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WO2024191675A1 - Procédés de préparation agonistes de sstr4 et de sels de ceux-ci - Google Patents

Procédés de préparation agonistes de sstr4 et de sels de ceux-ci Download PDF

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Publication number
WO2024191675A1
WO2024191675A1 PCT/US2024/018591 US2024018591W WO2024191675A1 WO 2024191675 A1 WO2024191675 A1 WO 2024191675A1 US 2024018591 W US2024018591 W US 2024018591W WO 2024191675 A1 WO2024191675 A1 WO 2024191675A1
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compound
formula
yield
mixing
methyl
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David Andrew Coates
Sandra Ann Filla
David Michael Remick
John Robert Rizzo
Jing TENG
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Eli Lilly and Co
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Eli Lilly and Co
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Priority to AU2024235423A priority Critical patent/AU2024235423A1/en
Publication of WO2024191675A1 publication Critical patent/WO2024191675A1/fr
Priority to MX2025010616A priority patent/MX2025010616A/es
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention is directed to methods for the preparation of SSTR4 agonists, such as 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives.
  • the present invention is also directed to the preparation of salts of SSTR4 agonists.
  • the present invention is also directed to novel hydrates and novel salts of certain SSTR4 agonists.
  • Somatostatin, or somatotropin-release inhibitory factor (SRIF) is a cyclic peptide found in humans.
  • Somatostatin is involved in the regulation of methodes such as for example cellular proliferation, glucose homeostasis, inflammation, and pain.
  • somatostatin or other members of the somatostatin peptide family are believed to inhibit nociceptive and inflammatory methodes via the SSTR4 pathway.
  • WO 2014/184275 discloses certain 3-azabicyclo[3.1.0]hexane-6- carboxamide derivatives which are SSTR4 agonists, and which are useful for preventing or treating medical disorders related to SSTR4.
  • Lab scale synthetic pathways are known, but many steps used in previous synthetic pathways can be impractical and/or too expensive to utilize at commercial scale.
  • the present invention is directed to methodes for the preparation of certain SSTR4 compounds, such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide and pharmaceutically acceptable salts, solvates, and/or hydrates thereof.
  • SSTR4 compounds such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide and pharmaceutically acceptable salts, solvates, and/or hydrates thereof.
  • DPNP Diabetic peripheral neuropathy
  • DPNP Diabetic peripheral neuropathy
  • Treatment options for DPNP are limited. There are only 3 medications approved by the US FDA for this indication: pregabalin, duloxetine, and tapentadol. While pregabalin and duloxetine each demonstrated efficacy in multiple placebo-controlled clinical trials, both medications require titration to minimize adverse reactions. Tapentadol is an opioid mu-receptor agonist, with the same pharmacological limitations and adverse reaction profile as other opioid analgesics.
  • opioids are used clinically in an off-label fashion, including gabapentin, selective serotonin norepinephrine uptake inhibitors, tricyclic antidepressants, and anticonvulsants. Dose-limiting toxicity of all these agents prevents patients from tolerating the therapeutic dose, leading to the use of a subtherapeutic dose in the clinic, and further decreasing the efficacy of these agents. In addition, only 50% of patients continue therapy after 3 months. [0009] Due to the suboptimal dosing and the poor tolerability profile of the nonopioid analgesics used for the management of DPNP, opioids are used as a last resort.
  • opioids are efficacious against acute pain, there is evidence suggesting they provide little clinical benefit in chronic pain, not to mention the possibility of reduced efficacy due to tolerance.
  • opioid compounds are known for providing relief from pain symptoms, opioid compounds are also associated with numerous undesirable side effects, including hallucinations, nausea, dizziness, sedation, constipation, urinary retention, dependency, and addiction. As many as 25% of patients undergoing opioid pain therapy for even a short duration can develop a dependence on opioid compounds. In fact, opioid addiction was declared as a National Public Health Emergency on October 26, 2017 by U.S. President Donald Trump.
  • the present invention is directed to new methods to synthesize SSTR4 agonists and novel hydrates and/or salts of SSTR4 agonists, which have potential uses in the treatment of pain, such as neuropathic pain and/or diabetic neuropathy and/or mixed neuropathy.
  • FIG.1 shows an XRPD pattern of (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol- 3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide monohydrate
  • FIG.2 shows an XRPD pattern of (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol- 3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate
  • FIG.3 shows an XRPD pattern of (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol- 3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide adipate SUMMARY OF THE INVENTION [0015]
  • a compound of the formula: [0017] Also disclosed herein is a compound of the formula: [0018] , or a hydrate thereof. [0019] Also disclosed herein is a compound of the formula: [0020] hydrate thereof. [0021] Also disclosed herein is a compound of the formula: [0022] . [0023] Also disclosed herein is a method for the preparation of certain SSTR4 agonist compounds, and pharmaceutically acceptable salts and/or hydrates thereof, such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide.
  • Y is covalent bond, O, S, C 1 to C 6 ether, or C 1 to C 6 thioether
  • Z is null
  • a covalent bond, CH2, or CH2CH2 is an 8-member to 10-member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C 6 to C 10 aryl, is substituted with one or more Rn
  • Each Rn is independently OH, F, Cl, Br, I, NH2, CF3, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, or C1 to C7 thioether, [0027] and the method comprising: [0028] mixing a compound of the formula: , wherein R is a C1 to C6 alkyl, with a sulfonium salt of the formula: , wherein X is a halogen
  • Also disclosed herein is a method for preparing a compound of the formula: [0030] pharmaceutically acceptable salts thereof; and the method comprising: [0031] mixing a compound of the formula: , wherein R is a C1 to C6 alkyl, with a sulfonium salt of the formula: , wherein X is a halogen and A is an anion to yield an intermediate compound of the formula: mixing the intermediate compound with to yield [0032] removing tosyl functional group from yield the compound.
  • a product comprising a compound, such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide, or pharmaceutically acceptable salts and/or hydrates thereof, prepared by the method described herein.
  • DETAILED DESCRIPTION OF THE INVENTION While methods for the preparation of certain SSTR4 compounds are disclosed in WO 2014/184275, WO 2021/233427, and WO 2022/012534, these compounds were produced at laboratory scale, which can include synthetic steps that are impractical at commercial scale.
  • SSTR4 compounds such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide and pharmaceutically acceptable salts, hydrates, or solvates thereof, which can be performed at commercial scale without the use of transition metal catalysts, such as Pd, Pt, Mo, Rh, Fe, Ni, Cr, W, or combinations thereof, and/or aluminum hydride salts, such as lithium aluminum hydride.
  • transition metal catalysts such as Pd, Pt, Mo, Rh, Fe, Ni, Cr, W, or combinations thereof
  • aluminum hydride salts such as lithium aluminum hydride.
  • the disclosed method includes a cyclization step including a reaction with a (2-haloethyl)diphenylsulfonium salt which leads to a single diastereomer intermediate without requiring a subsequent epimerization step.
  • the disclosed method has fewer total steps than the previously disclosed routes, such as less than 8 or from 4 to 7 total steps.
  • the present invention is also directed to novel hydrates of certain SSTR4 agonists, such as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide monohydrate.
  • the present invention is also directed to novel salts of certain SSTR4 agonists, such as (1R,5S,6r)-N-(2-(1-Methyl-1H- indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide succinate and as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide adipate.
  • SSTR4 agonists such as (1R,5S,6r)-N-(2-(1-Methyl-1H- indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6- carboxamide adipate.
  • SSTR4 Agonists [0038] The disclosed method can be used to prepare the compounds of Formula I or Formula I-A, wherein Z can be null, a covalent bond, CH2, or CH2CH2, Y can be covalent bond, O, S, C 1 to C 6 ether, or C 1 to C 6 thioether, is an 8-member to 10- member heteroaryl with from 1 to 4 heteroatoms in the heteroaryl or C6 to C10 aryl, can be substituted with one or more R n , and each R n can be independently OH, F, Cl, Br, I, NH2, CF3, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, C1 to C7 thioether, or combinations thereof.
  • the disclosed method can also be used to prepare salts, solvates, hydrates, and/or combinations thereof of Formula I or Formula I-A.
  • [0040] [0041]
  • Formula I. SSTR4 Agonist [0042] [0043]
  • Formula I-A. SSTR4 Agonist [0044] can be a C6 to C10 aryl or a 5-member to 10- member heteroaryl with from 1 to 4 heteroatoms selected from O, N, or S.
  • each of the ring systems can include a C 5 to C 6 aryl or five-member to six-member heteroaryl with 1 or 2 heteroatoms selected from O, N, or S.
  • R n can be independently selected from OH, F, Cl, Br, I, NH2, C1 to C6 alkyl, C3 to C7 cycloalkyl, C1 to C7 ether, C1 to C7 thioether, or combinations thereof.
  • n can represent the number of substitutions on .
  • R 1 can be a first substitution on m
  • R2 can be a second substitution on , etc.
  • Y can be covalent bond, O, S, C 1 to C 6 ether, or C 1 to C6 thioether. When Y is null, is connected via a covalent bond to the dimethyl substituted carbon atom immediately adjacent to the amide functional group.
  • Z can be null, a covalent bond, CH 2 , or CH 2 CH 2 . When Z is null, there no connection between the two methyl substituents at the alpha carbon atom.
  • the alpha carbon atom forms a cyclopropyl functional group.
  • Z is CH 2
  • the alpha carbon atom forms a cyclobutyl functional group.
  • Z is CH2CH2
  • the alpha carbon atom forms a cyclopentyl functional group
  • the C1 to C7 thioether can be a thioether selected from Formula II.
  • Formula II. Thioethers [0051] The disclosed method can be used to prepare the compounds of Formula III. The disclosed method can also be used to prepare solvates, hydrates, and/or combinations thereof of Formula III and/or Formula III-A.
  • Formula III SSTR4 Agonists that can be made by the disclosed method.
  • [0053] [0054]
  • Formula III-A Additional SSTR4 Agonists that can be made by the disclosed method
  • the disclosed method can be used to prepare the compounds of Formula IV.
  • the disclosed method can also be used to prepare solvates, hydrates, and/or combinations thereof of Formula IV.
  • [0056] [0057] Formula IV.
  • Method [0059] Disclosed herein is a method for preparing a SSTR4 agonist compound.
  • the method for preparing a SSTR4 agonist compound can be used in the commercial scale production of an SSTR4 agonist compound, a pharmaceutically acceptable salt, and/or a solvate/hydrate thereof, as further discussed herein.
  • the reactions are performed using batch methoding methodology.
  • the batches are produced at method scale.
  • the batches are produced in at least 1 kilogram.
  • the batches by are produced in at least 10 kilograms.
  • the batches are produced in at least 100 kilograms.
  • the method for preparing a SSTR4 agonist compound of the formula: [0061] pharmaceutically acceptable salts, solvates, or hydrates thereof, can comprises the steps of: [0062] (a) Mixing tert-Butyl tosyl carbamate with a suitable C 1 -C 6 Alkyl 4- halobut-2-enoate [0063] Step (a) of the method to prepare a SSTR4 agonist compound can include the mixing tert-Butyl tosyl carbamate with a suitable C1-C6 Alkyl 4-halobut-2-enoate compound in a polar aprotic solvent as shown in Formula V, wherein X is a halogen leaving group, such as Cl, Br, or I.
  • X is a halogen leaving group, such as Cl, Br, or I.
  • Step (a) of Method for Preparing SSTR4 Agonist Compound The components of step (a) can be combined in a polar aprotic solvent at a temperature of from about 10 oC to about 25 oC, from about 15 oC to 25 oC, or from 20 oC to 25 oC.
  • the temperature of the mixture of components in step (a) can be increased to from about 25 oC to about 50 oC, from about 25 oC to about 40 oC, or about 30 oC.
  • the product mixture of step (a) can be filtered, and the collected residue washed with a polar aprotic solvent to yield the product in solution.
  • Suitable polar aprotic solvents are well known to a person of ordinary skill in the art of organic synthesis design. Suitable polar aprotic solvents can include acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, among others. [0068] In another embodiment, the method can include the mixing tert-Butyl tosyl carbamate with (E) Methyl 4-bromobut-2-enoate compound in MeCN to yield Methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate, as shown in Formula VI.
  • step (a) of Method for Preparing SSTR4 Agonist Compound
  • step (a) can comprise mixing .
  • Additional components to step (a) may include a base, such as potassium carbonate, and/or a salt, such as potassium iodide.
  • Step (b) of the method to prepare a SSTR4 agonist compound can include the mixing the product generated in step (a), C 1 -C 6 Alkyl (E)-4-((N-(tert- butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate, with a suitable acid in a polar aprotic solvent as shown in Formula VII. [0075] Formula VII.
  • Step (b) of Method for Preparing SSTR4 Agonist Compound can be combined in a polar aprotic solvent at a temperature of from about 10 oC to about 25 oC, from about 15 oC to 25 oC, or from 20 oC to 25 oC.
  • the temperature of the mixture of components in step (b) can be increased to from about 40 oC to about 75 oC, from about 40 oC to about 60 oC, or from about 55 oC to about 60 oC.
  • the reaction solution can remain at the elevated temperature for at least 4 hrs., at least 10 hrs., or at least 12 hrs.
  • step (b) After mixture of the step (b) components are heated to the elevated temperatures, the solution can be concentrated, and the remaining polar aprotic solvent exchanged with toluene and/or ethyl acetate.
  • the polar aprotic solvent can be the same solvent as in step (a) so that the product can remain in solution without any additional purification steps other than filtration of byproducts or the solvent can be a different polar aprotic solvent.
  • the suitable acid in step (b) can be any acid that can be used to remove the tert-butyl ester from the tertiary amine to form a secondary amine.
  • step (b) can comprise mixing methyl (E)-4-((N- (tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but-2-enoate with TFA in MeCN to yield methyl (E)-4-((4-methylphenyl)sulfonamido)but-2-enoate as shown in Formula VIII. [0081] [0082] Formula VIII.
  • step (c) of Method for Preparing SSTR4 Agonist The components of step (c) can be combined at from -10 oC to 10 oC or about 0 oC.
  • potassium fluoride and/or potassium hydroxide may be added.
  • the temperature of the solution can be gradually or step-wise increased to 30 oC over a period of from about 10 hrs. to about 30 hrs.
  • Suitable heterocycle solvents include tetrahydrofuran, furan, 2-methyl- tetrahydrofuran, among others.
  • a base such as lithium hydroxide
  • the additional period of time can be from about from 8 hrs. to about 24 hrs., from about 12 hrs. to about 18 hrs., or about 16 hrs.
  • the intermediate compound, (1R,5S)-3-(p-Tolylsulfonyl)-3- azabicyclo[3.1.0]hexane-6-carboxylic acid can be separated from solution using traditional synthetic organic chemistry separation techniques well known to a person of ordinary skill in the art.
  • the sulfonium salt used in step (c) can be represented by Formula X, wherein X is a halogen leaving group, such as Cl, Br, or I and A is any suitable anion, which will be well known to a person of ordinary skill in the art.
  • Formula X is a halogen leaving group, such as Cl, Br, or I and A is any suitable anion, which will be well known to a person of ordinary skill in the art.
  • step (c) can also be represented by Formula XI.
  • Formula XI. Formula X. Sulfonium Salt for Step (c)
  • step (c) can comprise mixing Methyl (E)-4-((4- methylphenyl)sulfonamido)but-2-enoate with 2-(bromoethyl)diphenylsulfonium triflate to yield (1R,5S)-3-(p-Tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, the intermediate compound as shown in Formula XII.
  • step (c) of Method for Preparing SSTR4 Agonist
  • step (c) can comprise mixing yield , the intermediate compound, or salts or solvates thereof.
  • step (d) Mixing (1R,5S)-3-(p-Tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6- carboxylic acid with a suitable amine, such as 2-(1-methyl-1H-indazol-3-yl)propan-2- amine
  • Step (d) of the method to prepare a SSTR4 agonist compound can include the mixing the intermediate compound generated in step (c), (1R,5S)-3-(p-Tolylsulfonyl)- 3-azabicyclo[3.1.0]hexane-6-carboxylic acid, with a suitable as shown in Formula XIII- A.
  • Step (d) of the method to prepare a SSTR4 agonist compound can also include the mixing the intermediate compound generated in step (c), (1R,5S)-3-(p- tolylsulfonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid, with 2-(1-methyl-1H- indazol-3-yl)propan-2-amine, as shown in Formula XIII-B.
  • the solution temperature can be increased to from about 15 oC to about 25 oC after from about 2 to about 4 hrs.
  • suitable amines include 2-methyl-1-((3-methylpyridin- 2-yl)oxy)propan-2-amine, 2-(1-methyl-1H-indazol-3-yl)propan-2-amine, among others. Suitable amines can be selected to yield the desired SSTR4 agonist compound.
  • step (d) can comprise mixing intermediate compound [0116] In another embodiment, step (d) can comprise mixing intermediate [0117] Step (e) Removal of Tosyl Functional Group with potassium diphenylphosphine [0118] Step (e) of the method to prepare a SSTR4 agonist compound can include the mixing the product generated in step (d) with potassium diphenylphosphine as shown in Formula XIV-B. [0119] [0120] Formula XIV-A.
  • Step (e) of the method to prepare a SSTR4 agonist compound can include the mixing the product generated in step (d), such (1R,5S,6r)-N-(2-(1-methyl-1H-indazol- 3-yl)propan-2-yl)-3-tosyl-3-azabicylco[3.1.0]hexane-6-carboxamide, with potassium diphenylphosphine as shown in Formula XIV-B. [0122] [0123] Formula XIV-B.
  • Step (e) of Method for Preparing SSTR4 Agonist [0124] (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-tosyl-3- azabicylco[3.1.0]hexane-6-carboxamide, or another suitable SSTR4 agonist precursor generated in step (d) can be dissolved in a suitable solvent, such as methyl tert-butyl ether. The temperature can be decreased to from about -100 oC to about -50 oC, from about -80 oC to about -55 oC, or from about -70 oC to about -60 oC.
  • a suitable solvent such as methyl tert-butyl ether
  • Potassium diphenylphosphine can be added dropwise with the decreased temperature maintained. [0125] After the entire amount of potassium diphenylphosphine has been added, the solution decreased temperature can be maintained for at least 4 hrs., at least 6 hrs., or at least 8 hrs. The solution can then be allowed to rise to a temperature of from about 15 oC to about 25 o C and the SSTR agonist compound, (1R,5S,6r)-N-(2-(1-Methyl-1H- indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide can be isolated from solution using typical methods well known to a person of ordinary skill in the art.
  • step (e) can comprise mixing potassium diphenylphosphine to yield the SSTR4 agonist compound.
  • Salts of SSTR4 Agonist Compound [0128] Also disclosed herein is a method for preparing a pharmaceutically acceptable salt of a SSTR4 agonist compound.
  • the method for preparing a pharmaceutically acceptable salt of a SSTR4 agonist compound can comprise (1) the disclosed method for preparing a SSTR4 agonist compound and (2) generating a pharmaceutically acceptable salt of the SSTR4 agonist through: (i) reaction with an acid, (ii) a salt metathesis reaction, and/or (iii) other reactions that can result in the formation of a pharmaceutically acceptable salt of the SSTR4 agonist compound.
  • Suitable pharmaceutically acceptable salts of SSTR4 agonist compounds can comprise adipate, bromide, chloride, besylate, esylate, mesylate, tosylate, phosphate, succinate, sulfate, citrate, tartrate, L-tartrate, malate, and/or L-malate anions.
  • suitable salts can include (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide succinate, which can be described by the XRPD pattern of FIG.2, and as (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide adipate, which can be described by the XRPD pattern of FIG.3.
  • Other suitable salts are shown in Formula IV.
  • hydrates of SSTR4 agonist compound and hydrates of salts of SSTR4 agonist compound.
  • a suitable hydrate includes (1R,5S,6r)-N- (2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxamide hydrate, which can be described be described by the XRPD pattern shown in FIG.1.
  • compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the composition further comprises one or more therapeutic agents.
  • the pharmaceutical composition is a tablet composition, a capsule composition, or an aqueous composition. Suitable inactive ingredients in the tablet composition include microcrystalline cellulose, croscamellose sodium, sodium stearyl fumarate, among others.
  • the pharmaceutical composition is a capsule composition.
  • the capsule composition can include the SSTR4 agonist compound, or a hydrate or pharmaceutically acceptable salt thereof, without any inactive ingredients.
  • the capsule composition can include one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the capsule composition can include microcrystalline cellulose, silica dioxide, colloidal silica dioxide, among other suitable inactive ingredients.
  • Also disclosed herein 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 or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Also disclosed herein is a method of treating chronic back pain, including chronic lower back pain, in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Also disclosed herein is a method of treating neuropathic pain in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and/or mixed neuropathy.
  • Also disclosed herein is a method of treating pain associated with osteoarthritis in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Also disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof, for use in therapy. Additionally, disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof for use in the treatment of pain.
  • the neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and/or mixed neuropathy.
  • Also disclosed herein is a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof for use in the treatment of pain associated with osteoarthritis.
  • a compound of Formula I or a pharmaceutically acceptable salt or hydrate thereof, Formula I-A, or a pharmaceutically acceptable salt or hydrate thereof, Formula III or a pharmaceutically acceptable salt or hydrate thereof, or Formula IV or a hydrate thereof for the manufacture of a medicament for the treatment of a disease or condition selected from pain, chronic back pain, including chronic lower back pain, neuropathic pain and pain associated with osteoarthritis.
  • a disease or condition selected from pain, chronic back pain, including chronic lower back pain, neuropathic pain and pain associated with osteoarthritis.
  • the neuropathic pain is diabetic peripheral neuropathic pain, central neuropathic pain, and/or mixed neuropathy.
  • Intermediate Compound Also disclosed herein are new intermediate compounds generated during the disclosed method for the preparation of the SSTR4 agonist compounds or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof. Suitable intermediates can be generated at any time during the disclosed method. Suitable intermediates can be isolated as a neat compound or generated only in solution.
  • Suitable intermediates for the preparation of SSTR4 agonist compounds or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof can include the intermediates of Formula XV or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof, wherein Y is H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C1 to C6 ether, or combinations thereof, R1 and R2 are independently H, OH, NH2 Cl, Br, I, C1 to C6 alkyl, C1 to C6 ether, or combinations thereof, and the phenyl functional group is substituted with one or more R’ and wherein each R’ group are independently H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C 1 to C 6 ether, or combinations thereof.
  • Y can be OH, Cl, Br, I, or NH2 R1 and R2 can be H, and R’ can be CH3 in the para position.
  • the intermediate compound can also be represented by Formula XVI or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof, wherein Y can be H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C 1 to C 6 ether, or combinations thereof, R 1 and R 2 independently can be H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C1 to C6 ether, or combinations thereof; and the phenyl functional group is substituted with one or more R’ and wherein each R’ group are independently H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C 1 to C 6 ether, or combinations thereof.
  • Y can be OH, Cl, Br, I, or NH2 R1 and R2 can be H, and R’ can be CH3 in the para position.
  • Formula XVI. Intermediate Compound the intermediate compound can also be represented by Formula XVII or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof, Y can be H, OH, NH 2 Cl, Br, I, C 1 to C 6 alkyl, C 1 to C 6 ether, or combinations thereof. In an embodiment, Y can be OH, NH 2 Cl, Br, or I.
  • the intermediate compound can also be represented by Formula XVIII or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof.
  • Formula XVIII Formula XVIII.
  • the intermediate compound, as described herein, can be used for the preparation of the SSTR4 agonist compound or pharmaceutically acceptable salts thereof, hydrates thereof, and/or solvates thereof.
  • the intermediate compound offers a stable scaffold to produce a variety of SSTR4 agonist compounds through an amide-carboxylic acid coupling reaction, such as in step (d) of the method for preparing the SSTR4 agonist compound, as described herein and illustrated in Formula VIII.
  • TABLE A displays some possible SSTR4 agonist compounds that can be synthesized using the disclosed method through the intermediate compound.
  • TABLE 1. SSTR4 Agonist Compounds that Can be Synthesized Using Amide Coupling Reaction with Intermediate Compound
  • the terms “a,” “an,” “the,” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
  • the terms “treating” or “to treat” includes restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.
  • the term “patient” refers to a mammal, such as a mouse, guinea pig, rat, dog, or human. It is understood that the preferred patient is a human.
  • the term “effective amount” refers to the amount or dose of compound of the invention which, upon single or multiple dose administration to the patient, provides the desired effect in the patient under diagnosis or treatment. [0164] An effective amount can be readily determined by one skilled in the art by the use of known techniques.
  • alkyl means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms.
  • C1-C20 alkyl means a radical having 1-20 carbon atoms in a linear or branched arrangement.
  • C 1 -C n thioether refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal “S” in the chain, i.e., -S(alkyl), wherein the thioether group can be attached to the desired location at the sulfur atom.
  • C 1 -C n thioether also refers to a cycloalkyl or aryl radical containing a terminal “S” in the molecule, i.e. -S(aryl), wherein the thioether group can be attached to the desired location at the sulfur atom.
  • C1-Cn thioether can include a saturated hydrocarbon chain and either a cycloalkyl or aryl, i.e. - S-CH 2 -(aryl), with n referring to the number of total carbon atoms in the substituent.
  • C1-Cn ether refers to a straight, or branched chain saturated hydrocarbon containing 1 to n carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl), wherein the ether group can be attached to the desired location at the oxygen atom.
  • C 1 -C n ether also refers to a cycloalkyl or aryl radical containing a terminal “O” in the molecule, i.e. -O(aryl), wherein the ether group can be attached to the desired location at the oxygen atom.
  • C 1 -C n ether can also include a saturated hydrocarbon chain and either a cycloalkyl or aryl, i.e. -O-CH 2 -(aryl), with n referring to the number of total carbon atoms in the substituent.
  • cycloalkyl means a radical derived from a non- aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms.
  • the cycloalkyl can have one or more carbon-carbon double bonds in the ring as long as the ring is not rendered aromatic by their presence.
  • the cycloalkyl group can be unsubstituted or substituted with from one to three suitable substituents, which are well known to a person of ordinary skill in the art.
  • the cycloalkyl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring.
  • a C3 to C7 cycloalkyl includes cycloalkyl radical group with 3, 4, 5, 6, or 7 carbon atoms.
  • heterocycloalkyl means a radical derived from a non-aromatic monocyclic or polycyclic ring comprising one or more carbon atoms and one or more heteroatoms, such as nitrogen, oxygen, and sulfur.
  • a heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds in the ring as long as the ring is not rendered aromatic by their presence.
  • heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents.
  • the heterocycloakyl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring.
  • a four member to seven-member heterocycloalkyl includes four, five, six, or seven members (including carbon atoms and heteroatoms).
  • aryl means a radical derived from an aromatic monocyclic or polycyclic ring including only carbon atoms in the monocyclic or polycyclic ring.
  • the aryl group can be unsubstituted or the aryl group can be substituted with from 1 to 5 suitable substituents, which are well known to a person of ordinary skill in the art.
  • the aryl group can be referred to by the number of total carbon atoms in the monocyclic or polycyclic ring.
  • a C 5 to C 7 aryl includes an aryl radical group with 5, 6, or 7 carbon atoms.
  • heteroaryl means a radical derived from an aromatic monocyclic or polycyclic ring including one or more carbon atoms and one or more heteroatoms in the monocyclic or polycyclic ring.
  • the heteroaryl group can be unsubstituted or the heteroaryl group can be substituted with from 1 to 5 suitable substituents, which are well known to person of ordinary skill in the art.
  • the heteroaryl group can be referred to by the number of total atoms in the monocyclic or polycyclic ring.
  • a four member to seven-member heteroaryl includes four, five, six, or seven members (including carbon atoms and heteroatoms).
  • DCM dichloromethane
  • DMAP 4-dimethylaminopyridine
  • DMF dimethylformamide
  • EtOAC ethyl acetate
  • EtOH refers to ethanol
  • hr/hrs refers to hr/hrs
  • MeCN acetonitrile
  • MeOH refers to methanol
  • MTBE refers to methyl tert-butyl ether
  • MeTHF refers to methyltetrahydrofuran
  • Ph2PK refers to potassium diphenylphosphide
  • TAA triethylamine
  • TFA trifluoroacetic acid
  • TH methyltetrahydrofuran
  • Scheme 1 Commercial Synthesis of an SSTR4 Agonist
  • Ring A, R n , and Y are as defined earlier.
  • step A depicts a coupling mixing compound (1) with methyl 4- bromobut-2-enoate using an appropriate base such as potassium carbonate and potassium iodide in a suitable solvent such as MeCN at a suitable temperature (e.g., 30 to 60 oC) to give compound (2).
  • step B shows the deprotection of compound (2) using an acid such as TFA in solvents such as MeCN to give compound (3).
  • Step C shows a cyclization mixing compound (3) using (2-haloethyl)diphenylsulfonium such as (2- bromoethyl)diphenylsulfonium triflate in presence of base KOH, KF, and a suitable solvent such as 2-MeTHF to give compound (4).
  • step D water, and a base such as LiOH are used to convert compound (4) to compound (5).
  • Step E shows a coupling mixing compound (5) with a heteroaryl or aryl compound such as 2-(1-methyl-1H- indazol-3-yl)propan-2-amine or 2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-amine in the presence of a catalyst such as COCl 2 and solvents such as DMF, toluene, and DCM to give compound (6).
  • Step F shows conversion of compound (6) to compound (7) by reacting compound (6) with Ph2PK in a solvent such as MTBE or THF under a suitable temperature (e.g., heating from 60 to 70 oC) to give compound (7).
  • Step G shows the method of generating a salt with a method such as reaction with an acid, salt metathesis reaction, and/or other reactions that can result in the formation of a pharmaceutically acceptable salt (8).
  • the salt can include for example citrate, succinate, adipate, tartrate, L-tartrate, malate, and/or L-malate anions.
  • Preparation 1 [0177] Methyl (E)-4-((N-(tert-butoxycarbonyl)-4-methylphenyl)sulfonamido)but- 2-enoate Methyl 4-bromobut-2-enoate (36.29 g, 202.7 mmol) was dissolved in MeCN (500 mL) at 15 ⁇ 25 oC.
  • tert-Butyl tosylcarbamate (50.00 g, 184.3 mmol), K2CO3 (30.57 g, 221.2 mmol) and KI (3.06 g, 202.7 mmol) were added to the solution at 15 ⁇ 25 oC, and warmed under nitrogen at 30 oC for 20 hrs. The solution was cooled to 20 oC and the mixture filtered. The filtered residue was washed with MeCN (100 mL) to give the title product as a solution to be used directly in the next step without isolation.
  • reaction solution was concentrated in vacuo to ⁇ 50 mL and solvent exchanged with toluene (2 x 250 mL). Toluene (500 mL) was added followed by EtOAc (50 mL) at 15-25 oC, and heated to 60 oC for 1 hr., then cooled to 0 oC for 12 hrs. The solution was filtered, and the wet cake rinsed with n-heptane (50 mL). The cake was dried in vacuum at 50 oC to give the title compound (37.85 g, 74.4%) as a white solid.
  • the mixture was heated at 50 °C for 30 minutes. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residual was co-evaporated with THF (2 x 600 mL). THF (1350 mL) was added to the residual, followed by addition of TEA (145.7 g, 1443 mmol), DMAP (2.93 g, 24 mmol) and 2-(1-methyl-1H-indazol-3-yl)propan-2-amine (CAS No.1539323-37-9, 100 g, 529.1 mmol) at 0 °C. The reaction was stirred at 0 °C for 15 minutes, then at ambient temperature for 2 hrs.
  • the resulting potassium diphenylphosphine solution was then transferred to a solution of compound (1R,5S,6r)-N-(2-(1-methyl-1H-indazol-3-yl)propan-2-yl)-3-tosyl-3- azabicyclo[3.1.0]hexane-6-carboxamide (110 g, 243 mmol) in anhydrous THF (1500 mL) at 66 °C.
  • the fresh prepared potassium diphenylphosphine solution was added every 1.5 hrs.
  • the reaction was stirred at 66 °C for additional 16 hrs.
  • the reaction mixture was adjusted to pH 1 with 3.0 M HCl (650 mL). The volatiles were removed under reduced pressure.
  • the aqueous solution was washed with EtOAc (600 mL and 5 x 300 mL). The aqueous layer was adjusted to pH 8 with saturated potassium carbonate, and extracted with DCM (600 mL), then adjusted to pH 12 with saturated potassium carbonate and extracted with DCM (6 x 300 mL). The combined organic layers were dried over sodium sulfate (100 g), filtered, and concentrated under reduced pressure. The residue was purified using column chromatography eluting with 10% DCM in MeOH with 10% ammonium hydroxide to give the title product (62.77 g, 87% yield) as off-white solid.
  • Example 2 [0196] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide monohydrate [0198] Preparation of monohydrate (30 g) was placed in a reactor vessel with a 100 mL of ACN/H2O (20:80). The suspension was mixed at room temperature and isolated after 24 hours of mixing.
  • Example 3 [0200] (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide succinate [0202] 200 mg of (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide was dissolved in 3 mL of IPA at 40 oC. 67 mg of succinic acid (1.1 mol) was added in 3 mL IPA. A suspension was produced and cooled to room temperature for isolation.
  • adipic acid (1 mol) was added to the solution. After acid addition a suspension was produced and cooled to room temperature for isolation Scale up procedure used 15.4 grams of (1R,5S,6r)-N-(2-(1-Methyl-1H-indazol-3-yl)propan-2-yl)-3- azabicyclo[3.1.0]hexane-6-carboxamide dissolved in 225ml of IPA at 50 oC. 9.1 g of adipic acid was added and seeded with the small-scale lot. The seeds were held for crystal growth. The suspension was cooled to room temperature. The solids were isolated by vacuum filtration and dried to give the adipate salt.
  • X-Ray Powder diffraction (XRPD) method [0208] The XRPD patterns of crystalline solids are obtained on a Bruker D8 Endeavor X-ray powder diffractometer, equipped with a CuK ⁇ (1.5418 ⁇ ) source and a LynxeyeTM detector, operating at 40 kV and 40 mA. The sample is scanned between 4 and 422 ⁇ °, with a step size of 0.0092 ⁇ ° and a scan rate of 0.5 seconds/step, and using 0.3° primary slit opening, and 3.9° PSD opening. The dry powder is packed on a quartz sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity.
  • Crystal peak positions are determined in MDI-Jade after whole pattern shifting based on an internal NIST 675 standard with peaks at 8.853 and 26.7742 ⁇ °. It is well known in the crystallographic art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly.
  • peak positions can shift due to a variation in the temperature at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard.
  • a peak position variability of ⁇ 0.22 ⁇ ° is presumed to take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks.
  • Example 2 A prepared sample of Example 2 is characterized by an XRPD pattern using CuK ⁇ radiation as comprising diffraction peaks (2-theta values) as described/shown in Table 1, Table 2, and FIG.1, and, in particular, comprising a peak at diffraction angle 2- theta of 10.1 o and one or more of peaks 12.8 o, 17.3 o, or 21.9 o; with a tolerance for the diffraction angles of 0.2 degrees.
  • Example 3 A prepared sample of Example 3 is characterized by an XRPD pattern using CuK ⁇ radiation as comprising diffraction peaks (2-theta values) as described/shown in TABLE 3, TABLE 4, and FIG.2, and in particular comprising a peak at diffraction angle 2-theta of 22.6 o and one or more of peaks 12.9 o, 14.8 o, or 18.2 o; with a tolerance for the diffraction angles of 0.2 degrees.
  • Example 4 A prepared sample of Example 4 is characterized by an XRPD pattern using CuK ⁇ radiation as comprising diffraction peaks (2-theta values) as described/shown in TABLE 5, TABLE 6, and FIG.3, and in particular comprising a peak at diffraction angle 2-theta of 11.5 o and one or more of peaks 12.2 o, 18.0 o, or 22.4 o; with a tolerance for the diffraction angles of 0.2 degrees. TABLE 1. X-ray powder diffraction peaks of Example 2 arranged by angle

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Abstract

L'invention concerne un procédé de préparation de composés agonistes de SSTR4. L'invention se rapporte à un procédé de préparation de composés agonistes de SSTR4 par une réaction de cyclisation sélective diastéréomériquement sans nécessiter d'étape d'épimérisation séparée. L'invention concerne également de nouveaux intermédiaires pour la préparation de composés agonistes de SSTR4. L'invention concerne en outre de nouveaux sels de certains agonistes de SSTR4, tels que (1R,5S,6r)-N-(2-(1-méthyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3,1,0]hexane-6-carboxamide succinate et que (1R,5S,6r)-N-(2-(1-méthyl-1H-indazol-3-yl)propan-2-yl)-3-azabicyclo[3,1,0]hexane-6-carboxamide adipate. L'invention concerne également des méthodes de traitement de la douleur, tels que la douleur ostéoarthritique, la douleur neuropathique et la douleur du bas du dos par l'administration de certains agonistes de SSTR4 et de sels pharmaceutiquement acceptables de ceux-ci.
PCT/US2024/018591 2023-03-10 2024-03-06 Procédés de préparation agonistes de sstr4 et de sels de ceux-ci Pending WO2024191675A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2014184275A1 (fr) 2013-05-17 2014-11-20 Boehringer Ingelheim International Gmbh Nouveaux agonistes du récepteur de somatostatine de sous-type 4 (sstr4)
WO2021233427A1 (fr) 2020-05-21 2021-11-25 广州费米子科技有限责任公司 Composés cycliques condensés, leur procédé de préparation, compositions pharmaceutiques et leur utilisation
WO2022012534A1 (fr) 2020-07-13 2022-01-20 广州费米子科技有限责任公司 Composé hétérocyclique contenant de l'azote, composition pharmaceutique et applications

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014184275A1 (fr) 2013-05-17 2014-11-20 Boehringer Ingelheim International Gmbh Nouveaux agonistes du récepteur de somatostatine de sous-type 4 (sstr4)
WO2021233427A1 (fr) 2020-05-21 2021-11-25 广州费米子科技有限责任公司 Composés cycliques condensés, leur procédé de préparation, compositions pharmaceutiques et leur utilisation
WO2022012534A1 (fr) 2020-07-13 2022-01-20 广州费米子科技有限责任公司 Composé hétérocyclique contenant de l'azote, composition pharmaceutique et applications

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THE UNITED STATES PHARMACOPEIA, vol. 23, no. 18, 1995, pages 1843 - 1844

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