutical acceptable carrier, diluent, or excipient" is a substance that is administered to a mammal, e.g., a human, These are vehicles generally accepted in the art for the delivery of biologically active agents.

[0159] "Dose" refers to the compound of formula I, (1R, 5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propane propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide As used herein, "mg" means milligram (milligram). As used herein, the dosage ranges and amounts provided refer to the free base. In the form in which it is provided, such as a base, salt, co-crystal form, or any other composition or form. Regardless, the active pharmaceutical ingredient, Formula I, (1R,5S,6r)-N-(2-methyl-1-(( 3-Methylpyridin-2-yl)oxy)propan-2-yl)-3-azabicyclo[3 .1.0] represents the weight of hexane-6-carboxamide.

[0160] The term "about" is used herein to mean close enough to the stated numerical value. This means, for example, ±10% of the stated value.

[0161] As used herein, the term "alkyl" refers to any alkyl group containing the indicated number of carbon atoms. For example, "C1-C 20 Alkyl means a radical having 1 to 20 carbon atoms in a linear or branched arrangement.

[0162] As used herein, "C1-C n The term thioether refers to a terminal " S" containing 1 to n carbon atoms, i.e. linear or branched saturated hydrocarbons The thioether group can be attached to any desired position of the sulfur atom. "C1-C n The term "thioether" also refers to thioethers containing a terminal "S" in the molecule. A thioether group refers to a chloroalkyl or aryl group, i.e., -S(aryl); a thioether group refers to a sulfur The yellow atom can be bonded to any desired position. n The term "thioether" , a saturated hydrocarbon chain and either a cycloalkyl or aryl, i.e., -S-CH2- (aryl), where n refers to the total number of carbon atoms in the substituent.

[0163] As used herein, "C1-C n The term "ether" refers to a terminal "O" in the chain. Linear or branched chain saturated hydrocarbons containing 1 to n carbon atoms, i.e., -O (alkyl), and the ether group can be attached to any desired position of the oxygen atom. 1-C n The term ether also refers to cycloalkyl or aryl groups containing a terminal "O" in the molecule. The aryl group, i.e. -O(aryl), and the ether group, at the desired position of the oxygen atom. It can be combined. "C1-C n The term "ether" also refers to saturated hydrocarbon chains and Contains either cycloalkyl or aryl, i.e., -O-CH2- (aryl). where n refers to the total number of carbon atoms in the substituent.

[0164] As used herein, the term "cycloalkyl" refers to a group containing carbon and hydrogen atoms. Cycloalkyl means a radical derived from a non-aromatic monocyclic or polycyclic ring, including One or more carbon-carbon double bonds may be present in the ring, provided that the ring is not rendered aromatic by their presence. Cycloalkyl groups can be unsubstituted or can have any substituent that will be readily apparent to those skilled in the art. The cycloalkyl group may be a monocyclic or It can be expressed by the total number of carbon atoms in the polycyclic ring. For example, C3-C7 cycloalkenes. The alkyl includes cycloalkyl radical groups having 3, 4, 5, 6, or 7 carbon atoms. .

[0165] As used herein, the term "heterocycloalkyl" refers to an alkyl group having one or more carbon atoms. A non-aromatic monocyclic or A heterocycloalkyl group refers to a radical derived from a polycyclic ring. The carbon-carbon double bond or carbon-heteroatom double bond above is considered to be aromatic because of their presence. Examples of heterocycloalkyl groups include aziridinyl, Pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, mo morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, Examples include tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A cycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. Heterocycloalkyl groups are substituted or unsubstituted depending on the total number of atoms in the monocyclic or polycyclic rings. For example, a 4- to 7-membered heterocycloalkyl can be represented by 4, 5, 6, or Contains 7 members (including carbon atoms and heteroatoms).

[0166] As used herein, the term "aryl" refers to a ring system having carbon atoms in a monocyclic or polycyclic ring. Aryl means a radical derived from an aromatic monocyclic or polycyclic ring containing only atoms. The group may be unsubstituted or the aryl group may have one to five suitable substituents known to those skilled in the art. The aryl group may be substituted with a cyclic or polycyclic group depending on the total number of carbon atoms in the ring. For example, C5-C7 aryl can be represented by the formula: The aryl radical groups include

[0167] As used herein, the term "heteroaryl" refers to a heterocyclic or polycyclic ring. Aromatic monocyclic or polycyclic rings containing one or more carbon atoms and one or more heteroatoms. A heteroaryl group can be unsubstituted or The heteroaryl group may be substituted with 1 to 5 suitable substituents that are known to those skilled in the art. The cyclic group can be represented by the total number of atoms in the monocyclic or polycyclic ring. For example, A membered heteroaryl can contain 4, 5, 6, or 7 members (including carbon atoms and heteroatoms). EXAMPLES

[0168] Certain abbreviations are defined as follows: "DCM" is dichloromethane romethane, and "DMAP" stands for 4-dimethylaminopyridine. ridine), and "DMF" stands for dimethylformamide, "EtOAC" refers to ethyl acetate, "EtOH" refers to ethanol, and "hr / hr "s" refers to hour / hours, "MeCN" refers to acetonitrile, and "MeOH" refers to methanol, and "MTBE" refers to methyl tert-butyl ether ( methyl tert-butyl ether), and "MeTHF" is methyltetrahydrofuran (met hyltetrahydrofuran), and "OTf" refers to trifluoromethanesulfonate, "Ph2PK" stands for potassium diphenylphosphide, and "TEA" stands for triethylamine. "TFA" stands for triethylamine, and "TFA" stands for trifluoroacetic acid. ), and "THF" refers to tetrahydrofuran.

[0169] [ka]

[0170] Scheme 1. Commercial synthesis of SSTR4 agonists Scheme 1, Step A, is carried out in a suitable solvent, such as MeCN, at a suitable temperature (e.g., 30° C.). Compound (1) is converted to methyl ethyl ester using a suitable base such as potassium carbonate and potassium iodide. The coupling of 4-bromobut-2-enoate with 4-bromobutane to give compound (2) is shown. Step B involves deprotecting compound (2) using an acid such as TFA in a solvent such as MeCN. Step C shows the reaction of the compound (3) with the bases KOH, KF, and 2-MeT. In the presence of a suitable solvent such as HF, (2-bromoethyl)diphenylsulfonium trifluoride Compound (3) was mixed using (2-haloethyl)diphenylsulfonium such as ethyl acetate. In step D, water and a base such as LiOH are added to obtain compound (4). Step E converts compound (4) to compound (5) using a catalyst such as COCl2, and compound (5) is reacted with 2-methylphenylacetamide in the presence of a solvent such as DMF, toluene, or DCM. -1-((3-methylpyridin-2-yl)oxy)propan-2-amine, The coupling to give compound (6) is shown in step F. Step F is carried out at a suitable temperature in a solvent such as MTBE. Compound (6) is reacted with Ph2PK under high temperature (for example, heating to 60 to 70°C) to obtain the compound 1 shows the conversion of compound (6) to compound (7) by obtaining product (7).

[0171] Preparation 1 Methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate

[0172] [ka] Methyl 4-bromobut-2-enoate (36.29 g, 202.7 mmol) was added to Dissolved in MeCN (500 mL) at ~25 °C. tert-Butyl tosylcarbamate ( 50.00g, 184.3mmol) was added at 15-25°C. 7g, 221.2mmol) and KI (3.06g, 202.7mmol) for 15-25 min. The solution was added at 30° C. and warmed under nitrogen at 30° C. for 20 hours. The solution was cooled to 20° C. and the mixture was The residue was washed with MeCN (100 mL) to give methyl (E)-4-( (N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamide)buta In MeCN solution, methyl (E)-4-((N-(tert- Butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate ( 483.72g, 143mmol) to TFA (101.03g, 886.06mmol) The reaction solution was concentrated in vacuum to approximately 50 mL, and the mixture was heated to 55-60° C. for 16 hours. The solvent was exchanged with toluene (2×250 mL). Add EtOAc (50 mL), heat to 60° C. for 1 h, then cool to 0° C. for 12 h. The solution was filtered and the wet cake was rinsed with n-heptane (50 mL). was dried in vacuum at 50° C. to give the title compound (37.85 g, 74.4%) as a white solid Obtained as. 1 H NMR(CDCl3)δ 7.68(d,J=8.0Hz,2H)7 .25(d,J=8.0Hz,2H)6.71(dt,J=15.6,5.2Hz,1H )5.88(dt,J=15.6,1.6Hz,1H)4.55(t,J=6.4Hz, 1H)3.71-3.67(m,2H)3.65(s,3H)2.37(s,3H);H RMS(ESI + )[C 12 H 15 NO4S+H] + Calculated value for: 270.0795 , Measured value: 270.0788 (M+H).

[0173] Preparation 2 (1R,5S,6r)-3-Tosyl-3-azabicyclo[3.1.0]hexane-6- Carboxylic Acid

[0174] [ka] Methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate (51.90 g) was dissolved in 2-MeTHF (600 mL) at 0° C. (36.50g), KF (6.47g), KO H (18.75 g) was added to the solution at 0° C. The solution was heated to 15° C. for 22 hours and then to 30° C. The mixture was heated at RT for 3 h. Water (100 mL) and MeOH (100 mL) were added to the solution. iOH .H2O (4.77 g) was added and stirred at 30°C for 16 hours. The mixture was cooled and n-heptane (100 mL) was added. The mixture was stirred at 15 to 25°C for 10 minutes. The aqueous phase was separated and collected, and the aqueous phase was diluted with n-heptane / 2-MeTHF (50 mL / 200 mL x 2). The aqueous phase was concentrated in vacuo to approximately 50 mL, and 3M aqueous HCl was added dropwise to adjust the pH The mixture was stirred at 20-30°C for 2 hours. The solution was filtered and diluted with EtOH / The wet cake was dried at 45 °C for 8–10 h. This gave the title compound as a white solid (20.37 g, 65%). 1 H NMR(C DCl3)δ 7.67(d,J=8.2 Hz,2 H)7.34(d,J=8.2 Hz,2 H)3.63(d,J=9.4 Hz,2 H)3.12(d,J=9.4 Hz,2 H)2.46-2.40(m,4 H)2.07-2.01(m,2 H); HRMS(ESI + )[C 13 H 15 NO4S+H] + Calculated value for: 282.079 5. Measured value: 282.0795 (M+H).

[0175] Preparation 3 2-Methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine

[0176] [ka] 2-Amino-2-methylpropan-1-ol (50.14 g, 562.5 mmol) was dissolved in toluene (250 mL) at 15-25 °C. 60.59 g, 534.6 mmol) was added to the solution and heated to 30-40°C. Fluoro-3-methylpyridine (50.00 g, 450.0 mmol) was added to the solution, and 8 The mixture was warmed to 0° C. The mixture was stirred at 80° C. for 18 hours. The mixture was cooled to 15-25° C. Water (100 mL) was added and stirred for 30 min. The aqueous layer was separated and the organics were diluted with 10% NaCl. The organic matter was washed with toluene (250 mL) and purified by filtration. Concentration in air gave the title compound as a liquid (107.50 g, 98%). 1 H.N.M. R(CDCl3)δ 7.92-7.82(m,1H)7.32-7.22(m,1H) 6.74-6.66(m,1H)3.97(s,3H)2.14(s,3H)1.15( s,6H).

[0177] Preparation 4 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane -6-Carboxamide

[0178] [ka] (1R,5S,6r)-3-Tosyl-3-azabicyclo[3.1.0]hexane-6- Carboxylic acid (32.33 g, purity 88.2%) was dissolved in toluene (320 mL) at 15 to 25 °C. DMF (741.0 mg) and (COCl)2 (19.20 g) were added to the solution. The mixture was concentrated in vacuo and diluted with THF (100 mL). The mixture was then replaced with THF (320 mL) and cooled to 0-10°C. 23.6 0 g), TEA (30.80 g), and DMAP (620.0 mg) were added at 0 to 10°C, and then The mixture was concentrated in vacuo and the solvent was removed with EtOH ( The mixture was concentrated in vacuo to 140 mL and heated to 50° C. until the solids dissolved. Water (210 mL) was added dropwise to the solution at 40° C. The solution was cooled to 10° C. for 14 hours. The wet cake was filtered and rinsed with EtOH / H2O (75 mL, 1:1.5). Drying at 45°C for 20 hours gave the title compound as a solid (41.87g, 87.4%). Ta. 1 H NMR(CDCl3)δ 7.94-7.87(m,1 H)7.60(d, J=8.0 Hz,2 H)7.37(d,J=6.6 Hz,1 H)7.26(d, J=8.0 Hz,2 H)6.78(dd,J=6.6,5.0 Hz,1 H)6. 48(s,1 H)4.25(s,2 H)3.52(d,J=9.4 Hz,2 H) 2.95(d,J=9.4 Hz,2 H)2.39-2.33(m,3 H)2.17 (s,3 H)1.84(s,2 H)1.39(s,6 H);HRMS(ESI + ) [C 23 H 29 N3O4S+H] + Calculated value: 444.1952, measured value: 444 .2089(M+H).

[0179] Example 1 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Kisamide

[0180] [ka] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane -6-Carboxamide (5.00 g) was dissolved in MTBE (50 mL) under nitrogen. Cool to 0-60 °C and add 1 M Ph2PK in THF (56 mL, 56 mmol) to the solution. The mixture was stirred at -70 to 60°C for 6 to 8 hours. A 2M aqueous HCl solution (50 mL ) was added to the solution and the temperature was raised to 15-25°C. The aqueous phase was separated and collected, and 2-Me The mixture was washed with THF (50 mL x 3). 2-MeTHF (50 mL) was added and K2CO3 The pH was adjusted to 8-9 with ethyl acetate powder. The aqueous phase was separated and extracted with 2-MeTHF (50 mL). The organics were combined and concentrated in vacuo to give the title compound as a tan solid (3.05 g , 89.4%) 1 H NMR(CDCl3)δ 8.01-7.92(m,1 H)7. 45-7.36(m,1 H)6.81(dd,J=7.0,5.0 Hz,1 H)6 .39(s,1 H)4.31(s,2 H)3.09-2.89(m,4 H)2.2 1(s,3 H)1.94-1.86(m,2 H)1.69(s,1 H)1.47( s,6 H)1.12(t,J=2.8 Hz,1 H);HRMS(ESI + )[C1 6H 23 N3O2+H] + Calculated value: 290.1863, measured value: 290.191 7(M+H).

[0181] Example 2 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Oxamide L-tartrate

[0182] [ka] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo To the oxamide (5.5 g, 18.4 mmol), IPA (68 mL) and water (2 mL) were added. The mixture is heated to 65°C, at which point dissolution occurs. IPA (34 mL) is then added. ) and L-tartaric acid (2.86 g, 19.1 mmol) in water (1.5 mL) was added to the solution. The solution was then allowed to cool to ambient temperature overnight. The resulting white solid was isolated by vacuum filtration. Release and rinse with ice-cold IPA (20 mL) to give the title compound (5.7 g, 70%).

[0183] Example 3 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Oxamide Citrate

[0184] [ka] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo The oxamide (10.8 g, 33 mmol) was stirred at 300 rpm at 60 °C in anhydrous E The solution was dissolved in tOH (200 mL) and filtered through a 0.65 μm nylon filter. A clear solution was obtained. The solution was stirred for 5 min, resulting in a solid precipitate. The solution was heated at 60°C in anhydrous E A solution of citric acid (7.06 g, 36 mmol) in tOH (60 mL) was prepared. The citric acid solution was added slowly at 60° C. The mixture was stirred at 60° C. in a 0.45 μm flask. The mixture was filtered through a syringe filter, then the heat was removed and the mixture was allowed to cool slowly to ambient temperature. The mixture was stirred at 500 rpm. Upon complete equilibration to ambient temperature, a very thick A white slurry (cake) was obtained. The flask was rinsed with absolute EtOH (5 x 10 mL). The cake was rinsed with 100 ml of ethyl acetate. The cake solid was isolated on a nylon membrane under vacuum and dried under nitrogen. and then dried under vacuum at 70° C. overnight to give the title compound as a white solid (16.8 g, 98% ) was obtained.

[0185] Example 4 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Oxamide Malate

[0186] [ka] (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Add 25 g (88 mmol) of oxamide (100 ml) to a flask with stirring at approximately 400 rpm. The sample was heated to 60°C. Then, an aqueous solution of L-malic acid (14.6 mL A clear yellowish solution was formed, which was then cooled to room temperature. The mixture was cooled to 30° C. An oily phase was observed, so the phase separation was evaporated to dryness under a stream of nitrogen. The solid residue The product was suspended in acetone and water and recrystallized at 55°C. 25 g of the free base equivalent was obtained. The mixture was recrystallized in toluene (200 mL) and water (15 mL). The solids were isolated from the reaction vessel at ambient temperature by filtration. The resulting white cake was The mixture was washed with ethyl acetate and dried under vacuum at 50° C. to give the title compound (21 g, 57%).

[0187] Example 5 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Oxamide L-tartrate sesquihydrate

[0188] [ka] -(1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) )Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide Transfer voxamide L-tartrate (60 g, 136.5 mmol) to a 250 mL reaction vessel, THF / water 95:5 v / v was added to a volume of 225 mL. The mixture was heated to 60° C. and water was added in 1 mL aliquots to completely dissolve the starting material (8 mL water total). The reactor was allowed to cool naturally and the mixture was stirred at room temperature over the weekend. The resulting crystals were filtered under vacuum. The solid was filtered to give the title compound (42 Example 5 is also disclosed in U.S. Patent Application Serial No. 17 / 944,429. No. 6,399,413, which is incorporated herein by reference in its entirety.

[0189] Example 6 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Phase I Clinical Trial of Oxamide L-Tartrate Sesquihydrate (Example 5) (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Oxamide L-tartrate sesquihydrate (Example 5) is currently being used to treat diabetic neuropathy, diabetic It is currently in Phase 2 clinical trials for the treatment of peripheral neuropathic pain and mixed neuropathic pain. Previous data from two Phase 1 studies (J2P-MC-LXBB (LXBB) and LXBA) The data are for doses of about 50 mg to about 600 mg of Example 5, either once daily or twice daily. The present invention relates to a method for treating certain types of pain, such as neuropathic pain, in a patient, comprising administering to the patient Provide proof of concept for the safe use of Example 5 in the treatment and / or relief of pain .

[0190] Example 5 is a first-in-class SST if approved by the corresponding regulatory agency. R4 agonist. There are no available biomarkers or pharmacodynamic tests. Establishing a safe and effective dose for the treatment of stroke pain can only be achieved through in vivo testing. It is believed that this can be determined.

[0191] A total of 116 healthy subjects received at least 1 mg / kg / day in the Phase 1 LXBB and LXBA studies. Each patient received dose 5 of Example 1. Table 1 summarizes the complete Phase 1 pharmacology studies.

[0192] Single-dose pharmacokinetics (PK) of Example 5 was performed at doses of 20 to 400 mg. Across this dose range, the median time to peak plasma concentration of Example 5 was Value(t max ) ranges from 2 to 3 hours after administration, and the mean terminal half-life (t 1 / 2 ) is about 1 The apparent total body clearance (CL / F) ranged from 1 to 13 hours. Renal clearance was approximately 10 L / h, and the administered oral dose Approximately 39-45% of the compound was excreted unchanged in urine as Example 5, and the plasma concentration of Example 5 was generally increased in a dose-proportional manner with an intersubject coefficient of variation of <25%.

[0193] Multiple dose PK of Example 5 was compared at 200 mg, 400 mg, and 600 mg twice daily. The dose was evaluated. max The median time to onset ranged from 1 to 3 hours after administration. Cumulative ratio of Example 5 (R A ) is in the range of about 1 to 2, which is the t 1 / 2 In agreement with In addition, the steady state C max and AUC 0-24 The intersubject coefficient of variation was <25%. This is summarized in Table 2.

[0194] The safety and tolerability of Example 5 was initially evaluated in two completed Phase 1 trials (LXBB and LX Based on the results of the Phase 2 study, OA03, BP03, and BP40, which are disclosed below, , and NP03).

[0195] [Table 1] Abbreviations: BID = twice daily; MAD = multiple-ascending dose; P D=pharmacodynamics, PK=pharmacokinetics, Q12H=every 12 hours, QAM=every Morning, QD = once daily, QPM = nightly, SAD = single-ascending dose

[0196] [Table 2] Abbreviation: AUC 0-24 = area under the plasma concentration-time curve from 0 to 24 hours; AUC (0-τ) = area under the plasma concentration-time curve over one dosing interval; BID = approximately 12 hour interval; C ma x = maximum observed plasma concentration; CV% = coefficient of variation %; PK = pharmacokinetics; QD = once daily; R A =AUC (0-τ) where tau=12 hours; t max = Observation Time to reach the determined maximum plasma concentration. a AUC 0-24 =2×AUC (0-τ) , where tau=12 hours.

[0197] Phase 1 LXBB study: First-in-human single-dose gradual study in 89 healthy subjects The studies were ascending dose / multiple ascending dose (SAD / MAD) trials (Table 1). In the MAD study, Example 5 was well tolerated. All adverse events were t, AEs) were considered to be mild or moderate in severity. Death or serious adverse events (s No serious adverse events (SAEs) were reported. One subject reported a non-drug-related event of fever. In the SAD study, one subject each experienced temporomandibular joint syndrome and tension headache. In the food effect study, one subject reported dry eye and nausea. In a 10-day multiple-dose exposure study in young subjects, the most commonly reported AEs were: Headache (2 subjects), diarrhea (2 subjects), nausea, rhinitis, and orthostatic hypotension (1 subject each) The most commonly reported adverse events in 10-day multiple-dose exposure studies in elderly subjects were The AEs reported were headache (5 subjects), pain in extremities (1 subject), and vascular puncture site bruising (1 subject). The most common side effects were dizziness (1 subject), dizziness (1 subject), and orthostatic hypotension (1 subject).

[0198] Mean increase in PR interval from baseline in subjects receiving a single 400 mg dose (SAD) The highest PR interval change from baseline in any individual subject was 13 ms. The time to response was 45 ms (after a 300 mg dose at the MAD). No chemistry, hematology, or coagulation There were no clinically significant changes in solid parameters.

[0199] Study LXBA is a completed study consisting of two parts, Part A and Part B. Part A of the study included 18 healthy subjects in three dosing cohorts. Group B had 9 healthy subjects exposed to Example 5. Safety data showed that Example 5 The treatment was generally well tolerated, with the majority of AEs being mild in severity. No deaths, SAEs, or discontinuations due to AEs were reported. Treatment-emergent adverse events (TEAEs) observed during treatment included loss of consciousness. All events were mild in severity, except for one moderate event, constipation and insomnia (two events each). ) was the only TEAE reported in >1 subject. The TEAEs reported were dysgeusia, nausea, and vomiting, all of which were mild in severity. there were.

[0200] In total, results were demonstrated in two Phase 1 studies in a total of 116 healthy subjects. 20 mg to 1200 mg per day and / or 20 mg to 600 mg per dose The safety profile of Example 5 at doses was established.

[0201] Example 7 Capsule Composition

[0202] [Table 3]

[0203] Example 8 (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl) Oxy)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carbo Phase 2 Clinical Trial of Oxamide L-Tartrate Sesquihydrate (Example 5) Example 5 is a randomized, placebo-controlled Phase 2 bone study for the treatment of knee OA pain. Study OA03 for the treatment of CLBP, Study BP03 for the treatment of DPNP The results of the three Phase 2 trials are summarized in Table 3. Table 4 summarizes the results of the three Phase 2 trials. The populations studied in the Phase 2 study are shown.

[0204] [Table 4]

[0205] [Table 5]

[0206] For each of these studies, further analysis was performed to determine CV, thyroid, and abnormal renal function. CV AEs included cardiac arrhythmias, hypotension, major adverse cardiovascular events, and Pre-specified standardized MedDRA queries / bases for events and congestive heart failure were identified using standardized MedDRA query / preferred terms (SMQs / PTs). Thyroid-related AEs were identified in the SMQ "Hypothyroidism" and were associated with abnormal renal function. AEs were identified by the high-level terms (HLTs) renal failure and renal dysfunction and were Select T.

[0207] Three pooled intervention-specific appendix (ISA) measures were included: Safety data from A03, BP03, and NP03 are presented for the following safety topics: We analyzed the following.

[0208] Pooled data from studies OA03, BP03, and NP03 are presented in Example 5. There were no clinically significant changes in thyroid-related TEAEs or thyroid analytes between placebo-treated and placebo-treated patients. showed no significant differences.

[0209] Therefore, in three Phase 2 trials, 200 mg to 600 mg of Example 5 were administered. After treatment of a total of 282 patients, an adequate safety profile was established. The efficacy results of each study are discussed herein, while the safety of the studies are discussed together.

[0210] H0P-MC-OA03 - To evaluate Example 5 for the treatment of osteoarthritis pain , a randomized, placebo-controlled, phase 2 clinical trial The purpose of this study was to determine whether Example 5 is effective in reducing osteoarthritis (OA) pain in the knee. The objective of this study was to examine whether the effect of serotoninib on the efficacy and safety of serotoninib in this study population was significantly improved. The safety and tolerability of Example 5 were evaluated and discussed above. Pharmacokinetic and pharmacodynamic properties The overall data from this proof-of-concept study demonstrated the benefits and risks associated with Example 5. The score was evaluated.

[0211] OA03 is an 8-week, phase 2 study comparing Example 5 to placebo in participants with OA of the knee. This was a phase 2, randomized, double-blind, placebo-controlled trial.

[0212] The primary clinical problem addressed was "regarding the initiation of rescue or other permitted concomitant medications." Patients with OA of the knee, assuming they did not have any adverse events and continued in their originally randomized treatment condition Participants were assessed for mean scores measured using a numeric rating scale (NRS). Average pain intensity (API) was measured from baseline to endpoint. Treatment difference between Example 5 and placebo assessed using mean change from baseline (week 8) What is it?"

[0213] The main secondary clinical question addressed was: "Is it appropriate to initiate rescue or other permitted concomitant medications?" Regardless of the outcome and assuming continuation of the originally randomized treatment, Among participants with WOMAC® (Western Ontario nd McMaster Universities Arthritis Index ) Pain as measured by the pain subscale from baseline to endpoint The treatment difference between Example 5 and placebo was assessed using the mean change from baseline (week 8) to "What?"

[0214] Participants were randomly assigned to receive either Example 5 or placebo in a 2:1 ratio. Participants were asked to take up to three capsules (each capsule was 200 mg) twice daily (BI D) could be taken orally at a total dose of 600 mg approximately every 12 hours.

[0215] The protocol was amended to include titration to a target dose of 600 mg. , as long as the change occurred before the end of Visit 4, i.e., Week 2 of the study, the patient was considered to have discontinued participation due to tolerability. After discussion with the patient, the dose could be reduced from 600 mg to 400 mg. The medical monitor was contacted.

[0216] A total of 202 participants were enrolled in the OA03 ISA, with 135 participants randomized to the study. 16 were assigned to treatment 5, and 67 were assigned to placebo.

[0217] Demographic, medical, and baseline characteristics were balanced across treatment groups. The overall average age was 62.8 years old, the majority were women (57.4%), and The mean pain NRS rating at baseline was 5.6.

[0218] The exposure period (in days) was calculated by subtracting the first dose from the last dose during the treatment period. The mean number of days of exposure was 50.4 days in the placebo group compared with 50.4 days in the placebo group. The mean mean mean was 40.5 days in the Example 5 group and 40.5 days in the placebo group. Seven (10.6%) participants in the bono group had at least 60 days of exposure. allowed for dose modifications for individual participants. Twenty-six participants (13.0%) 21 Participants (15.7%) received 200 mg BID of Example 5 followed by 400 mg g BID, then increased to 600 mg BID, then increased to 400 mg BI D, and 5 participants (7.6%) received 1 capsule BID of placebo, followed by 2 capsules BID. The patient was administered 1 capsule BID, then 3 capsules BID, then reduced to 2 capsules BID. .

[0219] Baseline to endpoint for API measured by weekly average NRS Primary endpoint: assessing efficacy of Example 5 vs. placebo on overall mean change (by week 8) None of the objectives met the prespecified threshold for osteoarthritic pain.

[0220] From baseline to baseline, pain intensity as measured by the WOMAC pain subscale Efficacy of Example 5 vs. Placebo on Overall Mean Change to Endpoint (Week 8) The main secondary objective to assess did not meet prespecified thresholds.

[0221] Similarly, there is no statistical evidence that Example 5 is superior to placebo in this study. No other secondary endpoints were observed.

[0222] Overall, Example 5 compared to placebo showed significant benefits in treating osteoarthritis pain. In the study, Example 5 is There was no statistical evidence of superiority over placebo for (as shown in Table 5).

[0223] [Table 6]

[0224] H0P-MC-BP03 - To evaluate Example 5 for the treatment of chronic low back pain (CLBP) A randomized, placebo-controlled, phase 2 clinical trial to The purpose of this study was to test whether Example 5 is effective in relieving chronic low back pain (CLBP). The objective of this study was to test the safety and tolerability of Example 5 in this study population. The tolerability was evaluated and has been discussed previously. The pharmacokinetic (PK) and pharmacodynamic ( The overall data from this proof-of-concept study is presented in conjunction with the relevant benefits of Example 5. Evaluate the benefits and risks.

[0225] BP03 is an 8-week, randomized, placebo-controlled ... This was a two-phase randomized, double-blind, placebo-controlled study. Participants were randomized to receive either Example 5 or a placebo. Based on tolerability, participants received up to three capsules (each capsule was 200 mg) g) orally twice daily (BID) approximately every 12 hours for a total dose of 600 mg was ingested.

[0226] The primary clinical problem addressed was "regarding the initiation of rescue or other permitted concomitant medications." Participants with CLBP were randomized to either the primary or secondary endpoints, assuming they did not have a prior CLBP treatment and continued in their originally randomized treatment condition. The mean pain intensity (API) measured by the numerical rating scale (NRS) was The efficacy and safety of the study was assessed using the mean change from baseline to endpoint (week 8) What is the treatment difference between treatment 5 and placebo?

[0227] A total of 153 participants were enrolled in the BP03 ISA, with 102 participants randomized to the study. Allocated to treatment group 5, 51 participants were randomly assigned to placebo.

[0228] Demographic, medical, and baseline characteristics were balanced across treatment groups. The overall average age was 52.5 years old, the majority were women (56.9%), and The mean pain NRS rating at baseline was 5.7.

[0229] The exposure period (in days) was calculated by subtracting the first dose from the last dose during the treatment period. The mean number of days of exposure was 50.8 days in the placebo group compared with 50.8 days in the placebo group. The mean mean was 47.5 days in the group with Example 5. Seventeen participants (16.7%) in the group with Example 5 and the prognosis was 1. Seven (14.0%) participants in the placebo group had at least 60 days of exposure.

[0230] The protocol allowed for dose modification for individual participants. Most participants (n = 106, 69.7%) had a "two-times uptitration" regimen, and 61 Participants (59.8%) took 200 mg BID of Example 5 followed by 400 mg BID, then increased to 600 mg BID, and 45 participants (90.0%) ) were administered 1 capsule BID of placebo, followed by 2 capsules BID, followed by 3 capsules BID He was taking the following medication.

[0231] Thirty-five participants (23.0%) reported having two up-titrations and one down-titration. Thirty-two participants (31.4%) had the 200m treatment regimen of Example 5. g BID, then increased to 400 mg BID, then 600 mg BID and then decreased to 400 mg BID. Three participants (6.0%) Take 1 capsule of Sebo BID, then 2 capsules BID, then 3 capsules BID, This was then reduced to 2 capsules BID of placebo.

[0232] Baseline to endpoint for API measured by weekly average NRS Primary endpoint: assessing efficacy of Example 5 vs. placebo on overall mean change (by week 8) The objective of this study was not to meet the pre-specified threshold. Similarly, the efficacy of Example 5 over placebo was not demonstrated. No statistical evidence of efficacy was observed for any of the secondary endpoints in this study. (as shown in Table 6).

[0233] Overall, when comparing Example 5 to placebo, the results of this study for the treatment of chronic low back pain were Example 5 is superior to placebo in terms of the primary or secondary endpoints. There was no statistical evidence that this was the case (as shown in Table 6).

[0234] [Table 7]

[0235] H0P-MC-NP03 - Evaluating the examples for the treatment of diabetic peripheral neuropathic pain A randomized, placebo-controlled, phase 2 clinical trial to The purpose of this study is to determine whether Example 5 is effective in treating diabetic peripheral neuropathy pain. The aim of this study was to test whether sedatives are effective in reducing chronic uropathic pain (DPNP). Data was collected to evaluate the safety and tolerability of Example 5 in this study population, as already discussed above. The pharmacokinetic properties and pharmacodynamic effects were also investigated. Overall, the benefits and risks associated with Example 5 are evaluated.

[0236] NP03 is an 8-week, randomized, placebo-controlled, randomized, placebo-controlled, randomized, placebo-controlled, randomized, randomized, placebo-controlled, randomized, randomized, This was a phase 2, randomized, double-blind, placebo-controlled trial.

[0237] Participants received either Example 5 or a placebo. Based on tolerability, participants were Up to 3 capsules (each capsule was 200 mg) twice daily, approximately every 12 hours , given orally at a total dose of 600 mg.

[0238] The primary clinical problem addressed was "regarding the initiation of rescue or other permitted concomitant medications." Diabetic peripheral neuropathy, assuming no adverse events and continued treatment to which the patient was originally randomized In participants with dysphagia-related pain (DPNP), as measured by the Numeric Rating Scale (NRS), The mean pain intensity (API) from baseline to endpoint (week 8) was What is the treatment difference between Example 5 and placebo, assessed using the mean change?

[0239] Participants were randomly assigned 2:1 to receive either Example 5 or placebo. Participants were to take up to three capsules (each capsule was 200 mg) twice daily (BID). A total dose of 600 mg BID could be taken orally approximately every 12 hours.

[0240] The protocol allowed for dose modification for individual participants, but the maximum daily dose was 60 The starting dose level was 200 mg BID. The decision to change dose levels was based on tolerability, adverse events (AEs) reported, and By the investigator in discussion with the participant. All changes in dose level must occur before the end of Visit 4 (Study Week 2). It had to be.

[0241] The study enrolled men or women who met the following main criteria: 40% at Visits 1 and 2; Participant-reported pain scores of ≥ 95 and < 95 on the visual analogue scale (VAS) or had a medical history of at least 12 weeks of daily pain, using the Pain Catastrophizing Scale had a body mass index of less than 40 kg / m2 (including borderline values) have been present for at least 6 months and are certified by the Michigan Neuropathy Society Diagnosed through the use of reening instrument Part B 3 or more A patient with type 1 or type 2 diabetes mellitus who had daily symmetric foot pain secondary to peripheral neuropathy with a history and current diagnosis, and a glycated hemoglobin level of 11 or less at screening All patients had stable glycemic control as indicated by:

[0242] Participants received either Example 5 or a placebo. Based on tolerability, participants were Up to 3 capsules (each capsule is 200 mg) BID, approximately every 12 hours for 6 A total dose of 00 mg could be taken orally.

[0243] The study included an 8-week DB treatment period.

[0244] A total of 68 participants were enrolled in the NP03 Intervention Specific Index (ISA), with 45 participants were randomly assigned to treatment 5, and 23 participants were randomly assigned to placebo. Demographic, medical, and baseline characteristics were balanced across treatment groups. The overall mean age in the study 5 group was 60.2 years compared to 58.3 years in the placebo group. The majority were women (55.9%), and the mean age at baseline was 6.45 in the placebo group. The average NRS pain score for Group 5 was 6.44.

[0245] Duration of exposure (days) is the last visit date during the treatment period minus the first administration date + The mean number of days of exposure was 45.7 (min=7, max=63) in the placebo group. In comparison, the Example 5 group had a score of 38.7 (min=4, max=64). 4.4% of participants in the placebo group and 3 (13.0%) participants in the placebo group had a median survival of ≥ 60 days. Most participants (50, 73.5%) had been exposed to Eleven participants (16.2%) had a “two-up tight” regimen. The patients were administered a "titration and one down-titration" regimen.

[0246] The primary objective of this study was to determine the efficacy and safety of the API as measured by the weekly average NRS (shown in Table 7). Overall mean change from baseline to endpoint (week 8) in The objective of the study was to evaluate the efficacy of Example 5. The Example 5 group had a median AP score of 1.0 vs. placebo at week 8. have a greater improvement in change from baseline in I, with the posterior probability being pre-specified Similar findings were observed for the biweekly mean API measured by the NRS. was observed.

[0247] Secondary objectives were to assess pain severity and pain interference (Brief Pain Inventory) -Short Form Modified [BPI-SFM]), overall improvement (Pa tient Global Impression of Change [PGIC]) , worst pain intensity (NRS), pain intensity (VAS), sleep quality (Medical Outc omes Study Sleep Scale), and emotional functioning (European Quality of Life 5 Dimension 5 Level) For most secondary endpoints, the study showed better efficacy in the study 5 group compared with placebo. A significant numerical improvement was observed. The posterior probability met the pre-specified threshold, and Example 5 It was shown to be superior to placebo on the following endpoints: From baseline to endpoint for individual severity scores on the BPI-SFM Average change in: "Worst in the last 24 hours" and "Average" From baseline to endpoint for individual reasoning scores on the BPI-SFM Average change: "Mood" and "Ability to Walk" Participants demonstrated a reduction in mean interference from the BPI-SFM of at least 50% from baseline Percentage of people Participants who achieved at least a 30% reduction from baseline in their BPI-SFM individual interference scores Percentage of people: "In the normal course of business." Overall improvement from baseline in PGIC Mean change from baseline in worst pain intensity-NRS weekly average.

[0248] Mean Change From Baseline in Worst Pain Intensity-NRS Biweekly Mean Time to initial reduction in pain of at least 50% at worst pain Mean change from baseline in VAS, and Percentage of VAS scores decreasing by at least 30% (week 4 only).

[0249] NP03 is an 8-week, multicenter, randomized controlled trial to evaluate Example 5 for the treatment of DPNP. This was a randomized placebo-controlled, phase 2 proof-of-concept study. Participants were randomized to either Example 5 or placebo for 2 A total of 68 participants were enrolled in the NP03 ISA, with 45 Participants were randomly assigned to treatment 5 and 23 participants were assigned to placebo. The safety population consisted of 68 participants who received at least one dose of study intervention and were enrolled. All participants in the population were included. Using a titration scheme, Example 5 was administered at up to 3 caps. as cells (200 mg per capsule) for a total dose of 600 mg approximately every 12 hours, It was administered orally with or without food. 50% of participants completed the BD treatment phase.

[0250] The primary objective of this study was to assess baseline API as measured by weekly average NRS. The efficacy of Example 5 on the overall mean change from baseline to endpoint (week 8) The objective of the study was to evaluate the baseline API levels at week 8 compared to placebo in the Example 5 group. The results showed that the posterior probability of the variance was greater than the pre-specified threshold. This shows that Example 5 was more effective than placebo compared to the standard of care at week 8. Similar findings were observed for the biweekly average of the NRS. was observed.

[0251] Table 7 shows the efficacy of Example 5 in treating DPNP compared to placebo. Proof-of-concept data is presented.

[0252] Figure 1 shows the efficacy and safety of 400 mg BID and 600 mg BID in the treatment of DPNP compared to placebo. 13 shows proof-of-concept data to demonstrate the efficacy of Example 5 at 1.g BID.

[0253] [Table 8]

[0254] [Table 9]

[0255] [Table 10]

[0256] By weekly mean NRS by medication regimen using Bayesian repeated measures analysis with PS method Overall baseline to endpoint (week 8) outcomes for API were measured The efficacy of Example 5 on mean change in schizophrenia is shown in Tables 8 and 9 and in Figure 1. In the 400 mg dosing regimen compared with the 0 mg dosing regimen, as measured by NRS There was a larger reduction in APIs being used.

[0257] Surprisingly, the clinical efficacy was similar to that of the diabetic peripheral pulmonary edema, even though similar doses were tested. It has been demonstrated in neuropathy, but not in chronic lower back pain or knee osteoarthritis. Moreover, the efficacy results support the finding of non-opioid pain treatments without serious side effects. It is believed to be a solution to a long-standing need.

[0258] Example 9 Phase II(b) dose regimen study in DPNP (Study J2P-MC-LXBD) Protocol for As used herein, the dosage of DPNP at a particular dose of the dosing regimen of the present invention is Protocols for regimen testing are also provided. Those skilled in the art will be able to easily implement the teachings of this Example 8 and the present invention. Other disclosures provided herein may be applicable, and similar trials may be performed with additional doses and dosing regimens of the present invention. Experiments could be carried out.

[0259] The purpose of this study is to determine whether Example 5, at additional doses, is effective in treating diabetic peripheral neuropathic pain (DPNP). The aim of the study was to test whether it is effective in reducing

[0260] LXBD is a 12-week, placebo-controlled, randomized ... This was a phase 2, randomized, double-blind, placebo-controlled trial.

[0261] Participants will receive either Example 5 or placebo. Patients will receive placebo: Treatment group 1: The subjects were randomized into four groups in a 2:1:1:1 ratio for treatment group 2: treatment group 3. The randomized groups are given 4 weeks to achieve complete titration in all groups.

[0262] Based on tolerability, participants in treatment arm 1 will receive up to 3 capsules (each containing 50 mg of active (including Example 5 or placebo) twice daily, approximately every 12 hours, at a total dose of 50 mg. Receive verbally.

[0263] Based on tolerability, participants in treatment arm 1 will receive up to 3 capsules (each containing 50 mg of active (including Example 5 or placebo) twice daily, approximately every 12 hours, at a total dose of 50 mg. There is no titration schedule currently planned for Arm 1; therefore, Participants will receive 50 mg of Example 5 for 12 weeks.

[0264] Based on tolerability, participants in treatment arm 2 will receive up to 3 capsules (each containing 50 mg (including Example 5, 200 mg of Example 5, or placebo) twice daily for approximately 12 hours. Treatment arm 2 will receive a total dose of 200 mg of Example 5 orally every 24 hours. The titration schedule presented is contingent on tolerability of the higher doses in participants. 50 mg BID in week 1, 100 mg BID in week 2, and 200 mg BI D includes weeks 3 to 12.

[0265] Based on tolerability, participants in treatment arm 3 will receive up to 3 capsules (each containing 50 mg (including Example 5, 200 mg of Example 5, or placebo) twice daily for approximately 12 hours. Treatment arm 2 will receive a total dose of 400 mg of Example 5 orally every 24 hours. The titration schedule presented is contingent on tolerability of the higher doses in participants. 50mg BID for the first week, 100mg BID for the second week, and 200mg BID for the third week. week 3, 300 mg BID week 4, and 400 mg BID weeks 5-12.

[0266] Participants were randomized to receive the intended dose to minimize patient dropouts from the study. Based on the above, patients were transferred from arm 3 to arm 1, from arm 2 to arm 1, or from arm 3 to arm 1. LXBD may be allowed to move to each of the dose groups and each of the titration steps. Provide safety information (frequency, severity, duration of TEAEs, DCAEs).

[0267] In total, three treatment doses were administered to meet the primary efficacy endpoint: 50 mg, 200 mg , and 400 mg BID (twice daily) will be evaluated. The present disclosure includes the following aspects. (A) Formula: JPEG2024170613000062.jpg23170 or a pharma- ceutically acceptable salt and / or hydrate thereof, A compound, or a pharma- ceutically acceptable salt thereof and / or a hydrate thereof, wherein said compound is prepared by the methods described herein. (B) the compound has the formula: The compound according to (A), which is a compound of formula (1), or a combination thereof. (C) A compound prepared by the methods described herein, said compound having the formula: (D) A compound represented by the formula: JPEG2024170613000064.jpg23170, or a pharma- ceutically acceptable salt and / or hydrate thereof. JPEG2024170613000065.jpg96170, or a combination thereof. (D1) A pharmaceutical composition comprising the compound according to (A) or a pharma- ceutical acceptable salt thereof and / or a hydrate thereof, wherein the compound is administered to the patient in a tablet composition, a capsule composition, or an aqueous solution. (D2) The pharmaceutical composition described in (D1), wherein the capsule composition comprises microcrystalline cellulose, silicon dioxide, or a combination thereof. (E1) Formula: JPEG2024170613000066.jpg24170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: formula: JPEG2024170613000067.jpg24170 (Wherein R is C 1 ~C 6 wherein the compound is an alkyl group, formula: JPEG2024170613000068.jpg27170 where X is a halogen and A is an anion, to form a sulfonium salt of the formula: JPEG2024170613000069.jpg34170 and obtaining an intermediate compound of the formula: The intermediate compound JPEG2024170613000070.jpg26170 Mixed with JPEG2024170613000071.jpg34170 and JPEG2024170613000072.jpg33170 and removing the tosyl functionality from to obtain said compound. (E2) The process, formula: JPEG2024170613000073.jpg27170 with a compound of the formula: JPEG2024170613000074.jpg16170 with a sulfonium salt of the formula (E1) to obtain the intermediate compound. (E3) The method according to (E1) or (E2), wherein the method comprises less than 8 synthetic steps. (E4) The method according to (E1), wherein the method does not include a metal catalyst. (E5) The method according to (E1), wherein the method does not utilize a hydride salt. (E6) The method, (a) JPEG2024170613000075.jpg25170 Mixed with JPEG2024170613000076.jpg34170 and (b) JPEG2024170613000077.jpg35170 Mix with trifluoroacetic acid, JPEG2024170613000078.jpg26170 and (c) JPEG2024170613000079.jpg27170 Mixed with obtaining said intermediate compound. (E7) The method, (d) reacting said intermediate compound JPEG2024170613000080.jpg29170 Mixed with JPEG2024170613000081.jpg34170 and (e) JPEG2024170613000082.jpg31170 with potassium diphenylphosphine to obtain the compound, or a pharma- ceutically acceptable salt thereof and / or a hydrate thereof. (E8) The method, (a) combining methyl (E)-4-bromobut-2-enoate with tert-butyl tosylcarbamate to obtain methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate; (b) combining methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate with trifluoroacetic acid to obtain methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate; (c) mixing methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate with 2-bromoethyl)diphenylsulfonium triflate to obtain said intermediate compound; (d) combining the intermediate compound with 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine to obtain (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide; (e) mixing ((1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide with potassium diphenylphosphine to obtain the compound, or a pharma- ceutically acceptable salt thereof and / or a hydrate thereof. The method according to (E1), comprising the steps of: (E9) The compound is JPEG2024170613000083.jpg97170 or a combination thereof. (E10) The method, The method of (E1), further comprising: (f) combining the compound with L-tartaric acid, citric acid, L-malic acid, or a combination thereof. (E11) Formula: JPEG2024170613000084.jpg33170 or a pharma- ceutically acceptable salt thereof, comprising the steps of: formula: JPEG2024170613000085.jpg27170 (Wherein R is C 1 ~C 6 wherein the compound is an alkyl group, formula: JPEG2024170613000086.jpg26170 wherein X is a halogen and A is an anion, to obtain said intermediate compound. (E12) The method, formula: JPEG2024170613000087.jpg27170 with a compound of the formula: JPEG2024170613000088.jpg16170 with a sulfonium salt of to obtain said intermediate compound or a pharma- ceutically acceptable salt thereof. (E13) The method according to (E11) or (E12), wherein the method comprises less than 8 synthesis steps. (E14) The method according to (E11), wherein the method does not include a metal catalyst. (E15) The method according to (E11), wherein the method does not utilize a hydride salt. (E16) The method comprising: (a) JPEG2024170613000089.jpg25170 Mixed with JPEG2024170613000090.jpg34170 and (b) JPEG2024170613000091.jpg35170 Mix with trifluoroacetic acid, JPEG2024170613000092.jpg27170 and (c) JPEG2024170613000093.jpg26170 Mixed with Obtaining said intermediate compound or a pharma- ceutically acceptable salt thereof; and the process according to (E11). (E17) The method, (a) combining methyl (E)-4-bromobut-2-enoate with tert-butyl tosylcarbamate to obtain methyl (E)-4-((N-(ter(t-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate; (b) combining methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate with trifluoroacetic acid to obtain methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate; (c) mixing methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate with 2-bromoethyl)diphenylsulfonium triflate to obtain said intermediate compound or a pharma- ceutically acceptable salt thereof.

Claims

1. formula: 【Chemistry 5】 or a hydrate thereof.

2. The compound has the formula: 【Chemistry 6】 The composition of claim 1 , wherein the compound is

3. 3. The composition of claim 1 or 2, wherein the capsule composition further comprises microcrystalline cellulose, silicon dioxide, or a combination thereof.

4. The composition of claim 1, wherein the composition comprises from about 50 mg to about 600 mg of the compound.

5. The composition of claim 1, wherein the composition comprises about 50 mg to about 200 mg of the compound.

6. The composition of claim 1 , wherein the composition comprises about 50 mg of the compound.

7. The composition of claim 1 , wherein the composition comprises about 200 mg of the compound.

8. formula: 【Chemistry 7】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: formula: 【Chemistry 8】 (Wherein, R is C １ ~C ６ wherein the compound is an alkyl group, formula: 【Chemistry 9】 where X is a halogen and A is an anion, to form a sulfonium salt of the formula: 【Chemistry 10】 and obtaining an intermediate compound of the formula: The intermediate compound 【Chemistry 11】 Mixed with 【Chemistry 12】 and 【Chemistry 13】 and removing the tosyl functionality from to obtain said compound.

9. The method further comprising: formula: 【Chemistry 14】 with a compound of the formula: 【Chemistry 15】 with a sulfonium salt of to obtain said intermediate compound.

10. 10. The method of claim 8 or 9, wherein the method comprises less than 8 synthetic steps.

11. The method of claim 8 , wherein the method does not include a metal catalyst.

12. 10. The method of claim 8, wherein the method does not utilize a hydride salt.

13. The method further comprising: (a) 【Chemistry 16】 Mixed with 【Chemistry 17】 and (b) 【Chemistry 18】 Mix with trifluoroacetic acid, 【Chemistry 19】 and (c) 【Chemistry 20】 Mixed with obtaining said intermediate compound.

14. The method further comprising: (d) reacting said intermediate compound with 【Chemistry 21】 Mixed with 【Chemical 22】 and (e) 【Chemistry 23】 with potassium diphenylphosphine to obtain the compound, or a pharma- ceutically acceptable salt and / or hydrate thereof.

15. The method further comprising: (a) combining methyl (E)-4-bromobut-2-enoate with tert-butyl tosylcarbamate to obtain methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate; (b) combining methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate with trifluoroacetic acid to obtain methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate; (c) combining methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate with 2-bromoethyl)diphenylsulfonium triflate to obtain said intermediate compound; (d) combining the intermediate compound with 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine to obtain (1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide; (e) mixing ((1R,5S,6r)-N-(2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)-3-tosyl-3-azabicyclo[3.1.0]hexane-6-carboxamide with potassium diphenylphosphine to obtain the compound, or a pharma- ceutically acceptable salt and / or hydrate thereof.

16. The compound is 【Chemistry 24】 or a combination thereof.

17. The method further comprising:

10. The method of claim 8, further comprising: (f) mixing the compound with L-tartaric acid, citric acid, L-malic acid, or a combination thereof.

18. formula: 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof, comprising the steps of: formula: 【Chemistry 26】 (Wherein, R is C １ ~C ６ wherein the compound is an alkyl group, formula: 【Chemistry 27】 wherein X is a halogen and A is an anion, to obtain said intermediate compound.

19. The method further comprising: formula: 【Chemistry 28】 with a compound of the formula: 【Chemical 29】 to obtain the intermediate compound or a pharma- ceutically acceptable salt thereof.

20. 20. The method of claim 18 or 19, wherein the method comprises less than 8 synthetic steps.

21. 20. The method of claim 18, wherein the method does not include a metal catalyst.

22. 20. The method of claim 18, wherein the method does not utilize a hydride salt.

23. The method: (a) 【Chemistry 30】 Mixed with 【Chemistry 31】 and (b) 【Chemistry 32】 Mix with trifluoroacetic acid, 【Chemical 33】 and (c) 【Chemical Formula 34】 Mixed with Obtaining said intermediate compound or a pharma- ceutically acceptable salt thereof; and the method of claim 18.

24. The method further comprising: (a) combining methyl (E)-4-bromobut-2-enoate with tert-butyl tosylcarbamate to obtain methyl (E)-4-((N-(ter(t-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate; (b) combining methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate with trifluoroacetic acid to obtain methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate; (c) combining methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate with 2-bromoethyl)diphenylsulfonium triflate to obtain the intermediate compound or a pharma- ceutically acceptable salt thereof.

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