SSTR4 agonist salts

Abstract

To provide alternative solid-state forms of selective SSTR4 agonists with improved stability in excipients and favorable flow and bulk properties for the manufacturing of active pharmaceutical products and drug products.SOLUTION: The present invention relates to a specific organic acid salt of a compound represented by the formula in the figure, and a hydrate comprising the salt. Pharmaceutical compositions comprising these are useful for the prevention or treatment of medical disorders associated with SSTR4.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to novel SSTR4 agonist salts, pharmaceutical compositions containing such salts, methods of treating physiological disorders using such salts, and intermediates useful in the synthesis of such salts.

Background Art

[0002] Somatostatin or somatotropin release-inhibiting factor (SRIF) is a cyclic peptide found in humans. It is widely produced in the human body and acts both systemically and locally to inhibit the secretion of various hormones, growth factors, and neurotransmitters. The effects of somatostatin are mediated by a family of five known subtypes of G protein-coupled receptors. These subtypes are divided into two subfamilies, the first subfamily including SSTR2, SSTR3, and SSTR5, and the second subfamily including SSTR1 and SSTR4.

[0003] Somatostatin is involved in the regulation of processes such as cell proliferation, glucose homeostasis, inflammation, and pain. In this regard, somatostatin or other members of the somatostatin peptide family are thought to inhibit nociceptive and inflammatory processes via the SSTR4 pathway. Many additional therapeutic areas for SSTR4 agonists are being discussed (e.g., Crider, A; Mini Rev. Med. Chem. 2002, 7, 213 and references therein, International Publication No. 2010 / 059922 and references therein).

[0004] International Publication No. 2014 / 184275 discloses certain 3-azabicyclo[3.1.0]hexane-6-carboxamide derivatives that are SSTR4 agonists and are useful for preventing or treating medical disorders related to SSTR4.

[0005] There is a need for alternative solid state forms of selective SSTR4 agonists that have improved stability in excipients and favorable flow and bulk properties for the manufacture of active pharmaceutical and drug products.

Summary of the Invention

[0006] Accordingly, the present invention provides a compound of formula I,

Chemical Formula

[0007] The present invention further provides a compound of formula I that is not a hydrate.

[0008] The present invention further provides a compound of formula I that is a hydrate. The present invention further provides a compound of formula I that is a hydrate and has a water content in the range of 3 wt% to 9 wt% at ambient temperature.

[0009] The present invention further provides a compound of formula Ia below.

Chemical Formula

[0010] The present invention further provides a compound that is (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate. Further, the present invention provides a compound that is crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate

[0011] The present invention also provides a compound of formula II below.

Chemical Formula

[0012] The present invention further provides a compound which is (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide citrate. Further, the present invention provides a compound which is crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide citrate.

[0013] The present invention further provides a compound of formula III below. [Chemical formula]

[0014] Furthermore, the present invention provides a compound which is (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-malate. The present invention further provides a compound which is crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-malate.

[0015] The present invention provides a crystalline form of a compound of formula Ia, which is characterized by an X-ray powder diffraction pattern using CuKα radiation, including a peak at a diffraction angle 2 theta of 15.2°, and one or more peaks at 10.6° and 21.9° (±0.2° respectively).

[0016] The present invention further provides a crystalline form of a compound of formula II, which is characterized by an X-ray powder diffraction pattern using CuKα radiation, including a peak at a diffraction angle 2 theta of 20.8°, and one or more peaks at 10.3°, 16.2° and 5.4° (±0.2° respectively).

[0017] The present invention further provides a crystalline form of the compound of formula III, characterized by an X-ray powder diffraction pattern using CuKα radiation, comprising a peak at a diffraction angle 2θ of 18.1°, and one or more peaks at 4.9° and 17.3° (±0.2° respectively).

[0018] The present invention further provides a pharmaceutical composition comprising a compound of formula I or its hydrate, formula Ia, formula II or formula III, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In certain embodiments, the composition further comprises one or more therapeutic agents.

[0019] The present invention provides a method for treating pain in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, or a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention provides a method for treating chronic back pain including chronic low back pain in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III or a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. The present invention further provides a method for treating neuropathic pain in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, or a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, together with one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, the neuropathic pain is painful diabetic peripheral neuropathy. The present invention further provides a method for treating pain associated with osteoarthritis in a patient, comprising administering to a patient in need of such treatment a pharmaceutical composition comprising an effective amount of a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, or a compound of formula I or a hydrate thereof, formula Ia, formula II or formula III, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0020] Furthermore, the present invention provides a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III for use in therapy. In addition, the present invention provides a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III for use in the treatment of pain. The present invention further provides a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III for use in the treatment of chronic back pain including chronic low back pain. The present invention further provides a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III for use in the treatment of neuropathic pain. In some embodiments, the neuropathic pain is painful diabetic peripheral neuropathy. The present invention further provides a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III for use in the treatment of pain associated with osteoarthritis.

[0021] Furthermore, the present invention provides the use of a compound of formula I or a hydrate thereof, formula Ia, formula II, or formula III in the manufacture of a medicament for the treatment of a disease or condition selected from pain, chronic back pain (including chronic low back pain), neuropathic pain, and pain associated with osteoarthritis. In some embodiments, the neuropathic pain is painful diabetic peripheral neuropathy.

[0022] The present invention further encompasses novel intermediates for the synthesis of a compound of formula I or a hydrate thereof, and novel processes for the synthesis of a compound of formula I or a hydrate thereof, formula Ia, formula II, and formula III.

DETAILED DESCRIPTION OF THE INVENTION

[0023] As used herein, the term "hydrate" refers to a solid addition product containing a compound or a salt thereof and water, wherein water molecules are incorporated into the crystal lattice of the compound or the salt thereof. As used herein, the term "sesquihydrate" refers to a hydrate of a compound or a salt thereof, wherein the stoichiometric ratio of water to the compound or the salt thereof is 1.5:1.

[0024] As used herein, the term "treat" or "treating" includes inhibiting, slowing, halting, or reversing the progression or severity of an existing condition or disorder.

[0025] As used herein, 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.

[0026] As used herein, the term "effective amount" refers to the amount or dosage of a compound of the present invention that, when administered to a patient in single or multiple doses, provides the desired effect in the patient being diagnosed or treated.

[0027] Effective amount can be easily determined by those skilled in the art using known techniques.When determining the effective amount for a patient, several factors are taken into consideration, including but not limited to the patient's species, its size, age and general health condition; the specific disease or disorder involved; the extent or involvement or severity of the disease or disorder; the response of the individual patient, the specific compound administered, the mode of administration; the bioavailability characteristics of the administered preparation; the selected administration regimen; the use of concomitant medications; and other relevant circumstances.

[0028] The compounds of the present invention are preferably formulated as pharmaceutical compositions to be administered by any route that makes the compounds bioavailable, including the oral route. More preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for their preparation are well known in the art (e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23 rd Edition, Elsevier Academic Press, 2020).

[0029] The compounds of the present invention can be prepared according to the following preparations and examples by methods well known and understood in the art. Suitable reaction conditions for the steps of these preparations and examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the scope of the art. Similarly, one of ordinary skill in the art will understand that synthetic intermediates can be isolated and / or purified by various well-known techniques as needed or desired, and in many cases, can be used directly in subsequent synthetic steps without substantially or fully purifying the various intermediates. By way of example, the compounds of the preparations and examples can be isolated, for example, by silica gel purification or can be isolated directly by filtration or crystallization. Further, one of ordinary skill in the art will understand that in some circumstances, the order in which moieties are introduced is not important. The specific order of steps required to produce the compounds of the present invention depends on the specific compound being synthesized, the starting compounds, and the relative disadvantages of the substituents and is well understood by the skilled chemist. All substituents are as previously defined unless otherwise indicated, and all reagents are well known and understood in the art.

[0030] Certain abbreviations are defined as follows. "APCI" refers to atmospheric pressure chemical ionization. "BOC" represents tert-butyloxycarbonyl. "BSA" represents bovine serum albumin. "cAMP" represents cyclic adenosine monophosphate. "CTL" represents control. "DAD" represents diode array detection. "DCM" represents dichloromethane. "DIPEA" represents N,N-diisopropylethylamine. "DMF" represents N,N-dimethylformamide. "DMSO" represents dimethyl sulfoxide. "EDTA" represents ethylenediaminetetraacetic acid. "EtOAc" represents ethyl acetate. "HATU" represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate. "HBSS" represents Hank's balanced salt solution. "HEPES" represents 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid. "h" represents time / s. "HPLC-MS" represents high performance liquid chromatography-mass spectrometry. "hSSTR" means human somatostatin receptor. "IPA" represents isopropyl alcohol. "min" represents minute. "MS" represents mass spectrometry. "IBMX" represents 1-methyl-3-(2-methylpropyl)-7H-purine-2,6-dione. "m / z" represents mass-to-charge ratio. "MTP" represents microtiter plate. "R t " represents retention time. "NADPH" represents nicotinamide adenine dinucleotide phosphate. "RT" represents room temperature. "rpm" represents revolutions per minute. "TRIS" represents 2-amino-2-(hydroxymethyl)propane-1,3-diol. "UPLC" represents ultra performance liquid chromatography. "v / v" represents volume / volume.

[0031] [Chemical formula] Scheme 1 shows a general method for the synthesis of (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide.

[0032] In step A, 2-methylpropan-1-ol is deprotonated at low temperature using sodium hydride. The resulting anion is then reacted in situ with 2-fluoro-3-methylpyridine at high temperature to give 2-methyl-1-[(3-methyl-2-pyridyl)oxy]propan-2-amine. One skilled in the art will recognize that many alternative bases can be used for the deprotonation of 2-methylpropan-1-ol and that alternatively, the reaction can be carried out as a one-pot procedure using a milder base.

[0033] In step B, 2-methyl-1-[(3-methyl-2-pyridyl)oxy]propan-2-amine is reacted with (1R,5S,6r)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid in the presence of an organic base and the amide coupling reagent HATU to give tert-butyl (1R,5S,6r)-6-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate. One skilled in the art will recognize that a number of different amide coupling reagents and organic bases can be used to achieve this amide formation.

[0034] In the final step C, tert-butyl (1R,5S,6r)-6-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate is subjected to BOC deprotection using microwave irradiation at a high temperature in a mixture of methanol and water to obtain (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide. Those skilled in the art will be aware of numerous alternative methods for carrying out BOC deprotection. A comprehensive list of such methods can be found, for example, in the following. Wuts, P.G.M. and Greene, T.W. (2006), Protective groups in organic synthesis, Hoboken, N.J.: Wiley.

[0035] LC-MS Method 1 Equipment: LC / MS Thermo Scientific™ Finnigan, HPLC Surveyor DAD, MSQ Plus™ single quadrupole. Column: Synergi™ Hydro-RP 100Å, 2.5μm, 3×50mm. Mobile phase: A = H2O 90% + 10% CH3CN + 10 mM NH4COOH, B = CH3CN 90% + H2O 10% + 10 mM NH4COOH. Gradient: 0.0 min 0% B → 4.00 min 100% B → 5.30 min 100% B → 5.50 min 0% B → 6.00 min 0% B. Flow rate: 1.2 mL / min. Detection: UV254nm. Ion source: APCI+ / APCI-.

[0036] LC-MS Method 2 LC-MS Method 2: Instrument: LC / MS Waters Acquity® UPLC System DAD, SQD single quadrupole. Column: BEH C18 1.7 μM 2.1×50 mm, temperature 35 °C. Mobile phase: A = 90% H2O + 10% CH3CN + 5 mmol NH4COOH, B = 90% CH3CN + 10% H2O. Gradient: 0.0 min 0% B → 1.20 min 100% B → 1.45 min 100% B → 1.55 min 0% B → 1.75 min 0% B. Flow rate: 0.70 mL / min. Detection: UV254 nm. Detection: SQD single quadrupole. Ion source: ES+ / ES-. Scan range: 90 - 900 amu.

[0037] Preparation 1 2-Methyl-1-[(3-methyl-2-pyridyl)oxy]propan-2-amine.

Chem.

[0038] 2-Amino-2-methyl-propan-1-ol (11 mL, 118.8 mmol) was dissolved in dioxane (20 mL), and sodium hydride (60% suspension in mineral oil, 5.0 g, 124.7 mmol) was added portionwise at 0 °C. After 15 minutes, 2-fluoro-3-methyl-pyridine (3 mL, 29.7 mmol) was added. The resulting mixture was heated at 100 °C for 1 hour. The reaction was diluted with DCM and washed with water. The organic layer was separated, dried, and evaporated under reduced pressure to give the title compound (5.1 g, 95%), which was used as such. HPLC-MS (Method 1): R t = 1.78 min, MS (APCI): m / z = 181 (M + H) + .

[0039] Preparation 2 tert-Butyl (1R,5S,6r)-6-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate.

Chem.

[0040] (1R,5S,6r)-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (6.4 g, 28.3 mmol) (commercially available from ACBR or WuXi AppTec) in DMF (10 mL) was added to 2-methyl-1-[(3-methyl-2-pyridyl)oxy]propan-2-amine (5.1 g, 28.3 mmol), HATU (10.8 g, 28.3 mmol) and DIPEA (15.5 g, 56.589 mmol), and stirring was continued for 3 hours. The volatiles were evaporated under reduced pressure. EtOAc was added and the reaction mixture was washed with saturated NaHCO3 solution and then brine. The organic layer was separated by a phase separation cartridge, the solvent was evaporated to give a residue, which was purified by flash chromatography (eluent 20 - 50% EtOAc / cyclohexane) to give the title compound (8.4 g, 76%). HPLC-MS (Method 1): R t = 3.30 min, MS (APCI): m / z = 390 (M + H) + 。

[0041] Preparation 3 (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide

Chemical Structure

[0042] tert-Butyl (1R,5S,6r)-6-((2-methyl-1-((3-methylpyridin-2-yl)oxy)propan-2-yl)carbamoyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (13 g, 33.4 mmol) was suspended in methanol / water 1:1 v / v (35 mL / 35 mL), divided into seven equal batches, and heated under microwave irradiation for 70 minutes (150 °C). The solvent was removed under reduced pressure to give a residue, which was purified by flash chromatography (eluent 100% DCM~93:7:0.7 DCM / methanol / NH3) to give the title compound (7.0 g, 72%). LC-MS (method 2): R t = 0.68 min, MS (ESI pos): m / z = 290 (M+H) + 。

[0043] Preparation 4 (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate

Chemical formula

[0044] (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (5.5 g, 18.4 mmol) was added to IPA (68 mL) and water (2 mL). The mixture was heated to 65 °C, at which point dissolution occurred. Then, L-tartaric acid (2.86 g, 19.1 mmol) in IPA (34 mL) and water (1.5 mL) was added to the solution. The solution was then cooled to room temperature overnight. The resulting white solid was isolated by vacuum filtration, washed with ice-cold IPA (20 mL) to give the title compound (5.7 g, 70%).

[0045] Example 1 Crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate sesquihydrate [Chem.]

[0046] (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-tartrate (60 g, 136.5 mmol) was transferred to a 250 mL reaction vessel, and THF / water 95:5 v / v was added to make a volume of 225 mL. The mixture was heated to 60 °C, and water was added in 1 mL aliquots until the starting material was completely dissolved (total 8 mL of water). The reactor was cooled naturally, and the mixture was stirred at room temperature over the weekend. The resulting crystals were isolated by vacuum filtration and air-dried for several days. The obtained solid was sieved to give the title compound (42.3 g, 66%).

[0047] Example 2 Crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide citrate [Chem.] <C

[0048] (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (10.8 g, 33 mmol) is dissolved in absolute ethanol (200 mL) while stirring at 60 °C at 300 rpm. This solution is filtered through a 0.65 μm nylon filter to obtain a clear solution. When the solution is stirred for 5 minutes, a solid precipitate forms. A solution of citric acid (7.06 g, 36 mmol) dissolved in absolute ethanol (60 mL) at 60 °C is prepared. The citric acid solution is added slowly at 60 °C. The mixture is filtered through a 0.45 μm syringe filter maintained at 60 °C. Then the heating is stopped, the mixture is stirred at 500 rpm and gradually cooled to room temperature. When it is completely equilibrated to room temperature, a very thick white slurry (cake) is obtained. The flask is rinsed with absolute ethanol (5 × 10 mL) to wash the cake. The cake solid is isolated on a nylon membrane under vacuum, dried under nitrogen, and then dried under vacuum at 70 °C overnight to obtain the title compound as a white solid (16.8 g, 98%).

[0049] Example 3 Crystalline (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide L-malate

Chem.

[0050] (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (25 g, 88 mmol) is added to 100 mL of isopropanol while stirring at approximately 400 rpm. The sample is heated to 60 °C. Then, 14.6 mL of an aqueous L-malic acid solution (109 mmol) is added. A clear yellowish solution is formed. The mixture is cooled to room temperature. Since oiling out was observed, phase separation is evaporated to dryness under a nitrogen stream. The solid residue is suspended in acetone and water and recrystallized at 55 °C. 25 g of the free base equivalent material is recrystallized in 200 ml of acetone and 15 mL of water (total 215 mL of solvent). The solid is isolated from the reaction vessel at room temperature using a Buchner funnel under reduced pressure. The white cake is rinsed with acetone and dried at 50 °C under vacuum to give the title compound (21 g, 57%).

[0051] X-ray Powder Diffraction (XRPD) Method 1 The XRPD pattern of the crystalline solid is obtained on a Bruker D8 Endeavor X-ray powder diffractometer operating at 40 kV and 40 mA, equipped with a CuKα (1.5418 Å) source and a Lynxeye™ detector. The sample is scanned from 4 to 42 2θ° with a step size of 0.009 2θ° and a scan rate of 0.5 s / step, using a primary slit aperture of 0.3° and a particle size distribution (PSD) aperture of 3.9°. The dry powder is filled into a quartz sample holder, and a smooth surface is obtained using a glass slide. The crystalline form diffraction pattern is collected at ambient temperature and relative humidity. The crystalline peak positions are determined with MDI-Jade after global pattern shift based on an internal NIST 675 standard having peaks at 8.853 and 26.774 2θ°. In the field of crystallography, it is well known that for any given crystalline form, the relative intensities of the diffraction peaks can vary due to preferred orientations arising from factors such as crystalline form and crystal habit. When the effect of preferred orientation is present, the peak intensities are modified, but the characteristic peak positions of the polymorphs remain invariant. See, for example, The United States Pharmacopeia#23, National Formulary#18, pages 1843 - 1844, 1995. Further, it is also well known in the field of crystallography that for any given crystalline form, the angular peak positions can vary slightly. For example, the peak positions can be shifted by temperature fluctuations at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variability of ±0.2 2θ° is estimated to account for these potential variations without preventing the clear identification of the indicated crystalline form. The confirmation of the crystalline form can be made based on any unique combination of characteristic peaks.

[0052] X-ray Powder Diffraction (XRPD) Method 2 The XRPD pattern of the crystalline solid was obtained on a Bruker D4 Endeavor X-ray powder diffractometer operating at 35 kV and 50 mA with a CuKα (1.5418 Å) source and a Vantec™ detector. The sample was scanned from 4 to 40 2θ° using a 1.0 mm divergence slit, a 6.6 mm fixed anti-scatter slit, and an 11.3 mm detector slit, with a step size of 0.008 2θ° and a scan speed of 0.5 seconds / step. The dry powder was filled into a quartz sample holder, and a smooth surface was obtained using a glass slide. The diffraction pattern of the crystalline form was collected at ambient temperature and relative humidity. The crystalline peak positions were determined using MDI-Jade after global pattern shifting based on an internal NIST 675 standard having peaks at 8.853 and 26.774 2θ°. In the field of crystallography, it is well known that for any given crystalline form, the relative intensities of diffraction peaks can vary due to preferred orientations arising from factors such as crystal form and crystal habit. When the effect of preferred orientation is present, the peak intensities are modified, but the characteristic peak positions of the polymorphs remain invariant. See, for example, The United States Pharmacopeia#23, National Formulary#18, pages 1843-1844, 1995. Further, it is also well known in the field of crystallography that for any given crystalline form, the angular peak positions can vary slightly. For example, the peak positions can be shifted by fluctuations in the temperature at which the sample is analyzed, sample displacement, or the presence or absence of an internal standard. In this case, a peak position variability of ±0.2 2θ° is estimated to account for these potential variations without preventing the unambiguous identification of the indicated crystalline form. Confirmation of the crystalline form can be made based on any unique combination of characteristic peaks.

[0053] XRPD of Example 1 XRPD method 1 was used in Example 1. The prepared sample of Example 1 is characterized in that the XRPD pattern using CuKα radiation includes diffraction peaks (2θ values) described in Table 1 below, and in particular, includes a peak at a diffraction angle 2θ of 15.2°, and one or more of the peaks at 10.6° and 21.9°. It has an allowable error of the diffraction angle of 0.2 degrees.

Table 1

[0054] XRPD of Example 2 XRPD method 2 was used in Example 2. The prepared sample of Example 2 is characterized in that the XRPD pattern using CuKα radiation includes diffraction peaks (2θ values) described in Table 2 below, and in particular, includes a peak at a diffraction angle 2θ of 20.8°, and one or more of the peaks at 10.3°, 16.2°, and 5.4°. It has an allowable error of the diffraction angle of 0.2 degrees.

Table 2

[0055] XRPD of Example 3 XRPD method 2 was used in Example 3. The prepared sample of Example 3 is characterized in that the XRPD pattern using CuKα radiation includes diffraction peaks (2θ values) described in Table 3 below, and in particular, includes a peak at a diffraction angle 2θ of 18.1°, and one or more of the peaks at 4.9° and 17.3°. It has an allowable error of the diffraction angle of 0.2 degrees.

Table 3

[0056] cAMP assay Activation of the SSTR4 receptor (G-coupled) causes inhibition of intracellular cAMP after stimulation with forskolin and can be quantified by using an appropriate assay kit and an appropriate plate reader. This technique is used to characterize the pharmacological effects of SSTR4 receptor agonists by using hSSTR4-expressing H4 cells. Compounds are dissolved and diluted in DMSO. The final test solution contains 1% DMSO. cAMP standards (Lance™ cAMP 384 kit, PerkinElmer, catalog number AD0264) are prepared in assay buffer (HBSS containing 0.1% BSA, 5 mM HEPES, 0.5 M IBMX, pH 7.4) containing 1% DMSO, and a cAMP standard curve is included on at least one plate.

[0057] Centrifuge the cells and resuspend them in assay buffer (containing 1:100 diluted Alexa Fluor® antibody). For the assay, add 5 μL of the cell suspension (approximately 5000 cells / well) containing the Alexa Fluor® antibody (1:100 dilution) to a 384-well MTP microtiter plate, excluding one row or column reserved for the standard curve (depending on the plate layout). Then, add 2 μL of the compound sample, usually in triplicate, as a concentration-response curve (e.g., 1e-5 M to 6e-10 M). Each assay includes incubation with a vehicle control instead of the compound as a control for non-inhibited cAMP production (100% CTL, "high value") and incubation with 1 μM somatostatin as a control for complete inhibition and background (0% CTL, "low value"). After an incubation time of about 10 - 15 minutes, add 3 μL of forskolin (dissolved in DMSO, final concentration 15 μM). Then, briefly shake the plate and incubate at room temperature for 60 minutes. After 60 minutes, add 10 μL of the detection mixture to all wells and continue with an additional incubation period of 1 hour. Read the plate with an appropriate plate reader. Data analysis is based on the "ratio" of time-resolved fluorescence measurements of the donor fluorophore and the acceptor fluorophore (Ex: 320 nm, Em1: 665 nm, Em2: 615 nm, ratio 665 / 615). From this ratio, the cAMP concentration is calculated from the standard curve and the EC 50 is estimated by a least-squares curve fitting program. The free bases of Examples 1, 2, and 3 were mainly tested as follows.

[0058]

Table 4

[0059] Selectivity In the competition experiment, the unlabeled test compound competes with the binding site of the labeled ligand. Substitution of the labeled ligand by the test compound results in a decrease in signal. For the binding experiment, 200 μL of membrane homogenate from one of the following protein amounts is used: hSSTR1 (40 μg / well), hSSTR2 (25 μg / well), hSSTR3 (1.5 μg / well), hSSTR4 (0.5 μg / well), hSSTR5 (25 μg / well). The homogenate is incubated at room temperature for 180 minutes with 0.05 nM of radioactive ligand ([3-125I-Tyr]-somatostatin-(1-14)) in a total volume of 250 μL with increasing concentrations of the test compound or vehicle (100% binding), using Hepes buffer (10 mM, EDTA 1 mM, MgCl2 5 mM, pH 7.6, BSA 0.5%, bacitracin 0.003%, DMSO 1%). Incubation is terminated by filtration through a polyethyleneimine-treated (0.3%) grade GF / B glass fiber filter with ice-cold 0.9% NaCl using a cell harvester. The radioactivity bound to the protein is measured with an appropriate reader. Nonspecific binding is defined as the radioactivity bound in the presence of 1 μM somatostatin-14 during the incubation period. Analysis of the concentration-binding curve is performed by computer-assisted non-linear least squares curve fitting using a model of one receptor binding site.

[0060]

Table 5

[0061] Stability test (1S,5R)-(1α,5α,6α)-N-[1,1-Dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (Tablet A), the prototype tablets of Example 1 (Tablet B) and Example 3 (Tablet C) were prepared according to the formulations shown in Table 6, Table 7 and Table 8, respectively.

Table 6

Table 7

Table 8

[0062] The tablets were subjected to stability testing according to the ICH guidelines using accelerated storage conditions (40 °C / 75% RH) for periods of 1 week, 2 weeks, 4 weeks, 8 weeks and 12 weeks.

[0063] For chromatographic analysis, one tablet was dissolved in 50 / 50 mobile phase A / mobile phase B (see the following HPLC chromatographic conditions) to obtain a sample concentration of approximately 0.2 mg / mL as (1S,5R)-(1α,5α,6α)-N-[1,1-dimethyl-2-[(3-methyl-2-pyridyl)oxy]ethyl]-3-azabicyclo[3.1.0]hexane-6-carboxamide (free base). The sample was then analyzed by HPLC chromatography (XBridge™ BEH C18, 2.5 μm, 4.6 mm × 75 mm I.D., mobile phase: A = 99.9% H2O + 0.1% TFA, B = 99.9% CH3CN + 0.1% TFA, gradient: 0.0 min 5% B → 12.1 min 70% B → 13.0 min 95% B → 16.0 min 95% B → 16.1 min 5% B → 20.0 min 5% B, flow rate: 1.5 mL / min, column temperature: 30 °C, detection: UV220 nm, injection volume: 10 μL autosampler temperature: ambient temperature). For each sample tested, an individual standard curve was created.

[0064] Table 9 shows the total related substances percentage (TRS) formed during the stability testing.

Table 9

[0065] The results indicate that L-tartrate (Example 1, Tablet B) and L-malate (Example 3, Tablet C) have improved stability in the excipient under accelerated storage conditions compared to their respective free bases. Furthermore, the results indicate that L-tartrate (Example 1, Tablet B) has improved stability in the excipient compared to L-malate (Example 3, Tablet C).

Claims

1. A compound of the following formula, 【Chemical 1】 or a hydrate thereof, the compound.

2. The compound according to claim 1, which is a hydrate.

3. The compound according to claim 1 or 2, which is a hydrate and has a water content in the range of 3% to 9% by weight at ambient temperature.

4. The compound according to any one of claims 1 to 3, which is as follows: [Chemical 2]

5. The compound according to claim 4, which is crystalline.

6. The compound according to claim 1, which is as follows: 【Chemical 3】

7. A compound represented by the following formula: 【Chemical Formula 4】

8. The compound according to claim 7, which is crystalline.

9. A compound represented by the following formula: 【Chemical Formula 5】

10. The compound according to claim 9, which is crystalline.

11. The compound according to claim 4, which is crystalline and is characterized by an X-ray powder diffraction pattern using CuKα radiation, including a peak at a diffraction angle 2θ of 15.2° and one or more peaks at 10.6° or 21.9° (±0.2° each).

12. The compound according to claim 7, which is crystalline and is characterized by an X-ray powder diffraction pattern using CuKα radiation, including a peak at a diffraction angle 2θ of 20.8° and one or more peaks selected from 10.3°, 16.2°, or 5.4° (±0.2° each).

13. The compound according to claim 9, which is crystalline and is characterized by an X-ray powder diffraction pattern using CuKα radiation, including a peak at a diffraction angle 2θ of 18.1° and one or more peaks at 4.9° or 17.3° (±0.2° each).

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

15. A method of treating pain in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14.

16. A method of treating chronic back pain in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14.

17. A method for treating neuropathic pain in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14.

18. The method according to claim 17, wherein the neuropathic pain is diabetic peripheral neuropathic pain.

19. A method for treating pain associated with osteoarthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14.

20. A compound according to any one of claims 1 to 13 for use in therapy.

21. A compound according to any one of claims 1 to 13 for use in the treatment of pain.

22. A compound according to any one of claims 1 to 13 for use in the treatment of chronic back pain.

23. A compound according to any one of claims 1 to 13 for use in the treatment of neuropathic pain.

24. The compound for use according to claim 23, wherein the neuropathic pain is diabetic peripheral neuropathic pain.

25. A compound according to any one of claims 1 to 13 for use in the treatment of pain associated with osteoarthritis.

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