TRK-700

CAS 1463432-16-7C₁₄ H₂₄ N₄ O264.371-Propanone, 1-[4-(dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-

1-[4-(dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one

• 1-[4-(Dimethylamino)-1-piperidinyl]-3-(1-methyl-1H-imidazol-2-yl)-1-propanone

• OriginatorToray Industries
• ClassAnalgesics
• Mechanism of ActionUndefined mechanism

• Phase IIPostherpetic neuralgia
• PreclinicalPeripheral nervous system diseases

• 12 Sep 2018Pharmacodynamics data from a preclinical trial in Peripheral neuropathy presented at the 17^th World Congress on Pain (WCP-2018)
• 01 Jul 2017Toray Industries completes a phase II trial for Postherpetic neuralgia (In adults, In the elderly) in Japan (PO) (NCT02701374)
• 21 May 2017Toray Industries completes a phase I drug-drug interaction trial in Healthy volunteers in Japan (PO) (NCT03043248)

developed by Toray for treating neuropathic pain and investigating for fibromyalgia. In August 2021, this drug was reported to be in phase 1 clinical development.

PATENT

WO 2016136944

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016136944

(Reference Example 22) Synthesis of (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate:
[Chemical 56]


　1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, Methyl (triphenylphosphoranylidene) acetate (33.4 g, 99.9 mmol) was added to a solution of 90.8 mmol) in dichloromethane (240 mL) at room temperature, and the mixture was stirred for 16 hours and then concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 19/1, and the washing liquid was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give (E) -methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate as a white solid (11.9 g, 71. 6 mmol, 79%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 3.76 (3H, s), 3.81 (3H, s), 6.82 (1H, d, J = 15.6 Hz), 6.98 (1H, brs), 7.16 (1H, brs), 7.53 (1H, d, J = 15.6Hz).
ESI-MS: m / z = 167 (M + H) ⁺ .

(Reference Example 27) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 61]


　(E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propane. -1-one (0.179 g, 0.68 mmol, 63%) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) ⁺ .

(Comparative Example 1) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one hydrochloride:
[Chemical 66]


　1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (1.50 g, 5.67 mmol) diethyl ether (60) A dioxane solution of hydrogen chloride (4.0 M, 3.69 mL, 14.8 mmol) was added to the (0.0 mL) solution at 0 ° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 30 minutes. The precipitated white solid was collected by filtration, washed with diethyl ether (100 mL), dried at room temperature for 36 hours, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-). Imidazole-2-yl) propan-1-one hydrochloride (1.41 g, 4.18 mmol, 74%) (hereinafter, the compound of Comparative Example 1) was obtained as a white solid.
^{1 1} H-NMR (400 MHz, D ₂ O) δ: 1.53-1.80 (2H, m), 2.12-2.23 (2H, m), 2.68-2.80 (1H, m), 2.88 (6H, s), 3.01- 3.08 (2H, m), 3.15-3.26 (3H, m), 3.47-3.58 (1H, m), 3.84 (3H, s), 4.08-4.16 (1H, m), 4.50-4.59 (1H, m), 7.29-7.33 (2H, m).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) as propan-1-one : m / z = 265 (M + H) ⁺ .

(Comparative Example 2) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one sulfate monohydrate:
[Chemical 67]


　1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one (6.72 g, 25.4 mmol) Concentrated sulfuric acid (2.49 g, 25.4 mmol), water (1.83 g, 102 mmol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl) in a DMSO (100 mL) solution. Seed crystals (50 mg, 0.13 mmol) of -1H-imidazol-2-yl) propan-1-one sulfate monohydrate were added at 80 ° C. The reaction was stirred at the same temperature for 2.5 hours, at 50 ° C. for 2.5 hours and at room temperature for 15 hours. The precipitated white solid was collected by filtration, washed successively with DMSO (20 mL) and methyl ethyl ketone (40 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl). -1H-imidazol-2-yl) propan-1-one sulfate monohydrate (8.42 g, 22.1 mmol, 87%) (hereinafter, the compound of Comparative Example 2) was obtained as white crystals.
^{1 1} H-NMR (400 MHz, DMSO-d ₆₎) δ: 1.36 (1H, m), 1.58 (1H, m), 1.95 (2H, br), 2.44-2.57 (1H, m), 2.65 (6H, s), 2.74-2.88 (4H, m), 3.00 (1H, t, J = 12.0 Hz), 3.22 (1H, m), 3.61 (3H, s), 4.02 (1H, d, J = 14.0 Hz), 4.47 (1H, d, J = 12.8 Hz), 6.87 (1H, d, J = 1.2 Hz), 7.11 (1H, d, J = 1.2 Hz).
ESI-MS; 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-) As 1H-imidazol-2-yl) propan-1-one: m / z = 265 (M + H) ⁺ .

PATENT

WO-2021153744

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021153744&_cid=P10-KS5N4C-23080-1

PATENT

WO-2021153743

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021153743&tab=FULLTEXT&_cid=P10-KS5MS1-18911-1

Novel crystalline polymorphic form of 1-(4-(dimethylamino) piperidin-1-yl)-3-(1-methyl-1H-imidazol-2-yl)propan-1-one, useful as an analgesic in treating neuropathic pain and/or fibromyalgia.Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause. In addition, fibromyalgia is known as pain of unknown cause. 
　Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nervous tissue even though nociceptors are not stimulated. It refers to the pain that occurs. As a therapeutic agent for neuropathic pain, an anticonvulsant, an antidepressant, anxiolytic, or an antiepileptic drug such as gabapentin or pregabalin is used. 
　Fibromyalgia is a disease in which systemic pain is the main symptom and neuropsychiatric symptoms and autonomic nervous system symptoms are secondary symptoms. Pregabalin approved in the United States and Japan, duloxetine and milnacipran approved in the United States are mainly used as therapeutic agents for fibromyalgia, and non-approved agents for fibromyalgia are not approved. It has also been used for steroidal anti-inflammatory agents, opioid compounds, antidepressants, anticonvulsants and antiepileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally considered to be low (Non-Patent Document 1). 
　On the other hand, Patent Document 1 discloses that certain substituted piperidins have cardiotonic activity, and Patent Document 2 discloses that an imidazole derivative exhibits an FXa inhibitory effect. Patent Document 3 suggests that the substituted piperidins may have a medicinal effect on overweight or obesity, and Patent Documents 4 to 6 and Non-Patent Document 2 indicate that the imidazole derivative has an analgesic effect. It is disclosed. 
　In addition, the quality of pharmaceutical products needs to be maintained over a long period of time such as distribution and storage, and the compound as an active ingredient is required to have high chemical and physical stability. Therefore, as the active ingredient of a pharmaceutical product, a crystal that can be expected to have higher stability than an amorphous substance is generally adopted. Further, if crystals are obtained, a purification effect due to recrystallization during production can be expected. Further, it is preferable to have low hygroscopicity from the viewpoint of maintaining stability and handling during manufacturing, storage, formulation and analysis of the drug substance. In addition, since a drug needs to be dissolved in the digestive tract in order to exhibit its medicinal effect, it is preferable that the drug has excellent solubility, which is a physical property contrary to stability. 
　In order to obtain crystals of a compound that is an active ingredient of a pharmaceutical product, it is necessary to study various conditions for precipitating crystals from the solution. It is common to carry out crystallization under the condition of being dissolved in.

Patent documents

Patent Document 1: French Patent Invention No. 2567885
Patent Document 2: Japanese Patent Application Laid-Open No. 2006-0083664
Patent Document 3: International Publication No. 2003/031432
Patent Document 4: International Publication No. 2013/147160
Patent Document 5: International Publication No. 2015/046403
Patent Document 6: International Publication No. 2016/136944

Non-patent literature

Non-Patent Document 1: Okifuji et al., Pain and Therapy, 2013, Volume 2, p. 87-104
Non-Patent Document 2: Takahashi et al., Toxicological Pathology, 2019, Vol. 47. p. 494-503

Compound (I) was synthesized by the method described in the following reference example. For the compounds used in the synthesis of the reference example compounds for which the synthesis method is not described, commercially available compounds were used. 
(Reference Example 4) Synthesis of amorphous compound (I):
[Chemical formula 2] 2 of

crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanol (5.00 g, 27.4 mmol) Aqueous sodium hydroxide solution (1.0N, 30.2 mL, 30.2 mmol) was added to a solution of -propanol (55 mL) at 0 ° C., and the mixture was stirred at room temperature for 12 hours. 2-Propanol (220 mL) was added to the reaction solution at room temperature, and crude 4- (dimethylamino) piperidine (3.17 g, 24.7 mmol) and DMT-MM (8.35 g, 30.2 mmol) were added at room temperature to react. The liquid was stirred at the same temperature for 3 hours. A 10% aqueous sodium chloride solution and a 1.0N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound (I) (6.98 g) as an amorphous substance.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 (5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz) ), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) ⁺ .
(Reference Example 5) Synthesis of crude 4- (dimethylamino) piperidine:
[Chemical

formula 3] 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (20.1 g, 77.0 mmol) in methanol (154.0 mL) Palladium-carbon (10% wet, 2.01 g) was added thereto, and the mixture was stirred at room temperature for 19 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a crude product of 4- (dimethylamino) piperidine (9.86 g).
(Reference Example 6) Synthesis of crude ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate:
[Chemical

formula 4] Sodium hydride (55%, 4.36 g, 100 mmol) aqueous solution and tetrahydrofuran (150 mL) To the mixture was added triethylphosphonoacetate (19.1 mL, 95.0 mmol) at 0 ° C. After stirring the reaction solution for 20 minutes, a solution of 1-methyl-1H-imidazol-2-carbaldehyde (10.0 g, 91.0 mmol) in tetrahydrofuran (150 mL) was added at 0 ° C., and then ethanol (30 mL) was added in the same manner. The mixture was added at temperature and stirred at room temperature for 2 hours. A 10% aqueous sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, chloroform / methanol). After adding methanol (310 mL) to the residue, palladium-carbon (10% wet, 1.40 g) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (14.2 g) of ethyl 3- (1-methyl-1H-imidazol-2-yl) propanoate.
(Reference Example 7) Synthesis of 1-benzyloxycarbonyl-4- (dimethylamino) piperidine:
[Chemical

formula 5] dichloromethane (55.7 mL) of 1-benzyloxycarbonyl-4-oxopiperidine (13.0 g, 55.7 mmol) ) Solution of dimethylamine in tetrahydrofuran (2.0 M, 34.8 mL, 69.7 mmol), acetic acid (0.32 mL, 5.6 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). Added at ° C. After stirring the reaction solution at the same temperature for 30 minutes, sodium triacetoxyborohydride (4.8 g, 22.6 mmol) was added at 0 ° C. The reaction mixture was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (8.1 g, 38.2 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 12 hours. The reaction solution was cooled to 0 ° C. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) and then again by flash chromatography (silica gel, chloroform / methanol) to obtain 1-benzyloxycarbonyl-4- (dimethylamino) piperidine (dimethylamino) piperidine. 13.6 g, 51.8 mmol, 93%) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃) δ: 1.34-1.46 (2H, m), 1.78-1.86 (2H, m), 2.28 (6H, s), 2.29-2.34 (1H, m), 2.75-2.85 (2H, m), 4.14-4.28 ( 2H, m), 5.12 (2H, s), 7.29-7.36 (5H, m).
ESI-MS: m / z = 263 (M + H) ⁺ .
(Reference Example 8) Synthesis of 1-benzyloxycarbonyl-4-oxopiperidine:
[Chemical

formula 6] Hydrochloride (130 mL) and water (130 mL) of 4-piperidinone hydrochloride monohydrate (10.0 g, 65.1 mmol) Sodium carbonate (13.8 g, 130.2 mmol) and benzyl chloroformate (8.79 mL, 61.8 mmol) were added to the mixed solution with and at 0 ° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane / ethyl acetate) to give 1-benzyloxycarbonyl-4-oxopiperidine (13.1 g, 56.2 mmol, 86%) as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 2.42-2.50 (4H, m), 3.78-3.82 (4H, m), 5.18 (2H, s), 7.32-7.38 (5H, m).
(Example 1) Production of A-type crystal of
compound (I): Amorphous compound (6.98 g) of compound (I) prepared in Reference Example 4 is purified and concentrated with chloroform / methanol by silica gel column chromatography. After that, the wall surface of the flask was rubbed with a spartel and mechanical stimulation was applied to obtain A-type crystals of compound (I) as a powder. For the obtained crystals, measurement of powder X-ray diffraction using a powder X-ray diffractometer (Rigaku Co., Ltd .; 2200 / RINT ultima + PC) and TG-DTA using a TG-DTA device (Rigaku Co., Ltd .; TG8120) Was done. The results of these measurements are shown in FIGS. 1 and 2.
Diffraction angle 2θ: 5.9, 16.5, 17.7, 20.8, 26.7 °
Endothermic peak: 55 ° C

PATENT

WO2013147160

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013147160&_cid=P10-KS5MZ2-21335-1

Example 1 Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan-1-one:
[Chemical 27]

(E) )-Methyl 3- (1-methyl-1H-imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium-carbon (10% wet, 15 mg) at room temperature In a hydrogen atmosphere, the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (1.0 mL) was added to the obtained residue at room temperature to dissolve it, and the mixture was cooled to 0 ° C. An aqueous sodium hydroxide solution (1.0 N, 1.19 mL, 1.19 mmol) was added to the reaction solution at 0 ° C., the mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. Chloroform (10.0 mL) was added to the obtained residue at room temperature to dissolve it. Add diisopropylethylamine (0.568 mL, 3.25 mmol), HBTU (0.616 g, 1.63 mmol) and 4- (dimethylamino) piperidine (0.125 g, 0.975 mmol) to the reaction solution at room temperature, and add the reaction solution. The mixture was stirred at the same temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-imidazol-2-yl) propan- 1-one (0.179 g, 0.68 mmol, 63%) (hereinafter, the compound of Example 1) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃) δ: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (1H, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz), 6.91 (1H, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) ⁺ .

Publication Number	Title	Priority Date	Grant Date
WO-2016136944-A1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27
JP-WO2013147160-A1	Cyclic amine derivatives and their pharmaceutical use	2012-03-29
TW-201350119-A	Cyclic amine derivatives and their medical uses	2012-03-29
WO-2013147160-A1	Cyclic amine derivative and use thereof for medical purposes	2012-03-29

Publication Number	Title	Priority Date	Grant Date
RU-2667062-C1	Dynamic cyclic amine and pharmaceutical application thereof	2015-02-27	2018-09-14
TW-201639826-A	Cyclic amine derivatives and their medical uses	2015-02-27
TW-I682927-B	Cyclic amine derivatives and their medical uses	2015-02-27	2020-01-21
US-10173999-B2	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27	2019-01-08
US-2018065950-A1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27

Publication Number	Title	Priority Date	Grant Date
EP-3263565-A1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27
EP-3263565-B1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27	2019-06-26
ES-2744785-T3	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27	2020-02-26
JP-6569671-B2	Cyclic amine derivatives and their pharmaceutical use	2015-02-27	2019-09-04
JP-WO2016136944-A1	Cyclic amine derivatives and their pharmaceutical use	2015-02-27

Publication Number	Title	Priority Date	Grant Date
WO-2019189781-A1	Agent for inhibiting rise in intraneuronal calcium concentration	2018-03-30
AU-2016224420-A1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27
AU-2016224420-B2	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27	2019-08-22
CA-2977614-A1	Cyclic amine derivative and pharmaceutical use thereof	2015-02-27
CN-107250128-B	Cyclic amine derivatives and its medical usage	2015-02-27	2019-07-26

//////////TRK-700, phase 1, neuropathic pain, fibromyalgia, toray

O=C(CCc1nccn1C)N1CCC(CC1)N(C)C