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TRK 700

August 10, 2021 6:08 am / Leave a comment

1-[4-(Dimethylamino)piperidin-1-yl]-3-(1-methylimidazol-2-yl)propan-1-one.png

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) ⁺ .

NEW DRUG APPROVALS

ONE TIME

$10.00

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
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

Rutoside, Rutin

August 9, 2021 2:08 am / Leave a comment

Rutoside

RUTIN

Molecular FormulaC₂₇H₃₀O₁₆
Average mass610.518
рутозид [Russian] [INN]ルチン [Japanese]روتوسيد [Arabic] [INN]芦丁 [Chinese] [INN]

CAS 153-18-4

C.I. 75730
NSC-9220

2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one

Rutin trihydrate | CAS 250249-75-3 - Order from Adipogen

Rutin trihydrate | CAS 250249-75-3 RutinCAS Registry Number: 153-18-4
CAS Name: 3-[[6-O-(6-Deoxy-a-L-mannopyranosyl)-b-D-glucopyranosyl]oxy]-2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-1-benzopyran-4-one
Additional Names: rutoside; quercetin-3-rutinoside; 3,3¢,4¢,5,7-pentahydroxyflavone-3-rutinoside; melin; phytomelin; eldrin; ilixathin; sophorin; globularicitrin; paliuroside; osyritrin; osyritin; myrticolorin; violaquercitrin
Trademarks: Birutan (Merck KGaA)
Molecular Formula: C27H30O16Molecular Weight: 610.52Percent Composition: C 53.12%, H 4.95%, O 41.93%
Literature References: Identity with ilixanthin: Schindler, Herb, Arch. Pharm.288, 372 (1955). Found in many plants, especially the buckwheat plant (Fagopyrum esculentum Moench., Polygonaceae) which contains about 3% (dry basis): Couch et al.,Science103, 197 (1946). From tobacco (Nicotiana tabacum L., Solanaceae) Couch, Krewson, U.S. Dept. Agr., Eastern Regional Res. Lab.AIC-52 (1944).
In forsythia [Forsythia suspensa (Thunb.) Vahl. var. fortunei (Lindl.) Rehd., Oleaceae], in hydrangea (Hydrangea paniculata Sieb., Saxifragaceae), in pansies (Viola sp., Violaceae).
General extraction procedure: BeilsteinXXXI, 376. From leaves of Eucalyptus macroryncha F. v. Muell., Myrtaceae: Attree, Perkin, J. Chem. Soc.1927, 234.
Industrial production from Eucalyptus spp.: Humphreys, Econ. Bot.18, 195 (1964).
Structure: Zemplén, Gerecs, Ber.68B, 1318 (1935).
Synthesis: Shakhova et al.,Zh. Obshch. Khim.32, 390 (1962), C.A.58, 1426e (1963). Rutin is hydrolyzed by rhamnodiastase from the seed of Rhamnus utilis Decne, Rhamnaceae (Chinese buckthorn); emulsin is not effective: Bridel, Charaux, Compt. Rend.181, 925 (1925). Toxicity data: Harrison et al.,J. Am. Pharm. Assoc.39, 557 (1950). Book: J. Q. Griffith, Jr., Rutin and Related Flavonoids (Mack, Easton, Pa., 1955).
Comprehensive description: T. I. Khalifa et al.,Anal. Profiles Drug Subs.12, 623-681 (1983).UV

Properties: Pale yellow needles from water, gradual darkening on exposure to light. The crystals contain 3 H2O and become anhydr after 12 hrs at 110° and 10 mm Hg. Anhydr rutin browns at 125°, becomes plastic at 195-197°, and dec 214-215° (with effervescence). [a]D23 +13.82° (ethanol); [a]D23 -39.43° (pyridine). Anhydr rutin is hygroscopic. One gram dissolves in about 8 liters water, about 200 ml boiling water, 7 ml boiling methanol. Sol in pyridine, formamide and alkaline solns; slightly sol in alcohol, acetone, ethyl acetate. Practically insol in chloroform, carbon bisulfide, ether, benzene, petr solvents. Dil solns give green color with ferric chloride. Rutin is colored brown by tobacco enzyme under experimental conditions: Neuberg, Kobel, Naturwissenschaften23, 800 (1935). LD50 i.v. in mice: 950 mg/kg (propylene glycol soln) (Harrison).
Optical Rotation: [a]D23 +13.82° (ethanol); [a]D23 -39.43° (pyridine)
Toxicity data: LD50 i.v. in mice: 950 mg/kg (propylene glycol soln) (Harrison)Therap-Cat: Capillary protectant.Keywords: Vasoprotectant.
C13

MASS

Rutin, also called rutoside, quercetin-3-O-rutinoside and sophorin, is the glycoside combining the flavonol quercetin and the disaccharide rutinose (α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranose). It is a citrus flavonoid found in a wide variety of plants including citrus.

Rutin, also called rutoside, is the glycoside flavonoid found in a certain fruits and vegetables. Most rutine-rich foods are capers, olives, buckwheat (whole grain flour), asparagus, raspberry.In a clinical trial, rutin was found to aid control of intraocular pressure in patients with primary open angle glaucoma. As a component of dietary supplement Phlogenzym, rutin is used for treatment of osteoarthritis. Rutin is also used for treatment of post-surgical swelling of the arm after breast cancer surgery. Traditionally, rutin is used to prevent mucositis due to cancer treatment, to treat blood vessel disease such as varicose veins, bleeding, hemorrhoids.

Occurrences

Rutin is one of the phenolic compounds found in the invasive plant species Carpobrotus edulis and contributes to the antibacterial^[3] properties of the plant.

Its name comes from the name of Ruta graveolens, a plant that also contains rutin.

Various citrus fruit peels contain 32 to 49 mg/g of flavonoids expressed as rutin equivalents.^[4]

Citrus leaves contain rutin at concentrations of 11 and 7 g/kg in orange and lime trees respectively.^[5]

Metabolism

The enzyme quercitrinase can be found in Aspergillus flavus.^[6] It is an enzyme in the rutin catabolic pathway.^[7]

In food

Rutin is a citrus flavonoid glycoside found in many plants including buckwheat,^[8] the leaves and petioles of Rheum species, and asparagus. Tartary buckwheat seeds have been found to contain more rutin (about 0.8–1.7% dry weight) than common buckwheat seeds (0.01% dry weight).^[8] Rutin is one of the primary flavonols found in ‘clingstone’ peaches.^[9] It is also found in green tea infusions.^[10]

Approximate rutin content per 100g of selected foods, in milligrams per 100 milliliters:^[11]

Numeric	Alphabetic
332	Capers, spice
45	Olive [Black], raw
36	Buckwheat, whole grain flour
23	Asparagus, raw
19	Black raspberry, raw
11	Red raspberry, raw
9	Buckwheat, groats, thermally treated
6	Buckwheat, refined flour
6	Greencurrant
6	Plum, fresh
5	Blackcurrant, raw
4	Blackberry, raw
3	Tomato (Cherry), whole, raw
2	Prune
2	Fenugreek
2	Marjoram, dried
2	Tea (Black), infusion
1	Grape, raisin
1	Zucchini, raw
1	Apricot, raw
1	Tea (Green), infusion
0	Apple
0	Redcurrant
0	Grape (green)
0	Tomato, whole, raw

Research

Rutin (rutoside or rutinoside)^[12] and other dietary flavonols are under preliminary clinical research for their potential biological effects, such as in reducing post-thrombotic syndrome, venous insufficiency, or endothelial dysfunction, but there was no high-quality evidence for their safe and effective uses as of 2018.^[12]^[13]^[14]^{[needs update]} As a flavonol among similar flavonoids, rutin has low bioavailability due to poor absorption, high metabolism, and rapid excretion that collectively make its potential for use as a therapeutic agent limited.^[12]

Biosynthesis

The biosynthesis pathway of rutin in mulberry (Morus alba L.) leaves begins with phenylalanine, which produces cinnamic acid under the action of phenylalanine ammonia lyase (PAL). Cinnamic acid is catalyzed by cinnamic acid-4-hydroxylase (C4H) and 4-coumarate-CoA ligase (4CL) to form p–coumaroyl-CoA. Subsequently, chalcone synthase (CHS) catalyzes the condensation of p-coumaroyl-CoA and three molecules of malonyl-CoA to produce naringenin chalcone, which is eventually converted into naringenin flavanone with the participation of chalcone isomerase (CHI). With the action of flavanone 3-hydroxylas (F3H), dihydrokaempferol (DHK) is generated. DHK can be further hydroxylated by flavonoid 3´-hydroxylase (F3’H) to produce dihydroquercetin (DHQ), which is then catalyzed by flavonol synthase (FLS) to form quercetin. After quercetin is catalyzed by UDP-glucose flavonoid 3-O-glucosyltransferase (UFGT) to form isoquercitrin, finally, the formation of rutin from isoquercitrin is catalyzed by flavonoid 3-O-glucoside L-rhamnosyltransferase.^[15]

SYN

https://www.sciencedirect.com/science/article/abs/pii/S100184171300017X

The compound 2 was synthesized for the first time by highly selective esterification reaction and fully characterized. The by-products of the reaction were complex, which brought out many considerable difficulties in separation and purification of the target product. Our work was the first in using the improved pyrogallol autoxidation method to test the antioxidant activities of these two flavonoids compounds in vitro and discovered that the compound 2 was much more effective as a free radical scavenger than the compound 1.

SYN

Synthesis of Rutin

The synthesis of rutin can be achieved according to the following three schemes. These schemes differ in the synthesis of ouercetin (the aglycone moiety of rutin).

Scheme 1: Kostanecki — et al. 1904 (33 ). Based upon the Claisen reaction between 2-hydroxy4, 6-dimethoxyacetophenone [l] and 3, 4-dimethoxybenzaldehyde [2] to give the intermediate [3] which upon treatment with HC1, cyclization occurs to give 5, 7, 3 , which upon treatment with F2SO4 enolisation occurs to give 5, 7, 1’3 ,’4 -tetramethoxyflavonol [6]. tion with HI affords quercetin [7].

Scheme 2: Robinson et al. 1926 (34 ). , ‘4 -tetramethoxyflavonone [4]. Oximination affords [5] Demethyla- — Condensation ofw-methoxypholoroacetophenone [I] with veratric acid anhydride [2] in the presence of the potassium salt of veratric acid to give the diarylester [3]. On hydrolysis with alcoholic KOH affords 5, 7-dihydroxy-3, /3 , ‘4 -trimethoxyf lavone [ 41 , which on demethylation with HI gives quercetin [5].

Scheme 3: Shakhova et al. 1962 (35), complete synthesis of rutin. W-methoxyphloroacetophenone [2] was condensed with 0-benzylvanillinic acid, anhydride [ 13 in triethylamine to give 5 , 7-dihydroxy-4 -benzyloxy-3, /3 -dimethoxyf lavone [3]. On treatment with AcOH-HC1 mixture gave 5, 7, ‘4 -trihydroxy-3,’3 -dimethoxyflavone [4]. Demethylation of the latter with HI yielded (about 802) quercetin [5]. Ouercetin potassium salt [6] was produced upon treating [5] with AcOK in ethanol. Levoglucosan [7] was acetylated with Ac20 in the presence of AcONa to give 2, 3, 4-triacetyllevoglucosan [8] which with TIC14 gave 1-chloro-2, 3, 4-triacetyl Dglucose [9]. L-rhamnose tetraacetate [lo] treated with TiBr4 in CHC13 gave 1-bromo-2, 3, I-triacetyl-L-rhamnose [ll]. [lo] + [11] heated with Hg (OAC)~ in C6H6 gave (53x) CC – acetochloro-f3-l-L-rhamnosido-6-D-glucose [12]. [12] was treated with AgOAc and acetylated with Ac20 to prodilce (68.703 B-heptaacet yl-f3-1-L-rhamnos ido-6-D-glucose [13]. This with 33% HBr in AcOH gave (61%) d – acetobromo-~-l-L-rhamnosido-6-D-glucose [14]. [14] and quercetin potassium salt [6] were dissolved in NH40H which was evaporated and treated with methanol andpurified over a chromatographic column packed with polycaprolactum resin to give rutin [151.

References

^ Merck Index, 12th Edition, 8456
^ Krewson CF, Naghski J (Nov 1952). “Some physical properties of rutin”. Journal of the American Pharmaceutical Association. 41 (11): 582–7. doi:10.1002/jps.3030411106. PMID 12999623.
^ van der Watt E, Pretorius JC (2001). “Purification and identification of active antibacterial components in Carpobrotusedulis L.”. Journal of Ethnopharmacology. 76 (1): 87–91. doi:10.1016/S0378-8741(01)00197-0. PMID 11378287.
^ [1] p. 280 Table 1
^ [2] p.8 fig. 7
^ quercitrinase on www.brenda-enzymes.org
^ Tranchimand S, Brouant P, Iacazio G (Nov 2010). “The rutin catabolic pathway with special emphasis on quercetinase”. Biodegradation. 21 (6): 833–59. doi:10.1007/s10532-010-9359-7. PMID 20419500. S2CID 30101803.
^ Jump up to:^a ^b Kreft S, Knapp M, Kreft I (Nov 1999). “Extraction of rutin from buckwheat (Fagopyrum esculentumMoench) seeds and determination by capillary electrophoresis”. Journal of Agricultural and Food Chemistry. 47 (11): 4649–52. doi:10.1021/jf990186p. PMID 10552865.
^ Chang S, Tan C, Frankel EN, Barrett DM (Feb 2000). “Low-density lipoprotein antioxidant activity of phenolic compounds and polyphenol oxidase activity in selected clingstone peach cultivars”. Journal of Agricultural and Food Chemistry. 48 (2): 147–51. doi:10.1021/jf9904564. PMID 10691607.
^ Malagutti AR, Zuin V, Cavalheiro ÉT, Henrique Mazo L (2006). “Determination of Rutin in Green Tea Infusions Using Square-Wave Voltammetry with a Rigid Carbon-Polyurethane Composite Electrode”. Electroanalysis. 18 (10): 1028–1034. doi:10.1002/elan.200603496.
^ “foods in which the polyphenol Quercetin 3-O-rutinoside is found”. Phenol-Explorer v 3.6. June 2015.
^ Jump up to:^a ^b ^c “Flavonoids”. Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, Oregon. November 2015. Retrieved 25 February 2018.
^ Morling, J. R; Yeoh, S. E; Kolbach, D. N (November 2018). “Rutosides for treatment of post-thrombotic syndrome”. Cochrane Database of Systematic Reviews. 11 (11): CD005625. doi:10.1002/14651858.CD005625.pub4. PMC 6517027. PMID 30406640.
^ Martinez-Zapata, M. J; Vernooij, R. W; Uriona Tuma, S. M; Stein, A. T; Moreno, R. M; Vargas, E; Capellà, D; Bonfill Cosp, X (2016). “Phlebotonics for venous insufficiency”. Cochrane Database of Systematic Reviews. 4: CD003229. doi:10.1002/14651858.CD003229.pub3. PMC 7173720. PMID 27048768.
^ Yu X, Liu J, Wan J, Zhao L, Liu Y, Wei Y, Ouyang Z. Cloning, prokaryotic expression, and enzyme activity of a UDP-glucose flavonoid 3-o-glycosyltransferase from mulberry (Morus alba L.) leaves. Phcog Mag 2020;16:441-7


Names
IUPAC name3′,4′,5,7-Tetrahydroxy-3-[α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranosyloxy]flavone
Preferred IUPAC name(4²S,4³R,4⁴S,4⁵S,4⁶R,7²R,7³R,7⁴R,7⁵R,7⁶S)-1³,1⁴,2⁵,2⁷,4³,4⁴,4⁵,7³,7⁴,7⁵-Decahydroxy-7⁶-methyl-2⁴H-3,6-dioxa-2(2,3)-[1]benzopyrana-4(2,6),7(2)-bis(oxana)-1(1)-benzenaheptaphane-2⁴-one
Other namesRutoside (INN) Phytomelin Sophorin Birutan Eldrin Birutan Forte Rutin trihydrate Globularicitrin Violaquercitrin Quercetin rutinoside
Identifiers
CAS Number	153-18-4
3D model (JSmol)	Interactive image
ChemSpider	4444362
DrugBank	DB01698
ECHA InfoCard	100.005.287
KEGG	C05625
PubChem CID	5280805
RTECS number	VM2975000
UNII	5G06TVY3R7
CompTox Dashboard (EPA)	DTXSID3022326
show InChI
show SMILES
Properties
Chemical formula	C₂₇H₃₀O₁₆
Molar mass	610.521 g·mol⁻¹
Appearance	Solid
Melting point	242 °C (468 °F; 515 K)
Solubility in water	12.5 mg/100 mL^[1] 13 mg/100mL^[2]
Pharmacology
ATC code	C05CA01 (WHO)
Hazards
NFPA 704 (fire diamond)	2 0 0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
verify (what is ?)
Infobox references

/////////Rutoside, RUTIN, рутозид , ルチン , روتوسيد , 芦丁 , C.I. 75730, NSC 9220,

CC1C(C(C(C(O1)OCC2C(C(C(C(O2)OC3=C(OC4=CC(=CC(=C4C3=O)O)O)C5=CC(=C(C=C5)O)O)O)O)O)O)O)O

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Anifrolumab

August 8, 2021 4:41 am / Leave a comment

(Heavy chain)
EVQLVQSGAE VKKPGESLKI SCKGSGYIFT NYWIAWVRQM PGKGLESMGI IYPGDSDIRY
SPSFQGQVTI SADKSITTAY LQWSSLKASD TAMYYCARHD IEGFDYWGRG TLVTVSSAST
KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY
SLSSVVTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APEFEGGPSV
FLFPPKPKDT LMISRTPEVT CVVVDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY
RVVSVLTVLH QDWLNGKEYK CKVSNKALPA SIEKTISKAK GQPREPQVYT LPPSREEMTK
NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG
NVFSCSVMHE ALHNHYTQKS LSLSPGK
(Lihgt chain)
EIVLTQSPGT LSLSPGERAT LSCRASQSVS SSFFAWYQQK PGQAPRLLIY GASSRATGIP
DRLSGSGSGT DFTLTITRLE PEDFAVYYCQ QYDSSAITFG QGTRLEIKRT VAAPSVFIFP
PSDEQLKSGT ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL
TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC
(Disulfide bridge: H22-96, H144-H200, H220-L215, H226-H’226, H229-H’229, H261-H321, H367-H425, H’22-H’96, H’144-H’200, H’220-L’215, H’261-H’321, H’367-H’425, L23-L89, L135-L195, L’23-L’89, L’135-L’195)

Anifrolumab

アニフロルマブ (遺伝子組換え)

FDA APPROVED 2021/7/30, Saphnelo

MEDI 546

Formula	C6444H9964N1712O2018S44
Cas	1326232-46-5
Mol weight	145117.1846

Immunomodulator, Anti-IFN-type 1 receptor antibody
Disease	Systemic lupus erythematosus

Monoclonal antibody

Treatment of systemic lupus erythematosus (SLE)

OriginatorMedarex
DeveloperAstraZeneca; Medarex; MedImmune
ClassAntirheumatics; Monoclonal antibodies; Skin disorder therapies
Mechanism of ActionInterferon alpha beta receptor antagonists

RegisteredSystemic lupus erythematosus
Phase IILupus nephritis
DiscontinuedRheumatoid arthritis; Scleroderma

02 Jul 2021Phase-III clinical trials in Systemic lupus erythematosus in USA (SC) (NCT04877691)
25 Jun 2021AstraZeneca plans a phase III trial in Systemic lupus erythematosus (Adjunctive treatment) in the China, Hong Kong, South Korea, Philipines, Taiwan and Thailand (IV, Infusion), in July 2021 (NCT04931563)
02 Jun 2021Pharmacokinetic, efficacy and adverse events data from a phase II TULIP-LN1 trial in Lupus nephritis presented at the 22nd Annual Congress of the European League Against Rheumatism (EULAR-2021)

Anifrolumab, sold under the brand name Saphnelo, is a monoclonal antibody used for the treatment of systemic lupus erythematosus (SLE).^[1]^[2] It binds to the type I interferon receptor, blocking the activity of type I interferons such as interferon-α and interferon-β.^{[medical citation needed]}

Anifrolumab was approved for medical use in the United States in August 2021.^[1]^[3]^[4]^[5]

Anifrolumab is a monoclonal antibody that inhibits type 1 interferon receptors, indicated in the treatment of moderate to severe systemic lupus erythematosus.

Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus.^7,11 The standard therapy for systemic lupus erythematosus consists of antimalarials like hydroxychloroquine, glucocorticoids like dexamethasone, and disease modifying antirheumatic drugs like methotrexate.^8,11

Three monoclonal antibodies (anifrolumab, rontalizumab, and sifalimumab) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved.³

The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism.³ The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial.³

Anifrolumab has also been investigated for the treatment of Scleroderma.¹

Anifrolumab was granted FDA approval on 30 July 2021.¹¹

Adverse effects

The most common adverse effect was shingles, which occurred in 5% of patients in the low-dose group, to 10% in the high-dose group, and to 2% in the placebo group. Overall adverse effect rates were comparable in all groups.^[6]

History

The drug was developed by MedImmune, a unit of AstraZeneca, which chose to move anifrolumab instead of sifalimumab into phase III trials for lupus in 2015.^[7]^[8]^[9]

Clinical trial results

Anifrolumab failed to meet its endpoint of significant reduction in disease as assessed by the SLE Responder Index 4 instrument in the TULIP 1 phase III trial.^[10] This multi-center, double-blind, placebo-controlled study followed adults with moderate to severe SLE over the course of one year. Preliminary results were announced on 31 August 2018.

Names

Anifrolumab is the international nonproprietary name (INN).^[11]

References

^ Jump up to:^a ^b ^c https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761123s000lbl.pdf
^ Statement On A Nonproprietary Name Adopted By The USAN Council – Anifrolumab, American Medical Association.
^https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761123Orig1s000ltr.pdf
^ https://www.astrazeneca.com/media-centre/press-releases/2021/saphnelo-approved-in-the-us-for-sle.html
^ “Saphnelo (anifrolumab) Approved in the US for Moderate to Severe Systemic Lupus Erythematosus” (Press release). AstraZeneca. 2 August 2021. Retrieved 2 August 2021 – via Business Wire.
^ Spreitzer H (29 August 2016). “Neue Wirkstoffe – Anifrolumab”. Österreichische Apothekerzeitung (in German) (18/2016).
^ “Press release: New Hope for Lupus Patients”. MedImmune. 11 August 2015. Archived from the original on 31 July 2017.
^ “Anifrolumab”. NHS Specialist Pharmacy Service. Retrieved 31 July 2017.
^ “Anifrolumab”. AdisInsight. Retrieved 31 July 2017.
^ “Update on TULIP 1 Phase III trial for anifrolumab in systemic lupus erythematosus”. http://www.astrazeneca.com. Retrieved 2019-02-05.
^ World Health Organization (2014). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 71”. WHO Drug Information. 28 (1). hdl:10665/331151.

External links

“Anifrolumab”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT01438489 for “A Study of the Efficacy and Safety of MEDI-546 in Systemic Lupus Erythematosus” at ClinicalTrials.gov
Clinical trial number NCT02446912 for “Efficacy and Safety of Two Doses of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus” at ClinicalTrials.gov
Clinical trial number NCT02446899 for “Efficacy and Safety of Anifrolumab Compared to Placebo in Adult Subjects With Active Systemic Lupus Erythematosus” at ClinicalTrials.gov

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	Interferon α/β receptor
Clinical data
Trade names	Saphnelo
Other names	MEDI-546, anifrolumab-fnia
License data	US DailyMed: Anifrolumab
Routes of administration	Intravenous
Drug class	type I interferon receptor antagonist (IFN)
ATC code	None
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
CAS Number	1326232-46-5
DrugBank	DB11976
ChemSpider	none
UNII	38RL9AE51Q
KEGG	D11082
Chemical and physical data
Formula	C₆₄₄₄H₉₉₆₄N₁₇₁₂O₂₀₁₈S₄₄
Molar mass	145119.20 g·mol⁻¹

Goldberg A, Geppert T, Schiopu E, Frech T, Hsu V, Simms RW, Peng SL, Yao Y, Elgeioushi N, Chang L, Wang B, Yoo S: Dose-escalation of human anti-interferon-alpha receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study. Arthritis Res Ther. 2014 Feb 24;16(1):R57. doi: 10.1186/ar4492. [Article]
Peng L, Oganesyan V, Wu H, Dall’Acqua WF, Damschroder MM: Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-alpha receptor 1 antibody. MAbs. 2015;7(2):428-39. doi: 10.1080/19420862.2015.1007810. [Article]
Massarotti EM, Allore HG, Costenbader K: Editorial: Interferon-Targeted Therapy for Systemic Lupus Erythematosus: Are the Trials on Target? Arthritis Rheumatol. 2017 Feb;69(2):245-248. doi: 10.1002/art.39985. [Article]
Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, Illei GG, Drappa J, Wang L, Yoo S: Anifrolumab, an Anti-Interferon-alpha Receptor Monoclonal Antibody, in Moderate-to-Severe Systemic Lupus Erythematosus. Arthritis Rheumatol. 2017 Feb;69(2):376-386. doi: 10.1002/art.39962. [Article]
Tummala R, Rouse T, Berglind A, Santiago L: Safety, tolerability and pharmacokinetics of subcutaneous and intravenous anifrolumab in healthy volunteers. Lupus Sci Med. 2018 Mar 23;5(1):e000252. doi: 10.1136/lupus-2017-000252. eCollection 2018. [Article]
Riggs JM, Hanna RN, Rajan B, Zerrouki K, Karnell JL, Sagar D, Vainshtein I, Farmer E, Rosenthal K, Morehouse C, de Los Reyes M, Schifferli K, Liang M, Sanjuan MA, Sims GP, Kolbeck R: Characterisation of anifrolumab, a fully human anti-interferon receptor antagonist antibody for the treatment of systemic lupus erythematosus. Lupus Sci Med. 2018 Apr 5;5(1):e000261. doi: 10.1136/lupus-2018-000261. eCollection 2018. [Article]
Bui A, Sanghavi D: Anifrolumab . [Article]
Trindade VC, Carneiro-Sampaio M, Bonfa E, Silva CA: An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. Paediatr Drugs. 2021 Jul;23(4):331-347. doi: 10.1007/s40272-021-00457-z. Epub 2021 Jul 10. [Article]
Ryman JT, Meibohm B: Pharmacokinetics of Monoclonal Antibodies. CPT Pharmacometrics Syst Pharmacol. 2017 Sep;6(9):576-588. doi: 10.1002/psp4.12224. Epub 2017 Jul 29. [Article]
Koh JWH, Ng CH, Tay SH: Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials. Lupus. 2020 Dec;29(14):1845-1853. doi: 10.1177/0961203320959702. Epub 2020 Sep 22. [Article]
FDA Approved Drug Products: Saphnelo (Anifrolumab-fnia) Intravenous Injection [Link]

SAPHNELO (anifrolumab) Approved in the US for Moderate to Severe Systemic Lupus Erythematosus | Business Wire //////////Anifrolumab, Saphnelo, FDA 2021, APPROVALS 2021, peptide, Monoclonal antibody, アニフロルマブ (遺伝子組換え) , MEDI 546, AstraZeneca, Medarex, MedImmune

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Ezutromid

August 2, 2021 9:13 am / Leave a comment

Ezutromid

945531-77-1
Chemical Formula: C19H15NO3S
Molecular Weight: 337.39

945531-77-1, SMT c1100, BMN-195, BMN 195, C 1100

5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole

BMN-195; BMN 195; BMN195; SMTC-1100; SMTC1100; SMTC 1100; VOX-C1100; Ezutromid

Ezutromid, also known as BMN-195 and SMTC-1100, is a first orally bioavailable utrophin’s translation modulator. Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fibers leading to the gradual depletion of skeletal muscle.

Ezutromid is an orally administered small molecule utrophin modulator currently involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD).^[1]^[2] DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency.^[3] Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease.^[3] Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure.^[3]^[4] Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development.^[3]^[5] Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell.^[4]^[6] However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers.^[7] Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration.^[7]^[8] Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation.^[5]^[9] The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.^[5]^[10]

The Phase 2 clinical trial was ended in 2018 and the medication discontinued after it failed to show any benefit in slowing the disease.^[11]

Clinical trials

The first Phase 1b trial (NCT02056808) began on November 2013 and involved 12 patients aged 5–11 years old.^[12] The patients were divided into three groups given escalating oral doses testing the safety and tolerability after each increase over the course of 10 days.^[12]

Another completed Phase 1b trial (NCT02383511) began February 2015 and involved 12 patients aged 5–13 years old.^[13] The goal was to determine the safety, tolerability, and pharmacokinetic parameters by measuring plasma concentration and major metabolite levels over 28 days for three sequence groups.^[13] Each sequence involved placebo, 1250 mg, and 2500 mg BID (twice a day) doses given for one week each.^[4]^[13]

A PhaseOut DMD, Phase 2, Proof of Concept (NCT02858362) clinical trial is underway that tests the clinical safety and efficacy of an oral suspension of ezutromid.^[2] The 48-week open-label trial is enrolling 40 boys, ages 5–10, living in the U.K. or U.S.^[2] MRI leg muscle change will be measured as well as ezutromid plasma concentration levels, with a secondary goal of obtaining quantifiable images of utrophin membrane stained biopsies at baseline and either 24 or 48 weeks.^[2]

Commercial aspects

As of 2016, ataluren was the only approved drug in the EU to treat a specific subpopulation of patients with nmDMD, or DMD caused by a nonsense mutation.^[14] However, nonsense mutations only account for approximately 15% of all patients with DMD.^[15] Therefore, Summit Therapeutics projects to file for regulatory approval in the US and EU by 2019 and to reach market in 2020.^[8] They expect to profit just over £24,046 in 2020 and £942,656 in 2025, which amounts to ~10% CGR for the first 7 years on the basis of treating all DMD patients in the US, EU, Iceland, Norway, Switzerland and Russia.^[8]

Furthermore, Summit Therapeutics has entered an agreement with Sarepta Theraputics as of October 2016 regarding the commercialization of ezutromid.^[16] The agreement consists of a collaboration between Sarepta and Summit to share the research and developing costs for the development of novel therapies to treat DMD patients.^[16]

PAPER

https://onlinelibrary.wiley.com/doi/10.1002/anie.201906080

4-(ethylthio)Phenol S2: To a 250 mL round bottle, 4-mercaptophenol S1 (12.6 g, 100 mmol), K2CO3 (15.3 g, 110 mmol), acetone (100 mL) were added, then, iodoethane (15.6 g, 8.0 mL, 130 mmol) was added slowly at 0 oC. The system was stirred at room temperature overnight. After filtration, distillation of solvent, and flash chromatography, S2 (10.780 g) was obtained with 70% yield.

4-(ethylthio)-2-Nitrophenol S3: To a 250 mL round bottle, 4-(ethylthio)Phenol S2 (3.084 g, 20 mmol), 300-400 mesh silica gel (2 g), distilled water (2 g), and CH3CN (60 mL) was added. The system was then cooled by an ice water bath. Subsequently, citric acid (3.842 g, 20 mmol), NaNO2 (2.760 g, 40 mmol) were separately added slowly in portionwise. The system was reacted at room temperature overnight. After filtration and distillation of solvent, EA (50 mL) and water (50 mL) was added, after separation, the aqueous phase was extraction with EA (30 mL) twice. The combined organic phase was dried with MgSO4. Following by filtration and chromatography, S3 (3.590 g) was obtained with 90% yield.

4-(ethylthio)-2-Nitrophenol S4: To a 100 mL round bottle, S3 (2.46 g, 12.3 mmol), reductive iron powder (2.07 g, 36.9 mmol), and EtOH (50 mL) was added. Then, HCl (aq.) (0.15 M) (12 mL, 1.85 mmol) was added slowly. The system was refluxed overnight. After filtration, distillation of solvent, and flash chromatography, S4 (1.040 g) was obtained with 50% yield.

5-(ethylthio)-2-(naphthalen-2-yl)Benzo[d]oxazole S6 (Ezutromid-S): S4 (324 mg1.91 mmol), 2-naphthoyl chloride S5 (545.7 mg, 2.87 mmol), dry 1,4-dioxane (5 mL) was added into a sealing tube. Then, the system was vacuumed and filled with nitrogen for three times. Subsequently, the reaction was run at 160 oC for 10 hours. After distillation of solvent and flash chromatography, S6 (361.7 mg) was obtained with 62% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.28 (dd, J = 8.5, 1.7 Hz, 1H), 7.96 (t, J = 7.5 Hz, 2H), 7.92 – 7.84 (m, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.57 (pd, J = 6.8, 3.4 Hz, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.4, 1.8 Hz, 1H), 2.99 (q, J = 7.3 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H).13C NMR (126 MHz, Chloroform-d) δ 163.79, 149.70, 142.92, 134.76, 132.89, 132.38, 128.92, 128.78, 128.20, 127.87, 127.85, 126.91, 124.11, 123.84, 121.38, 110.72, 29.17, 14.40

Dibenzoate5-(ethylsulfone)-2-(naphthalen-2- yl)benzo[d]oxazole (Ezotrumid) 5a:

5- (ethylthio)-2-(naphthalen-2-yl)Benzo[d]oxazole (30.5 mg, 0.1 mmol), UO2(OAc)2 . 2H2O (0.8 mg, 0.002 mol), H2O (10 equiv., 36 μL), o-xylene (8.3 equiv., 0.2 mL), CH3CN (1 mL) were stirred under oxygen atmosphere (1 atm, balloon) at room temperature until the total consumption of sulfide and sulfoxide under the irradiation of three 2 w blue LEDs in a paralleled reactor. 5a (27.3 mg, 81%) was obtained through column chromatography (PE/EA = 20/1-5/1) as a white solid, Rf = 0.6 (PE/EA = 2/1);

1H NMR (500 MHz, Chloroform-d) δ 8.82 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.99 – 7.89 (m, 2H), 7.84 – 7.76 (m, 1H), 7.61 (t, J = 7.3 Hz, 2H), 3.28 – 3.08 (m, 2H), 1.32 (dt, J = 7.3, 3.6 Hz, 3H)..

13C NMR (126 MHz, Chloroform-d) δ 165.57, 153.87, 142.86, 135.26, 135.14, 132.86, 129.09, 128.97, 128.37, 127.99, 127.19, 125.35, 123.87, 123.34, 121.00, 111.36, 51.04, 7.62.

IR (KBr) 2933, 1507, 1498, 1258, 1064, 1046, 756, 474 cm-1 .

HRMS (ESI) Calcd for C19H16NO3S 338.0851 (M+H), Found 338.0865.

PATENT

WO 2007091106

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007091107

PATENT

WO 2009021749

WO 2009019504

WO 2013167737 A

CN 110437170

CN 110483345

CN 110563619

PATENT

WO 2009021748

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009021748

It has been discovered that the compound of formula I (5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole) has excellent properties for the treatment of Duchenne muscular dystrophy (see, e.g., international patent application publication no. WO 2007/091106).

The compound of formula I (R = 5-ethylsulfonyl; R₉ = 2-naphthalen-2-yl) may be synthesised according to the following procedure, as disclosed in WO 2007/091106 (page 51):

Experimental

S nthesis of 5- eth lsulfon -2- na hthalen-2- l^‘benzo d oxazole

Procedure:
A vessel was equipped with a retreat blade stirrer and downward pumping turbine, a five necked flange lid, seal and clamp, stirrer gland and overhead stirrer, thermometer pocket, Dean- Stark trap, dropping funnel and condenser. The water to the condenser was then switched on.
The sodium hydroxide and 0.80 L of water were then mixed (whilst cooling in an ice bath until all the sodium hydroxide has dissolved – caution exothermic). The resulting solution was then transferred to a scrubber appropriately attached to the vessel.

The 2-amino-4-(ethylsulfonyl)phenol and 2.00 L of xylenes (mixed) were then transferred to the vessel, and the reagents and solvent were stirred at 100 rpm.
Then, the 2-naphtholyl chloride was dissolved in 2.00 L of xylenes (mixed) and transferred into the vessel. The stirring rate was increased to 150 rpm.

The temperature of the solution was gradually increased to 100°C over a period of not less than 30 mins, and then maintained at that level for 10 mins. (Caution: HCl gas is evolved during this process through the gas scrubber). The stirrer speed was then increased to 315 rpm and the temperature gradually increased over a period of 30 minutes until reflux (155°C) at which level it was maintained for 90 mins. (Caution: HCl gas is evolved during this process through the gas scrubber).
The methanesulfonic acid was then added drop-wise over a period of 30 mins and relux was maintained until no further water was being collected in the Dean-Stark apparatus (approx 15 mins).
The heat was then removed and the pipe adapter from the Dean- Stark apparatus disconnected. The resulting solution was allowed to cool to 90⁰C, and then filtered using Whatman 1 filter paper.
The resulting solution was then left at ambient temperature for 18h, after which time the product crystallised, and the product was separated by filtration using Whatman 1 filter paper. The product was then washed with Ix 1.0 L of tert-butyl methyl ether (TBME)

The product was then dried in a vacuum oven at 65°C at a pressure of 1 Ombar until constant weight was achieved (less than 0.5 g difference between consecutive measurements of mass which must be at least 1 h apart).
The product was obtained as a sandy-beige powder in a yield of 80%.

Characterisation:
5-(EthylsuIf onyl)-2-(naphthalen-2-yl)benzo [d] oxazole
LCMS RT= 6.94min, MH⁺ 338.1;
¹H NMR (DMSO): 8.90 (IH, br), 8.34 (IH, d, J 1.4 Hz), 8.30 (IH, dd, J 8.6 1.7 Hz), 8.24-8.05 (4H, m), 7.99 (IH, dd, J 8.5 1.8 Hz), 7.73-7.64 (2H, m), 3.41 (2H, q, J 7.3 Hz), 1.15 (3H, t, J7.3 Hz);

MP = 160-161⁰C.

Synthesis of polymorphic forms

1. Procedure
100 mg of the compound of formula I was dissolved in the minimum amount of good solvent and then the anti-solvent was added to induce crystallisation. The supernatant liquor was then removed, and the resulting solid was dried under vacuum for 12 his.

PAPER

Journal of medicinal chemistry (2011), 54(9), 3241-50

https://pubs.acs.org/doi/10.1021/jm200135z

Abstract

A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure–activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials.

PAPER

Angewandte Chemie, International Edition (2019), 58(38), 13499-13506

Angewandte Chemie, International Edition (2020), 59(3), 1346-1353.

PAPER

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01547

Journal of medicinal chemistry (2020), 63(5), 2547-2556.

Abstract

5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles.

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S004040201931227X

Abstract

Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.

Graphical abstract

Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model - ScienceDirect

References

^ “About Summit Therapeutics – Summit”. Summit. Retrieved 2016-11-14.
^ Jump up to:^a ^b ^c ^d Clinical trial number NCT02858362 for “PoC Study to Assess Activity and Safety of SMT C1100 (Ezutromid) in Boys With DMD” at ClinicalTrials.gov
^ Jump up to:^a ^b ^c ^d “Duchenne Muscular Dystrophy – Summit”. Summit. Archived from the original on 2016-11-15. Retrieved 2016-11-14.
^ Jump up to:^a ^b ^c Ricotti V, Spinty S, Roper H, Hughes I, Tejura B, Robinson N, et al. (2016-01-01). “Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy”. PLOS ONE. 11 (4): e0152840. Bibcode:2016PLoSO..1152840R. doi:10.1371/journal.pone.0152840. PMC 4824384. PMID 27055247.
^ Jump up to:^a ^b ^c “Potential DMD Therapy, Ezutromid, Shows Promise in Upgraded Form”. Retrieved 2016-11-14.
^ Janghra N, Morgan JE, Sewry CA, Wilson FX, Davies KE, Muntoni F, Tinsley J (2016-03-14). “Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies”. PLOS ONE. 11 (3): e0150818. Bibcode:2016PLoSO..1150818J. doi:10.1371/journal.pone.0150818. PMC 4790853. PMID 26974331.
^ Jump up to:^a ^b “Home – Summit”. Summit. Retrieved 2016-11-14.
^ Jump up to:^a ^b ^c Werther CA (2016). Ezutromid Has the Potential to Treat All Duchenne Patients; Initiating Coverage With a Buy. H.C. Wainwright & Co. pp. 1–29.
^ “Search Orphan Drug Designations and Approvals”. http://www.accessdata.fda.gov. Retrieved 2016-11-14.
^ Office of the Commissioner. “Developing Products for Rare Diseases & Conditions”. http://www.fda.gov. Retrieved 2016-11-14.
^ Inacio P (2018-06-29). “Summit Therapeutics Ends Development of Ezutromid Therapy for DMD After Trial Failure”. Muscular Dystrophy News. Retrieved 2019-11-17.
^ Jump up to:^a ^b Clinical trial number NCT02056808 for “A Phase 1b Study of SMT C1100 in Subjects With Duchenne Muscular Dystrophy (DMD)” at ClinicalTrials.gov
^ Jump up to:^a ^b ^c Clinical trial number NCT02383511 for “Modified Diet Trial: A Study of SMT C1100 in Paediatric Patients With DMD Who Follow a Balanced Diet ” at ClinicalTrials.gov
^ “PTC Therapeutics | ataluren”. PTC Therapeutics. Retrieved 2016-11-15.
^ Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Howard MT, Sampson JB, et al. (March 2011). “Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene”. Human Mutation. 32 (3): 299–308. doi:10.1002/humu.21426. PMC 3724403. PMID 21972111.
^ Jump up to:^a ^b Summit Therapeutics PLC. “Sarepta Therapeutics and Summit Enter Into Exclusive License and Collaboration Agreement for European Rights to Summit’s Utrophin Modulator Pipeline for the Treatment of Duchenne Muscular Dystrophy”. GlobeNewswire News Room. Retrieved 2016-11-15.

/////////Ezutromid, BMN-195, BMN 195, BMN195, SMTC-1100, SMTC1100, SMTC 1100, VOX-C1100, Ezutromid

O=S(C1=CC=C(OC(C2=CC=C3C=CC=CC3=C2)=N4)C4=C1)(CC)=O

NEW DRUG APPROVALS

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$10.00

MIRDAMETINIB

July 31, 2021 2:46 am / Leave a comment

MIRDAMETINIB

391210-10-9
Chemical Formula: C16H14F3IN2O4
Molecular Weight: 482.19

PD0325901; PD 0325901; PD-325901; mirdametinib

FDA APPROVED 2/11/2025, Gomekli, To treat neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection

IUPAC/Chemical Name: (R)-N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide

SpringWorks Therapeutics (a spin out of Pfizer ) is developing mirdametinib, a second-generation, non-ATP competitive, allosteric MEK1 and MEK2 inhibitor derived from CI-1040, for treating type 1 neurofibromatosis (NF1) and advanced solid tumors. In June 2021, a phase I/II trial was initiated in patients with low grade glioma.

OriginatorPfizer
DeveloperAstraZeneca; BeiGene; BIOENSIS; Pfizer; SpringWorks Therapeutics; St. Jude Childrens Research Hospital; University of Oxford
ClassAniline compounds; Anti-inflammatories; Antineoplastics; Benzamides; Immunotherapies; Small molecules
Mechanism of ActionMAP kinase kinase 1 inhibitors; MAP kinase kinase 2 inhibitors
Orphan Drug StatusYes – Neurofibromatosis 1

Phase IINeurofibromatosis 1
Phase I/IIGlioma
Phase ISolid tumours
PreclinicalChronic obstructive pulmonary disease
No development reportedCervical cancer
DiscontinuedBreast cancer; Cancer; Colorectal cancer; Malignant melanoma; Non-small cell lung cancer

22 Jul 2021SpringWorks Therapeutics receives patent allowance for mirdametinib from the US Patent and Trademark Office for the treatment of Neurofibromatosis type 1-associated plexiform neurofibromas
16 Jun 2021SpringWorks Therapeutics and St. Jude Children’s Research Hospital agree to develop mirdametinib in USA for glioma
15 Jun 2021Efficacy and safety data from the phase IIb RENEU trial for Neurofibromatosis type 1-associated plexiform neurofibromas released by SpringWorks Therapeutics

Mirdametinib, sold under the brand name Gomekli, is a medication used for the treatment of people with neurofibromatosis type 1.^[1] Mirdametinib is a kinase inhibitor.^[1]^[2] It is taken by mouth.^[1]

The most common adverse reactions in adults include rash, diarrhea, nausea, musculoskeletal pain, vomiting, and fatigue.^[3] The most common grade 3 or 4 laboratory abnormalities include increased creatine phosphokinase.^[3] The most common adverse reactions in children include rash, diarrhea, musculoskeletal pain, abdominal pain, vomiting, headache, paronychia, left ventricular dysfunction, and nausea.^[3] The most common grade 3 or 4 laboratory abnormalities include decreased neutrophil count and increased creatine phosphokinase.^[3]

Mirdametinib was approved for medical use in the United States in February 2025.^[1]^[3]

SCHEME

SIDE CHAIN

MAIN

Medical uses

Mirdametinib is indicated for the treatment of people with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection.^[1]

Adverse effects

Mirdametinib can cause left ventricular dysfunction and ocular toxicity including retinal vein occlusion, retinal pigment epithelial detachment, and blurred vision.^[3]

History

The efficacy of mirdametinib was evaluated in ReNeu (NCT03962543), a multicenter, single-arm trial in 114 participants aged two years of age and older (58 adults, 56 pediatric participants) with symptomatic, inoperable NF1-associated plexiform neurofibromas causing significant morbidity.^[3] An inoperable plexiform neurofibromas was defined as a plexiform neurofibromas that could not be completely surgically removed without risk for substantial morbidity due to encasement or close proximity to vital structures, invasiveness, or high vascularity.^[3]

The US Food and Drug Administration (FDA) granted the application for mirdametinib priority review, fast track, and orphan drug designations along with a priority review voucher.^[3]

Society and culture

Legal status

Mirdametinib was approved for medical use in the United States in February 2025.^[3]^[4]^[5]

PATENT

US-11066358

https://patentscope.wipo.int/search/en/detail.jsf?docId=US330982129&tab=PCTDESCRIPTION&_cid=P11-KRR5IB-89620-1

On July 20, 2021, SpringWorks Therapeutics announced that the United States Patent and Trademark Office (USPTO) has issued US11066358 , directed to mirdametinib , the Company’s product candidate in development for several oncology indications, including as a monotherapy for patients with neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and was assigned to Warner-Lambert Company (a subsidiary of Pfizer ).This patent was granted on July 20, 2021, and expires on Feb 17, 2041. Novel crystalline forms of mirdametinib and compositions comprising them are claimed.

N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (“mirdametinib”, or “PD-0325901”) is a small molecule drug which has been designed to inhibit mitogen-activated protein kinase kinase 1 (“MEK1”) and mitogen-activated protein kinase kinase 2 (“MEK2”). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase (“MAPK”) signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Mirdametinib is a highly potent and specific allosteric non-ATP-competitive inhibitor of MEK1 and MEK2. By virtue of its mechanism of action, mirdametinib leads to significantly inhibited phosphorylation of the extracellular regulated MAP kinases ERK1 and ERK2, thereby leading to impaired growth of tumor cells both in vitro and in vivo. In addition, evidence indicates that inflammatory cytokine-induced increases in MEK/ERK activity contribute to the inflammation, pain, and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.

Crystal forms of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide have been described previously. WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 (“the ‘856 patent”) describes a method of producing Form IV. The ‘856 patent indicates that the material produced by this method was greater than 90% Form IV (The ‘856 patent, Example 1). The ‘856 patent also states that the differential scanning calorimetry (“DSC”) of the material produced shows an onset of melting at 110° C., as well as a small peak with an onset at 117° C., consistent with the material being a mixture of two forms.

WO 2006/134469 (“the ‘469 PCT publication”) also describes a method of synthesizing N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. The ‘469 PCT publication reports the method yields a product conforming to the polymorphic Form IV disclosed in U.S. patent application Ser. No. 10/969,681 which issued as the ‘856 patent.

Compositions containing more than one polymorphic form are generally undesirable because of the potential of interconversion of one polymorphic form to another. Polymorphic interconversion can lead to differences in the effective dose or physical properties affecting processability of a drug, caused by differences in solubility or bioavailability. Thus, there is a need for a composition containing essentially pure Form IV of N—((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide, for use in treatment of a tumor, a cancer, or a Rasopathy disorder.

Example 1: Production of Essentially Pure Form IV

Lab Scale Production of Essentially Pure Form IV

2 kg PD-0325901 has been prepared using the below convergent synthesis scheme starting from commercially available 2,3,4-Trifluorobenzoic Acid (TFBA), 2-Fluoro-4-Iodoaniline (FIA) and chiral S-Glycerol Acetonide (SGA)

All reactions were performed in toluene other than otherwise stated. Triflic anhydride gave the best yield.

[TABLE-US-00002]TABLE 1 Coupling Agents for Step 1Entry No.Coupling AgentYieldNotes 1Mesyl Chloridedid not react 2Benzyl chloride27Had to heat 70° C. for 166 hr34-fluorobenzensulfonylchloride27Ran 93 hrs. at 70° C.44-chlorobenzensulfonylchloride35Complete after 68 hrs. 50° C.5Tosyl Chloride36Had to heat to 70° C. for 164 hrs6Benzyl chloride52study solvent effects: DMF, DMSO, NMP – all similar DMSO fastest all complete after 110 hrs., heated to 70° C. after 66 hrs.7Triflic anhydride91Cooled to −74° C.

Recognizing that triflate gave the highest yield, the possibility of eliminating the cryogenic conditions was investigated, set possibly due to stability concerns of the “methanesulfonate” intermediate. The following experiments suggest no significant yield loss for experiments run at −20° C.

[TABLE-US-00003]TABLE 2 Yield of Coupling ReactionExperimentalHold time afterYield (Alcohol toDescription*TFMSA addn.IPGAP) 1.07 equiv. NHP15min.85%1.07 equiv. NHP2hours86%1.77 equiv. NHP2hours72%1.07 equiv. NHP (reverse1hours91%addition) * 2 g (1 eq.) SGA in 16 ml toluene was treated with triflic anhydride, trifluoromethanesulfonic acid (TFMSA) (4.2 g, 1.002 equiv.) at −20° C. and then stirred for a prescribed time prior to solid N-hydroxyphthalimide (NIP) addition or transfer to a flask containing solid NHP.

The data presented above suggest no detrimental effect was observed after prolonged stirring of the “trifluoromethane sulfonate” intermediate prior to the N-hydroxyphthalimide addition. Reverse addition of intermediate mixture to solid NHP appears to give the highest yield.

An additional advantage of the triflate usage was easy removal of the Et ₃N triflate salts side product simply by water wash. This resulted in highly pure N-hydroxyphthalimide-protected alcohol, IPGAP (PD-0333760) in Toluene, which can be isolated as crystals or carried through to the final deprotection reaction.

Both aqueous and anhydrous ammonia base were examined as deprotecting agents. The results were both successful. The phthalimide side product was simply filtered out from solution of product (PD-0337792) in toluene when anhydrous ammonia was used. Similarly, it was filtered out from the solution after performing azeotropic water removal from toluene when aqueous ammonia (28% solution) was used. Anhydrous ammonia however, requires the reaction to be performed at high-pressure containment. Experiments conducted by sparging the ammonia gas gave acceptable yields; however, they required large volumes and use of a cryogenic condenser (to avoid gas from escaping the reactor headspace).

[TABLE-US-00004]TABLE 3 Yields for base deprotection ReagentYield* Methyl hydrazine85-95% Anhydrous NH₃(sparged)78-90% Anhydrous NH₃(50 psi)80-92% Aqueous NH₃90-97% *from PD-0333760

Step 2: Fluoride Displacement

Examination of the reaction in an automated reactor reveals that the reaction is essentially dosed-controlled after the initiation period. Increasing the amount of lithium amide and increased agitation rate appear to shorten the induction time. The addition of water was shown to prolong the induction time. However, it is not clear whether it is due to lithium hydroxide formation.

Induction time is increased when 0.1 equivalent H ₂O was added. The trend was reversed however when 0.1 equivalent lithium hydroxide was added. Induction times were decreased upon increasing lithium amide equivalents and agitation.

CDI-assisted coupling of PD-0315209 acid and sidechain reagent followed by the acid (with aqueous HCl) hydrolysis consistently yielded good results in the laboratory. The development focus of this step was to ensure that impurity levels are within the specification limit. The known impurities in the final isolated diol product are excess PD-0315209 acid, dimeric impurities and chiral impurities. The chiral impurities are controlled by limiting the R-enantiomer in the starting s-glycerol acetonide. Elevated levels of dimeric impurity (d) has been known to cause difficulties in the polymorph transformation step. The dimeric impurity is formed initially by the reaction of imidazole (CDI-activated acid) in the presence of excess acid PD-0315209 forming dimer (a) and possibly (b) which are then carried through in the subsequent IPGA coupling and acid hydrolysis steps forming dimer (c) and (d), respectively. Impurity d is referred to as PF-00191189.

The reaction can be easily carried out in the laboratory either by charging both solids, FIPFA and CDI, followed by solvent (acetonitrile) or charging solids CDI into a slurry of FIPFA in acetonitrile. None of the solids is initially soluble in acetonitrile. The acid activation reaction was fast (almost instantaneous), forming highly soluble imidazolide product that turned the slurry into a clear homogenous solution while CO ₂gas evolution occurs.

Lab experiments generally resulted in impurity levels under 3%, which can be completely removed by the subsequent recrystallization from a 3-5% ethanol-toluene system. An additional recrystallization was performed in the few instances where the impurity level was above 0.3%. Table 4 shows selected results of lab experiments where elevated levels of impurities were observed and how they were removed in the subsequent recrystallization. The crude PD-0325901 was obtained using the acetonitrile/toluene system and the purified product was recrystallized from a 5% ethanol/toluene system. Entries no. 4 and 5 used additional solvent to ensure impurity removal with entry 5 requiring two recrystallizations in order to achieve a level of “ND” in the polymorph transformation. The 8-10 ml/g crude crystallization volume was chosen to limit product loss while maintaining a filterable slurry and ensuring removal of impurities.

[TABLE-US-00005]TABLE 4 Purification of PD-0325901 Tot. Imp. In Final Tot.isolated Tot. Imp.assay (after Imp. InCrude PurifiedpolymorphEntryreactionPD-RecrystallizationPD-trans-Nomixture0325901Vol (ml/g crude)0325901formation) 1 2.4%ND8ND99.8%210.5% 2%8ND99.6%3 6% 1%8ND99.4%4 10%3.2%15ND98.6%5 20%12%130.6%98.4%*

A scale up procedure that would give tolerable levels of impurities prior to the polymorph transformation (<0.3%), without losing too much product in the recrystallization was developed considering the solid CDI addition rate. Fast addition is preferred to minimize impurity formation; however, the addition needs to be performed at a rate that ensures safely venting of the evolved CO ₂.

A half portion of solid CDI was initially added to the PD-0325901 acid, followed by solvent addition. The remaining CDI was added then through a hopper in less than 30 minutes to ensure that the impurity levels were below 3%.

Pilot Plant Preparation of Essentially Pure Form IV

Step 1: Preparation of “Side Chain”, PD-0337792

14.4 kg alcohol (chemical purity 99.4%, optical purity 99.6% enantiomeric excess) was converted to 97.5 kg 9.7% w/w PD-0337792 (IPGA) solution in toluene (overall yield ˜60%). The triflate activation was performed in the 200 L reactor by maintaining temperatures under −20° C. during triflic anhydride addition. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxypthalimide (NHP) and the reaction was allowed to occur at ambient temperature to completion. The final base de-protection was performed by adding aqueous ammonia (˜28% soln, 5 equiv., 34 kg). After reaction completion, water was removed by distillation from toluene, and the resulting solid side product was filtered out to yield the product solution.

Step 2: Preparation of PD-0315209

The process yielded 21.4 kg (99.4% w/w assay), which is 80% of theoretical from starting materials 2,3,4-trifluorobenzoic acid (12 kg, 1 eq.) and 2-fluoro-4-iodoaniline (16.4 kg, 1.02 eq.) with lithium amide base (5 kg, 3.2 eq.). The reaction was initiated by adding 5% of total solution of TFBA and FIA into lithium amide slurry at 50° C. This reaction demonstrated a minimal initiation period of ˜10 minutes, which was observed by color change and slight exotherm. The remaining TFBA/FIA solution in THE was slowly added through a pressure can in an hour while maintaining the reaction temperatures within 45-55° C. There was no appreciable pressure rise (due to ammonia gas release) observed during the entire operation.

Step 3: Preparation of PD-0325901

A modification was made to the CDI charging to mitigate potential gas generation. Two equal portions of CDI were added into solid FIPFA before and after solvent addition (through a shot loader). The timing between the two solid CDI additions (4.6 kg each) should not exceed 30 minutes. Then two intermediate filter cakes were dissolved with ethanol. The excess ethanol was distilled and replaced with toluene to approximately 5% v/v ethanol prior to PD-0325901 recrystallization. Lab studies suggested that the crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene would not be able to reduce impurities which is essential for the polymorph transformation. The presence of a dimeric impurity (PF-00191189) at a level greater than 0.2% has been known to result in the formation of undesired polymorph.

The crude crystallization from the final reaction mixture reduced dimeric impurity PF-00191189 to approximately 1.9% and the subsequent recrystallization further reduced it to approximately 0.4%. As a consequence, undesired polymorphs were produced. The DSC patterns indicated two different melting points ˜80° C. (low melt Form II) and ˜117° C. (Form I). Also during the processing, the solids crystallized at a much lower temperature than expected (actual ˜10° C., expected ˜40° C.). It is suspected that the unsuccessful recrystallization is due to a change in the solvent composition as a result of incomplete drying of the crude. Drying of the crude wet cake prior to ethanol dissolution was stopped after about 36 hours when the crude product was ˜28 kg (26 kg theoretical).

Polymorph Transformation

Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final EtOH/Water crystallization and precipitated materials from the earlier EtOH/Toluene filtrate were taken forward to the polymorph transformation. Both crops were separately dried in the filter until constant weights and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC and resulted in an estimated amount of 16.4 kg PD-0325901. The recrystallization was started after removing EtOH via vacuum distillation and adjusting the solvent composition to about 5% EtOH in Toluene at 65° C. (i.e., EtOH is added dropwise at 65° C. until complete solids dissolution).

A slow 4-hour cooling ramp to 5° C. followed by 12 h stirring was performed to ensure satisfactory results. The resulting slurry was filtered and again it was completely dried in the filter until constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with not detected level of dimeric impurity PF-00191189.

The dried solid (15.4 kg) was re-dissolved in exactly 4 volumes of EtOH (62 L) off of the filter, transferred to the reactor and precipitated by a slow (˜3 h) water addition (308 L) at 30-35° C., cooled to 20° C. and stirred for 12 h. The DSC analysis of a slurry sample taken at 2 h shows the solids to be completely Form IV (desired polymorph).

21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv.), 91 kg solution of 9.7% PD-0337792 in Toluene (1.1 equiv.) were used and resulted in 12.74 kg of PD-0325901 (assay 99.4%, 100% Form IV, Yield 48%).

PATENT

WO2006134469 , claiming methods of preparing MEK inhibitor, assigned to Warner-Lambert Co .

https://patents.google.com/patent/WO2006134469A1/enThe compound Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide represented by formula 1

i is a highly specific non-ATP-competitive inhibitor of MEK1 and MEK2. The compound of formula ± (Compound I) is also known as the compound PD 0325901. Compound I is disclosed in WO 02/06213; WO 04/045617; WO 2005/040098; EP 1262176; U.S. Patent Application Pub. No. 2003/0055095 A1 ; U.S. Patent Application Pub. No. 2004/0054172 A1; U.S. Patent Application Pub. No. 2004/0147478 A1 ; and U.S. Patent Application No. 10/969,681, the disclosures of which are incorporated herein by reference in their entireties.Numerous mitogen-activated protein kinase (MAPK) signaling cascades are involved in controlling cellular processes including proliferation, differentiation, apoptosis, and stress responses. Each MAPK module consists of 3 cytoplasmic kinases: a mitogen-activated protein kinase (MAPK), a mitogen-activated protein kinase kinase (MAPKK), and a mitogen-activated protein kinase kinase kinase (MAPKKK). MEK occupies a strategic downstream position in this intracellular signaling cascade catalyzing the phosphorylation of its MAP kinase substrates, ERK1 and ERK2. Anderson et al. “Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase.” Nature 1990, v.343, pp. 651-653. In the ERK pathway, MAPKK corresponds with MEK (MAP kinase ERK Kinase) and the MAPK corresponds with ERK (Extracellular Regulated Kinase). No substrates for MEK have been identified other than ERK1 and ERK2. Seger et al. “Purification and characterization of mitogen-activated protein kinase activator(s) from epidermal growth factor-stimulated A431 cells.” J. Biol. Chem., 1992, v. 267, pp. 14373-14381. This tight selectivity in addition to the unique ability to act as a dual-specificity kinase is consistent with MEK’s central role in integration of signals into the MAPK pathway. The RAF-MEK-ERK pathway mediates proliferative and anti-apoptotic signaling from growth factors and oncogenic factors such as Ras and Raf mutant phenotypes that promote tumor growth, progression, and metastasis. By virtue of its central role in mediating the transmission of growth- promoting signals from multiple growth factor receptors, the Ras-MAP kinase cascade provides molecular targets with potentially broad therapeutic applications.One method of synthesizing Compound I is disclosed in the above-referenced WO 02/06213 andU.S. Patent Application Pub. No. 2004/0054172 A1. This method begins with the reaction of 2-fluoro-4- iodo-phenylamine and 2,3,4-trifluoro-benzoic acid in the presence of an organic base, such as lithium diisopropylamide, to form 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid, which is then reacted with (R)-0-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of a peptide coupling agent (e.g., diphenylphosphinic chloride) and a tertiary amine base (e.g., diisopropylethylamine). The resulting product is hydrolyzed under standard acidic hydrolysis conditions (e.g., p-TsOH in MeOH) to provide Compound 1. (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine is prepared by reaction of [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol with N-hydroxyphthalimide in the presence of Ph₃P and diethyl azodicarboxylate.Another method of synthesizing Compound I, which is disclosed in the above-referenced U.S.Patent Application No. 10/969,681, comprises reaction of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzoic acid with (R)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine in the presence of N₁N¹– carbonyldiimidazole. The resulting product is hydrolyzed with aqueous acid and crystallized to provide polymorphic form IV of Compound I.Although the described methods are effective synthetic routes for small-scale synthesis of Compound I, there remains a need in the art for new synthetic routes that are safe, efficient and cost effective when carried out on a commercial scale.The present invention provides a new synthetic route including Steps I through Step III to the MEK inhibitor Λ/-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I).Step I: Preparation of 0-{r(4RV2.2-dimethyl-1.3-dioxolan-4-ynmethyl}hydroxylanπine (6) The method of the present invention comprises a novel Step I of preparing of 0-{[(4R)-2,2- dimethyl-1 ,3-dioxolan-4-yl]methyl}hydroxylamine (6) from [(4S)-2,2-dimethyl-1 ,3-dioxoIan-4-yl]methanol (1) through the formation of [(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methyl trifluoromethanesulfonate (3) and its coupling with N-hydroxyphthalimide (4) to afford 2-{[(4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl]methoxy}-1 H- isoindole-1 ,3(2H)-dione (5), which is subsequently de-protected to give 6 as shown in Scheme 1.Scheme 1

The reaction of compound (1) with trifluoromethanesulfonic anhydride (2) is carried out in the presence of a non-nucleophilic base, such as, for example, a tertiary organic amine, in an aprotic solvent at a temperature of from -5O⁰C to 5⁰C, preferably, at a temperature less than -15⁰C, to form triflate (3). A preferred tertiary organic amine is triethylamine, and a preferred solvent is toluene. Treatment of triflate (3) with N-hydroxyphthalimide (4) furnishes phthalimide (5), which can be isolated if desired. However, in order to minimize processing time and increase overall yield, 0-{[(4R)- 2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) can be prepared in a one-pot process with no phthalimide (S) isolation. Cleavage of the phthalimide function could be achieved by methods known in the art, for example, by hydrazinolysis. However, the use of less hazardous aqueous or anhydrous ammonia instead of methyl hydrazine (CH₃NHNH₂) is preferred.Step II: Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) As shown in Scheme 2, Step Il of the method of the present invention provides 3,4-difluoro-2-(2- fluoro-4-iodophenylamino)-benzoic acid (9).Scheme 2

Preparation of compound (9) can be carried out by reacting compound (7), wherein X is halogen, or O-SC^R^ or 0-P(³O)(OR^, wherein R^ is alkyl or aryl, with compound (8) optionally in a solvent, and in the presence of from about 1 mol equivalent to about 10 mol equivalents of at least one base, wherein the base is selected from: a Group I metal cation hydride or a Group 2 metal cation hydride, including lithium hydride, sodium hydride, potassium hydride, and calcium hydride, a Group I metal cation dialkylamide or a Group 2 metal cation dialkylamide, including lithium diisopropylamide, a Group I metal cation amide or a Group 2 metal cation amide, including lithium amide, sodium amide, potassium amide, a Group I metal cation alkoxide or a Group 2 metal cation alkoxide, including sodium ethoxide, potassium terf-butoxide, and magnesium ethoxide, and a Group I metal cation hexamethyldisilazide, including lithium hexamethyldisilazide; for a time, and at a temperature, sufficient to yield compound (9).Preferably, preparation of compound (9) is carried out by reacting compound (7), wherein X is halogen, more preferably, X is fluorine, in an aprotic solvent with compound (8) in the presence of from about 3 mol equivalents to about 5 mol equivalents of a Group I metal cation amide at a temperature of from 2O C to 55^°C, more preferably, at a temperature from 45^°C to 55^°C. A catalytic amount of Group I metal cation dialkylamide can be added if necessary. A preferred Group I metal cation amide is lithium amide, a preferred Group I metal cation dialkylamide is lithium diisopropylamide, and a preferred solvent is tetrahydrofuran. Preferably, the reaction is performed by adding a small amount of compound (7) and compound (8) to lithium amide in tetrahydrofuran followed by slow continuous addition of the remaining portion. This procedure minimizes the risk of reactor over-pressurization due to gas side product (ammonia) generation.Step III: Preparation of N-((RV2.3-dihydroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I)Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using a carboxylic acid activating reagent such as, for example, COCI2, S(O)C^, S(O)2Cl2, P(O)Cl3, triphenylphosphine/diethylazodicarboxylate, diphenylphosphinic chloride, N, N’-dicyclohexylcarbodiimide, (benzotriazol-1 -yloxy)tripyrolidinophosphonium hexafluorophosphate, (benzotriazol-1 – yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide hydrochloride, or 1,1′-carbonyldiimidazole (CDI).A preferred carboxylic acid activating reagent is 1,1′-carbonyldimidazole (CDI) shown in Scheme 3. Preparation of the desirable polymorphic Form IV of Compound I using CDI is described in the above- referenced U.S. Patent Application No. 10/969,681.Scheme 3

10 11 Compound IIn according to the present invention, the method was modified to include the advantageous procedure for product purification and isolation, which procedure is performed in single-phase systems such as, for example, toluene/acetonitrile for the first isolation/crystallization and ethanol/toluene for the second recrystallization. Water addition, implemented in the previous procedure, was omitted to avoid the two-phase crystallization from the immiscible water-toluene system that caused inconsistent product purity. The one-phase procedure of the present invention provides consistent control and removal of un- reacted starting material and side products. Alternatively, Compound I can be obtained by coupling 0-{[(4R)-2,2-dimethyl-1,3-dioxolan-4- yl]methyl}hydroxylamine (6) with 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) using thionyl chloride (SOCI₂) as shown in Scheme 4.Scheme 4

Compound IExamplesThe reagents and conditions of the reactions described herein are merely illustrative of the wide variety of starting materials, their amounts and conditions which may be suitably employed in the present invention as would be appreciated by those skilled in the art, and are not intended to be limiting in any way.HPLC (Conditions A): 10 μL injection volume onto Agilent Zorbax RX-C18 150 mm x 4.6 mm x 3.5 μm column at 30^°C column temperature, 1.0 mL/min flow rate and detection at 246 nm. Mobile phase A (v/v): 25 mM Acetate Buffer, pH 6.0; Mobile phase B (v/v): Acetonitrile, and Linear Gradient Table:

Sample Preparation: Dilute 100 μL reaction mixture to 10 mL with acetonitrile. Mix in a vial 200 μL of this sample solution with 300 μL carbonate buffer pH 10.0 and 300 μL solution of 2-mercaptopyridine in acetonitrile (18 mM), heat the vial for 10 minutes at 50⁰C and dilute to 1:1 ratio in mobile phase A.GC (Conditions B): 1 μL injection onto an RTX-5 column (30 m x 0.25 mm x 0.25 μm) with initial oven temperature of 120^°C for 2 min. to final temperature of 250^°C in 15^°C/minute ramping and a final time of 2.33 min; Flow rate: 1 mL/min.HPLC (Conditions C): 5 μL injection onto Phenomenex Luna C18(2) 150 mm x 4.6 mm x 3μm column ; flow rate : 1.0 mL/min; detection at 225 nm; mobile phase A: 95/5 v/v Water/Acetonitrile with 0.1% Trifluoroacetic acid (TFA), mobile phase B: 5/95 v/v Water/Acetonitriie with 0.1% TFA; Linear Gradient Table:

Sample preparation: Dilute 1 ml_ reaction mixture to 100 mL with acetonitrile and dilute 1 mL of this solution to 10 mL with 50:50 Water/Acetonitrile.HPLC (Conditions D): 5 μL injection onto Waters SymmetryShield RP 18, 150 mm x 4.6 mm x 3.5 μm column; flow rate: 1.0 mL/min; detection at 235 nm; mobile phase A: 25 mM Acetate Buffer adjusted to pH 5.5, mobile phase B: Acetonitrile; Linear Gradient Table:

Sample preparation: Dilute 40 μL of reaction mixture in 20 mL acetonitrile.HPLC (Conditions E): 10 μL sample injection onto YMC ODS-AQ 5 μm, 250 mm x 4.6 mm column; flow rate: 1.0 ml_/min; detection at 280 nm; temperature 30^°C; mobile phase : 75/25 v/v Acetonitrile/Water with 0.1% Formic acid.Sample preparation: Quench reaction mixture sample with dipropylamine and stir for about 5 minutes before further dilution with mobile phase.DSC measurement was performed using a Mettler-Toledo DSC 822, temperature range 25^° to 150^°C with 5^°C/min heating rate in a 40 μL aluminum pan. Experimental Conditions for Powder X-Rav Diffraction (XRD):A Rigaku Miniflex+ X-ray diffractometer was used for the acquisition of the powder XRD patterns. The instrument operates using the Cu Ka₁ emission with a nickel filter at 1.50451 units. The major instrumental parameters are set or fixed at:X-ray: Cu / 30 kV (fixed) / 15 mA (fixed)Divergence Slit: Variable Scattering Slit: 4.2° (fixed) Receiving Slit: 0.3 mm (fixed) Scan Mode: FT Preset Time: 2.0 s Scan Width: 0.050° Scan Axis: 2Theta/Theta Scan Range: 3.000° to 40.000°Jade Software Version: 5.0.36(SP1) 01/05/01 (Materials Data, Inc.) Rigaku Software: Rigaku Standard Measurement for Windows 3.1 Version 3.6(1994-1995) Example 1. Preparation of 0-ffl4R)-2.2-dimethyl-1.3-dioxolan-4-vπmethyl}hvdroxylamine (6)A solution containing [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol (1) (13.54 ml_, 0.109 mol) (DAISO Co., Ltd., CAS# 22323-82-6) and triethylamine (18.2 ml_, 0.131 mol) in 115 mL toluene was cooled to -15 C, then trifluoromethanesulfonic anhydride (2) (18.34 mL, 30.75 g, 0.109 mol) (Aldrich, Catalog # 17,617-6 ) was added drop wise while maintaining the temperature at less than -15^°C. The mixture was then stirred for 2 hours, and transferred to a separate flask containing a mixture (slurry) of N- hydroxyphthalimide (4) (18.99 g, 0.116 mol) (Aldrich, Catalog # H5.370-4) and 18.2 mL (0.13 mol) triethylamine in 95 mL toluene. The resulting mixture was warmed to 20-25^°C and stirred for at least 5 hours or until reaction completion (determined by HPLC (Conditions A)). Water (93 mL) was then added to quench the reaction mixture, the phases were separated, and the bottom aqueous layer was discarded. The water quench was repeated two more times resulting in a pale yellow organic layer. The organic layer was heated to 35 C and treated with 36.7 mL ammonium hydroxide solution (contains about 28-29% wt/wt ammonia). The mixture was stirred for at least 12 hours or until the reaction was deemed complete as determined by GC (Conditions B). The water was then removed under reduced pressure by co- distilling it with toluene to about half of the original volume at temperatures around 35-45 C. Toluene (170 mL) was added to the concentrated solution and the distillation was repeated. A sample was drawn for water content determination by Karl Fisher method (using EM Science Aquastar AQV-2000 Titrator with a sample injected to a pot containing methanol and salicylic acid). The distillation was repeated ifl water content was more than 0.1%. The concentrated solution was filtered to remove the white solid side product, and the filtrate was stored as 112mL (98 g) product solution containing 9.7% w/w compound 6 in toluene. This solution was ready for use in the final coupling step (Example 3). Overall chemical yield was 59%. A small sample was evaporated to yield a sample for NMR identification.¹H NMR (400 MHz, CDCI₃): δ 5.5 (bs, 2H), 4.35 (m, 1H), 4.07 (dd, 1H), 3.77 (m, 2H), 3.69 (dd, 1H), 1.44 (s, 3H), 1.37 (s, 3H).Example 2. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9)A solution of 2-fluoro-4-iodoaniline (8) (16.4 g, 0.069 mol) (Aldrich, Catalog # 30,660-6) and 2,3,4- trifluorobenzoic acid (7) (11.98 g, 0.068 mol) (Aldrich, Cat # 33,382-4) in 38 mL tetrahydrofuran (THF) was prepared and a portion (about 5%) of this solution was added to a stirring slurry of lithium amide (5 g, 0.22 mol) in 40 mL THF at 50-55 C. After about 15-30 min. an exotherm followed by gas release and color change are observed. The remaining portion of the (8) and (7) solution was added slowly over 1-2 hr while maintaining temperatures within 45-55^°C. The mixture was stirred until the reaction was deemed complete (by HPLC (Conditions C). The final mixture was then cooled to 20-25^°C and transferred to another reactor containing 6 N hydrochloric acid (47 mL) followed by 25 mL acetonitrile, stirred, and the bottom aqueous phase was discarded after treatment with 40 mL 50% sodium hydroxide solution. The organic phase was concentrated under reduced pressure and 57 mL acetone was added. The mixture was heated to 50^°C, stirred, and added with 25 mL warm (40-50^°C) water and cooled to 25-30^°C to allow crystallization to occur (within 1-4 hours). Once the crystallization occurred, the mixture was further cooled to 0 to -5^°C and stirred for about 2 hours. The solid product was filtered and the wet cake was dried in vacuum oven at about 55^°C. Overall chemical yield was 21.4 g, 80%. ¹H NMR (400 MHz, (CD₃)₂SO): δ 13.74 (bs, 1H), 9.15 (m, 1 H), 7.80 (dd, 1H), 7.62 (d, 1H), 7.41 (d, 1H), 7.10 (q, 1H), 6.81 (m, 1H).Example 2B. Preparation of 3.4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) by the solid addition of lithium amide methodTo a stirring solution of 2,3,4-trifluorobenzoic acid (13) (5.0 g, 28.4 mmol) and 2-fluoro-4- iodoaniline (14) (6.73 g, 28.4 mmol) in MeCN (100 mL), under N₂ atmosphere was added lithium amide (2.61 g, 113.6 mmol) in small portions. The reaction mixture was heated to reflux for 45 minutes, cooled to ambient temperature and quenched with 1 N HCI and then water. The yellowish white precipitate was filtered, washed with water. The solid was triturated in CH₂CI₂ (30 mL) for 1h, filtered and dried in a vacuum oven at 45^°C for 14 hours to give 8.Og (72%) of compound (9) as an off-white solid, mp 201.5-203 ^°C.Example 3. Preparation of N-((R)-2.3-dihvdroxypropoxy)-3.4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound \)3,4-Difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (20 g, 0.051 mol) in 100 mL acetonitrile was treated with 1,1′-carbonyldiimidazole (CDI) (8.66 g, 0.053 mol) (Aldrich, Cat # 11,553-3) and stirred for about 2 hours at 20-25^°C until the reaction was deemed complete by HPLC (Conditions D). 94 mL (84.9 g) of 9.7% w/w solution of O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) in toluene was then added and stirred for about 4 hours or until the reaction was deemed complete by HPLC (Conditions D). To this mixture was added 66 mL of 5.6 % hydrochloric acid solution, and after stirring, the bottom aqueous phase was discarded. Again 66 mL of 5.6 % hydrochloric acid solution was added to the organic phase and stirred at 20-25^°C for 12-18 hours or until the reaction was deemed complete by HPLC (Conditions D). The bottom layer was then discarded and the remaining organic layer was concentrated under reduced pressure to remove about 10-20% solvent, and the volume was adjusted to about 9-11 mL/g with toluene (80 mL). Crude product was then crystallized at 10-15^°C. The slurry was allowed to stir for about 2 hours and the crude solid product was filtered, and dried. The dried crude product was recharged to the reactor and dissolved into 150 mL of 5% v/v ethanol/toluene mixture at 55- 67^°C. The solution was then clarified at this temperature through filter (line filter) to remove any remaining particulate matter. The solution was then cooled slowly to 5^°C to crystallize and stirred for at least 2 h, filtered and dried. The dried solid product was redissolved in EtOH (60 mL) at 35^°C, and product was precipitated out by adding water (300 mL) at 35^°C followed by cooling to 20⁰C. The slurry was stirred for at least 2 hours to transform the crystals to the desired polymorphic Form IV as determined by DSC and Powder X-ray Diffraction pattern (PXRD). The slurry was filtered and dried under vacuum oven at 70- 90^°C to yield the final N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- benzamide (Compound I) product. Overall chemical yield was 13 g, 53%. Melting point (DSC): 112+1^° C. Appearance: White to off-white crystals.Shown in Figure 1, PXRD conforms to polymorphic crystal Form IV disclosed in the above mentioned U.S. Patent Application No. 10/969,681 ¹H NMR (400 MHz, (CD₃)₂SO): δ 11.89 (bs, 1H), 8.71 (bs, 1H), 7.57 (d, 1H), 7.37 (m, 2H), 7.20 (q, 1H), 6.67 (m, 1H), 4.84 (bs, 1H), 4.60 (m, 1H), 3.87 (m, 1 H), 3.7 (m, 2H), 3.34 (m, 2H).Example 4. Preparation of N-((R)-2.3-dihydroxypropoxyV3.4-difluoro-2-(2-fluoro-4-iodo-phenylanrιinoV benzamide (Compound \)To a stirring solution of 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzoic acid (9) (120 g, 0.30 mol) in a mixture of 1 mL N,N-dimethylformamide and 1000 mL toluene was added thionyl chloride (55 g, 0.462 mol). The mixture was heated to 50-65 C and stirred for 2 hours or until reaction completion as determined by HPLC (Conditions E). The final reaction mixture was then cooled and concentrated under reduced pressure to a slurry keeping the temperature below 35^°C. Toluene (600 mL) was added to dissolve the slurry and vacuum distillation was repeated. Additional toluene (600 mL) was added to the slurry dissolving all solids and the solution was then cooled to 5^° -10^°C. The solution was then treated with O-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}hydroxylamine (6) (63 g, 0.43 mol) solution in 207 mL toluene followed by potassium carbonate (65 g) and water (200 mL), stirred for at least 2 hours at 20- 25^°C. The stirring was stopped to allow phase separation and the bottom phase was discarded. The remaining organic layer was treated with hydrochloric acid solution (7.4%, 240 mL) until pH was less than 1 and stirred for 2 hours. The final reaction mixture was slightly concentrated under vacuum collecting about 100 mL distillate and the resulting organic solution was cooled to 5^°C to crystallize the product and filtered. The filter cake was washed with toluene (1000 mL) followed by water (100 mL) and the wet cake (crude product Compound I) was charged back to the flask. Toluene (100 mL), ethanol (100 mL) and water (100 mL) are then added, stirred at 30-35^°C for about 15 min, and the bottom aqueous phase was discarded. Water (200 mL) was then added to the organic solution and the mixture was stirred at about 3O C to allow for crystallization. The stirring was continued for 2 hours after product crystallized, then it was further cooled to about 0^°C and stirred for at least 2 hours. The slurry was filtered and wet cake was dried under reduced pressure at 55-85^°C to yield the final product N-((R)-2,3-dihydroxypropoxy)-3,4- difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (Compound I) product. Overall chemical yield was 86 g, 58%.

PATENT

WO2002/006213 describes crystalline Forms I and II. U.S. Pat. No. 7,060,856 (“the ‘856 patent”)

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2002006213

Clinical data

Trade names	Gomekli
Other names	PD-0325901
AHFS/Drugs.com	Gomekli
License data	US DailyMed: Mirdametinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	L01EE05 (WHO)
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	391210-10-9
PubChem CID	9826528
IUPHAR/BPS	7935
DrugBank	DB07101
ChemSpider	10814340
UNII	86K0J5AK6M
KEGG	D11675
ChEBI	CHEBI:9826528
ChEMBL	ChEMBL507361
PDB ligand	4BM (PDBe, RCSB PDB)
Chemical and physical data
Formula	C₁₆H₁₄F₃IN₂O₄
Molar mass	482.198 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Gomekli- mirdametinib capsule; Gomekli- mirdametinib tablet, for suspension”. DailyMed. 27 February 2025. Retrieved 2 April 2025.
^ Armstrong AE, Belzberg AJ, Crawford JR, Hirbe AC, Wang ZJ (June 2023). “Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas”. BMC Cancer. 23 (1): 553. doi:10.1186/s12885-023-10996-y. PMC 10273716. PMID 37328781.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ “FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection”. U.S. Food and Drug Administration (FDA). 11 February 2025. Archived from the original on 13 February 2025. Retrieved 16 February 2025. This article incorporates text from this source, which is in the public domain.
^ “UPDATE: SpringWorks Therapeutics Announces FDA Approval of Gomekli (mirdametinib) for the Treatment of Adult and Pediatric Patients with NF1-PN” (Press release). SpringWorks Therapeutics. 12 February 2025. Archived from the original on 13 February 2025. Retrieved 16 February 2025 – via GlobeNewswire News Room.
^ “Novel Drug Approvals for 2025”. U.S. Food and Drug Administration (FDA). 14 February 2025. Retrieved 16 February 2025.

External links

“Mirdametinib (Code C52195)”. NCI Thesaurus.
Clinical trial number NCT03962543 for “MEK Inhibitor Mirdametinib (PD-0325901) in Patients With Neurofibromatosis Type 1 Associated Plexiform Neurofibromas (ReNeu)” at ClinicalTrials.gov

Moertel CL, Hirbe AC, Shuhaiber HH, Bielamowicz K, Sidhu A, Viskochil D, Weber MD, Lokku A, Smith LM, Foreman NK, Hajjar FM, McNall-Knapp RY, Weintraub L, Antony R, Franson AT, Meade J, Schiff D, Walbert T, Ambady P, Bota DA, Campen CJ, Kaur G, Klesse LJ, Maraka S, Moots PL, Nevel K, Bornhorst M, Aguilar-Bonilla A, Chagnon S, Dalvi N, Gupta P, Khatib Z, Metrock LK, Nghiemphu PL, Roberts RD, Robison NJ, Sadighi Z, Stapleton S, Babovic-Vuksanovic D, Gershon TR: ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children With Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma. J Clin Oncol. 2025 Feb 20;43(6):716-729. doi: 10.1200/JCO.24.01034. Epub 2024 Nov 8. [Article]
Weiss BD, Wolters PL, Plotkin SR, Widemann BC, Tonsgard JH, Blakeley J, Allen JC, Schorry E, Korf B, Robison NJ, Goldman S, Vinks AA, Emoto C, Fukuda T, Robinson CT, Cutter G, Edwards L, Dombi E, Ratner N, Packer R, Fisher MJ: NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas. J Clin Oncol. 2021 Mar 1;39(7):797-806. doi: 10.1200/JCO.20.02220. Epub 2021 Jan 28. [Article]
Ioannou M, Lalwani K, Ayanlaja AA, Chinnasamy V, Pratilas CA, Schreck KC: MEK Inhibition Enhances the Antitumor Effect of Radiotherapy in NF1-Deficient Glioblastoma. Mol Cancer Ther. 2024 Sep 4;23(9):1261-1272. doi: 10.1158/1535-7163.MCT-23-0510. [Article]
FDA Approved Drug Products: GOMEKLI (mirdametinib) capsules and tablets for oral and oral suspension use (Feb 2024) [Link]
FDA News: FDA approves mirdametinib for adult and pediatric patients with neurofibromatosis type 1 who have symptomatic plexiform neurofibromas not amenable to complete resection [Link]

////////MIRDAMETINIB, Orphan Drug Status, Neurofibromatosis 1, PHASE 2, PD0325901, PD 0325901, PD-325901, FDA 2025, GOMEKLI, APPROVALS 2025

O=C(NOC[C@H](O)CO)C1=CC=C(F)C(F)=C1NC2=CC=C(I)C=C2F

OTESECONAZOLE

July 29, 2021 9:17 am / 1 Comment on OTESECONAZOLE

OTESECONAZOLE

VT 1161

オテセコナゾール;

(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(tetrazol-1-yl)-1-[5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl]propan-2-ol

C₂₃H₁₆F₇N₅O₂ 527.4
Synonyms	VT 1161 Oteseconazole CAS1340593-59-0

Other Names

(αR)-α-(2,4-Difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(2,2,2-trifluoroethoxy)phenyl]-2-pyridineethanol
(2R)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)- 1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol

UPDATE MAY 2022… FDA APPROVED 2022/4/26, Vivjoa

Oteseconazole, sold under the brand name Vivjoa, is a medication used for the treatment of vaginal yeast infections.^[1]

It was approved for medical use in the United States in April 2022.^[2][3] It was developed by Mycovia Pharmaceuticals.^[3]

Names

Oteseconazole is the international nonproprietary name (INN).^[4]

Oteseconazole is an azole antifungal used to prevent recurrent vulvovaginal candidiasis in females who are not of reproductive potential.

Oteseconazole, also known as VT-1161, is a tetrazole antifungal agent potentially for the treatment of candidal vaginal infection. VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection. VT-1161 dosed once daily or once weekly exhibits potent efficacy in treatment of dermatophytosis in a guinea pig model.

Oteseconazole has been used in trials studying the treatment of Tinea Pedis, Onychomycosis, Candidiasis, Vulvovaginal, and Recurrent Vulvovaginal Candidiasis.

Mycovia Pharmaceuticals is developing oteseconazole, the lead from a program of metalloenzyme Cyp51 (lanosterol demethylase) inhibitors, developed using the company’s Metallophile technology, for treating fungal infections including onychomycosis and recurrent vulvovaginal candidiasis (RVVC). In July 2021, oteseconazole was reported to be in phase 3 clinical development. Licensee Jiangsu Hengrui Medicine is developing otesaconazole, as an oral capsule formulation, for treating fungal conditions, including RVVC, onychomycosis and invasive fungal infections, in Greater China and planned for a phase 3 trial in April 2021 for treating VVC.

OriginatorViamet Pharmaceuticals
DeveloperMycovia Pharmaceuticals; Viamet Pharmaceuticals
ClassAntifungals; Foot disorder therapies; Pyridines; Small molecules; Tetrazoles
Mechanism of Action14-alpha demethylase inhibitors

PreregistrationVulvovaginal candidiasis
Phase IIOnychomycosis
No development reportedTinea pedis

01 Jun 2021Preregistration for Vulvovaginal candidiasis (In adolescents, In adults, In children, Recurrent) in USA (PO)
01 Jun 2021Mycovia intends to launch otesaconazole (Recurrent) for Vulvovaginal candidiasis in the US in early 2022
06 Jan 2021Interim efficacy and adverse events data from a phase III ultraVIOLET trial in Vulvovaginal candidiasis released by Mycovia Pharmaceuticals

Synthesis Reference

Hoekstra, WJ., et al. (2020). Antifungal compound process (U.S. Patent No. US 10,745,378 B2). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/f4/62/19/5ba525b1caad0e/US10745378.pdf

PATENT

WO 2017049080

WO 2016149486

US 20150024938

WO 2015143172

WO 2015143184

WO 2015143180

WO 2015143142

WO 2013110002

WO 2013109998

WO 2011133875

PATENT

WO 2017049080,

Syn

J. Med. Chem. 2024, 67, 4376−4418

Oteseconazole was approved by the USFDA in April 2022 for the treatment of recurrent vulvovaginal candidiasis in women with a history of vulvovaginal candidiasis and who are not of reproductive
potential. Additional studies for other invasive and opportunistic infections and for onychomycosis are underway.40, The design and discovery of oteseconazole is published by a group from Viamet Pharmaceuticals, now part of Mycovia Pharmaceuticals. It details the racemic synthesis of the drug on
<1 g scale in which the metal-binding tetrazole is installed by treatment of ester 5.2 (Scheme 10) with diazomethane and tetrazole.42
A more scale-friendly asymmetric route that avoided the use of diazomethane was subsequently disclosed in patents and is detailed in Scheme 10 and Scheme 11.43
First, a mixture of ethyl bromodifluoroacetate, stoichiometric copper
powder, and 2,5-dibromopyridine (5.1) in DMSO provided ester 5.2 as an oil that was purified via distillation (Scheme10). Conversion to the aryl ketone 5.5 was achieved via direct addition of lithiated 5.3 or via a two-step process by first conversion to morpholine amide 5.4 followed by addition of
the Grignard generated from aryl bromide 5.3. The resulting ketone 5.5 was a liquid that was carried into the next step without purification.
The key step in the synthesis of 5 is an asymmetric Henry reaction using cinchona alkaloid catalyst 5.6. Addition of nitromethane to ketone 5.5 furnished alcohol 5.7 in 75% yield and ∼90:10 ratio of enantiomers. Next, reduction of the nitro group to the primary amine was accomplished using Pt
catalyzed hydrogenation. The chiral purity of the resulting amine was upgraded by classical resolution using di-p-toluoyl L-tartaric acid to provide 5.8·L-DTTA in 33% yield and >99% chiral purity.Conversion of amino alcohol 5.8 to oteseconazole (5) required two steps: cross coupling to introduce the aryltrifluoroethyl ether fragment and tetrazole formation. These steps were performed in either sequence in the patent. The route shown in Scheme 11 represents the largest scale demonstrated (>100 g input of 5.8). While the use of azide containing reagents presents significant safety risks, no information was provided on safe operation of the tetrazole forming step in the laboratory or on plant scale. Some of the
procedures for tetrazole formation described in the patent would likely require modification for safe scale-up.
To complete the synthesis of oteseconazole, resolved amino alcohol 5.8 first underwent a salt break followed by Suzuki coupling using boronic acid 5.9 to provide biaryl product 5.10 as the L-tartrate salt (Scheme 11). Conversion of 5.10 to 5 was accomplished using TMSN3 in acetic acid with sodium acetate and trimethoxy orthoformate. Treatment of the resulting solution with a Pd scavenger preceded crystallization of the product from EtOH and water after pH adjustment with potassium carbonate. The product was isolated in 85% yield as a hydrated form. Another patent described conversion of the oteseconazolehydrate totheanhydrous form byrecrystallizationfrom EtOHandn-heptanetofurnish5 in90%yield.45

(40) Hoy, S. M. Oteseconazole: First approval. Drugs 2022, 82,1017−1023.
(41) Sobel, J. D.; Nyirjesy, P. Oteseconazole: an advance in
treatment of recurrent vulvovaginal candidiasis. Future Microbiol 2021,
16, 1453−1461.
(42) Hoekstra, W. J.; Garvey, E. P.; Moore, W. R.; Rafferty, S. W.;
Yates, C. M.; Schotzinger, R. J. Design and optimization of highly
selective fungal CYP51 inhibitors. Bioorg. Med. Chem. Lett. 2014, 24,
3455−3458.
(43) Wirth, D. D.; Yates, C. M.; Hoekstra, W. J.; Bindl, M. F.;
Hartmann, E. Process for enantioselective preparation of tetrazolyl
pyridinyl diaryl propanols as antifungal drugs and their precursors.
WO 2017049080, 2017.
(44) González-Bobes, F.; Kopp, N.; Li, L.; Deerberg, J.; Sharma, P.;
Leung, S.; Davies, M.; Bush, J.; Hamm, J.; Hrytsak, M. Scale-up of
Azide Chemistry: A Case Study. Org. Process Res. Dev. 2012, 16,
2051−2057.
(45) Hoekstra, W. J.; Wirth, D. D.; Ehiwe, T.; Bonnaud, T.
Antifungal compounds and processes for making. WO 2016149486,
2016.

PATENT

WO-2021143811

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021143811&_cid=P21-KROODI-31077-1

Novel crystalline polymorphic form of VT-1161 (also known as oteseconazole) phosphate disodium salt, useful as a prodrug of oteseconazole, for treating systemic fungal infection (eg Candida albicans infection) or onychomycosis.The function of metalloenzymes is highly dependent on the presence of metal ions in the active site of the enzyme. It is recognized that reagents that bind to and inactivate metal ions at the active site greatly reduce the activity of the enzyme. Nature uses this same strategy to reduce the activity of certain metalloenzymes during periods when enzyme activity is not needed. For example, the protein TIMP (tissue inhibitor of metalloproteinases) binds to zinc ions in the active sites of various matrix metalloproteinases, thereby inhibiting enzyme activity. The pharmaceutical industry has used the same strategy in the design of therapeutic agents. For example, the azole antifungal agents fluconazole and voriconazole contain 1-(1,2,4-triazole) group, which exists in the active site of the target enzyme lanosterol demethylase The heme iron binds, thereby inactivating the enzyme. Another example includes zinc-bound hydroxamic acid groups, which have been introduced into most of the published inhibitors of matrix metalloproteinases and histone deacetylases. Another example is the zinc-binding carboxylic acid group, which has been introduced into most of the published angiotensin converting enzyme inhibitors.
VT-1161, the compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2, 2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol, is an antifungal drug developed by VIAMET, currently in the clinical research stage, its structure is as follows Shown:

This compound mainly acts on the CYP51 target of fungal cells. Compared with the previous triazole antifungal drugs, it has the advantages of wider antibacterial spectrum, low toxicity, high safety and good selectivity. However, this compound is not suitable for Liquid preparations (including or excluding the parenteral delivery carrier) are used to treat patients in need thereof.
2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-trifluoro Ethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate is a prodrug of VT-1161.
On the other hand, nearly half of the drug molecules are in the form of salts, and salt formation can improve certain undesirable physicochemical or biological properties of the drug. Relative to 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2- Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl dihydrogen phosphate, it is of great significance to develop salts with more excellent properties in terms of physical and chemical properties or pharmaceutical properties.To this end, the present disclosure provides a new pharmaceutically acceptable salt form of a metalloenzyme inhibitor.Example 1:[0161](R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2, 2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate disodium salt (Compound 1)[0162]

[0163](R)-2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2 ,2-Trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-yl phosphate (compound 1a, prepared according to the method of patent WO2013110002, 0.28g, 0.46mmol, 1.0eq) and ethanol (5mL ) Add to the reaction flask and stir evenly. A solution of NaOH (36.90 mg, 2.0 eq) dissolved in water (1 mL) was added dropwise into the above reaction flask, stirring was continued for 2 h, and concentrated to obtain compound 1, 300 mg of white solid.[0164]After X-ray powder diffraction detection, the XRPD spectrum has no sharp diffraction peaks, as shown in FIG. 10.[0165]Ms:608.10[M-2Na+3H] ⁺ .[0166]Ion chromatography detected that the sodium ion content was 6.23%.[0167]Example 2: (R)-((2-(2,4-Difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4 -(2,2,2-Trifluoroethoxy)phenyl)pyridin-2-yl)prop-2-yl)oxy)methyl phosphate disodium salt (compound 2)

[0169]Under ice-cooling, NaH (58mg, 0.87mmol) was added to the reaction flask, 1.5mL of N,N-dimethylformamide and 0.6mL of tetrahydrofuran were added, followed by iodine (38mg, 0.15mmol), and then Compound 2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-tetrazol-1-yl)-1-(5-(4-(2,2,2-tri Fluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (2b, prepared according to the method of patent WO2013110002, 158mg, 0.3mmol) tetrahydrofuran (1ml) solution was added to the reaction solution, stirred and reacted for 1-4h , And then add compound 2a (519mg, 2.01mmol) in tetrahydrofuran (1ml) solvent to the reaction, stir until the reaction is complete, 10% aqueous ammonium chloride solution to quench the reaction, extract, concentrate and drain, the crude product 2c is directly used for the next One-step reaction, Ms: 750.0[M+H] ⁺ .[0170]

[0171]Under ice-bath cooling, add trifluoroacetic acid (0.5mL) to the crude product 2c (300mg) in dichloromethane (2mL) solution, stir until the reaction is complete, and after concentration, the target compound 2d, 82mg, Ms was separated by high performance liquid phase separation. :638.0[M+H] ⁺ .[0172]

Add compound 2d (0.29g, 0.46mmol, 1.0eq) and ethanol (5mL) obtained in the previous step into the reaction flask, stir, and add NaOH (36.90mg, 2.0eq) water (1ml) solution dropwise to the aforementioned reaction solution , Stirred for 2-5 h, and concentrated to obtain 2,313 mg of the target compound.
Ms:638.10[M-2Na+3H] ⁺ .

PATENT

WO2011133875

https://patents.google.com/patent/WO2011133875A2/en

Product pat, WO2011133875 , protection in the EU states and the US April 2031.

PATENT

WO2015143184 ,

https://patents.google.com/patent/WO2015143184A1/en

Mycovia, claiming a process for preparing antifungal compounds, particularly oteseconazole.EXAMPLE 11

2-(2,4-Difluorophenyl)-l,l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (11)Compound 11 was prepared using the conditions employed for 1: 0.33 g as a solid. The precursor l-bromo-4-(2,2,2-trifluoroethoxy)benzene was prepared as described below in one step.1H NMR (500 MHz, CDC1₃): δ 8.76 (s, 1 H), 8.70 (s, 1 H), 7.95 (d, / = 8.0 Hz, 1 H), 7.70 (s, 1 H), 7.64 (d, / = 8.5 Hz, 1 H), 7.54 (d, / = 8.5 Hz, 2 H), 7.42- 7.37 (m, 1 H), 7.08 (d, / = 8.5 Hz, 2 H), 6.79- 6.75 (m, 1 H), 6.69- 6.66 (m, 1 H), 5.58 (d, / = 14.0 Hz, 1 H), 5.14 (d, / = 14.0 Hz, 1 H), 4.44 – 4.39 (m, 2 H). HPLC: 99.1%. MS (ESI): m/z 528 [M⁺+l].Chiral preparative HPLC Specifications for (+)-ll:Column: Chiralpak IA, 250 x 4.6mm, 5uMobile Phase: A) w-Hexane, B) IPAIsocratic: A: B (65:35)Flow Rte: l.OO mL/minOptical rotation [a]_D: + 24° (C = 0.1 % in MeOH). 1 -Bromo-4-( 2,2,2-trifluoroethoxy )benzeneTo a stirred solution of trifluoroethyl tosylate (1.5 g, 5.8 mmol) in DMF (20 mL) was added K₂CO₃ (4 g, 29.4 mmol) followed by addition of p-bromo phenol (1.1 g, 6.46 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 120 °C for 6 h. The volatiles were evaporated under reduced pressure; the residue was diluted with water (5 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water, brine and dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 5% EtOAc/hexane to afford the desired product (0.8 g, 3.13 mmol, 53.3%) as semi solid. 1H NMR (200 MHz, CDC1₃): δ 7.44 – 7.38 (m, 2 H), 6.86-6.80 (m, 2 H), 4.38- 4.25 (m, 2 H).ExamplesThe present invention will now be demonstrated using specific examples that are not to be construed as limiting.General Experimental ProceduresDefinitions of variables in the structures in schemes herein are commensurate with those of corresponding positions in the formulae delineated herein.Synthesis of 1 or la

A process to prepare enantiopure compound 1 or la is disclosed. Syntheses of lor la may be accomplished using the example syntheses that are shown below (Schemes 1-4). The preparation of precursor ketone 3-Br is performed starting with reaction of 2,5-dibromo- pyridine with ethyl 2-bromo-difluoroacetate to produce ester 2-Br. This ester can be reacted with morpholine to furnish morpholine amide 2b-Br, followed by arylation to provide ketone 3-Br. Alternatively, ketone 3-Br can be afforded directly from ester 2-Br as shown in Scheme 1. Scheme 1. Synthesis of ketone 3-Br r

Ketone 3 may be prepared in an analogous fashion as described in Scheme 1 starting from corresponding substituted 2-bromo-pyridines, which can be prepared according to synthetic transformations known in the art and contained in the references cited herein (Scheme 2).Scheme 2. Synthesis of ketone 3

R-i = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, – 0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S0₂)-alkyl, -0(S0₂)-substituted alkyl, – 0(S0₂)-aryl, or -0(S0₂)-substituted aryl.Alternatively, compound 1 can be prepared according to Scheme 3 utilizing diols 2-6b (or 2- 6d, the enantiomer of 2-6b, or mixtures thereof) or 2-6a (or 2-6c, the enantiomer of 2-6a, or mixtures thereof). Olefins 2-5a and 2-5 can be prepared by reacting ketones 3 and 1-4 under Wittig olefination conditions (e.g., Ph₃PCH₃Br and BuLi). Also, as indicated in Scheme 5, any of pyridine compounds, 3, 2-5a, 2-6b, 2-7b, 4*, 4b, or 6 can be converted to the corresponding 4-CF₃CH₂O-PI1 analogs (e.g., 1-4, 2-5, 2-6a, 2-7a, 5*, 1-6*, or 1 or the corresponding enantiomers, or mixtures thereof) by cross-coupling with 4,4,5, 5-tetramethyl-2- (4-(2,2,2-trifluoroethoxy)phenyl)-l,3,2-dioxaborolane (or the corresponding alkyl boronates or boronic acid or the like), in a suitable solvent system (e.g., an organic-aqueous solvent mixture), in the presence of a transition metal catalyst (e.g., (dppf)PdCl₂), and in the presence of a base (e.g., KHCO₃, K₂C0₃, Cs₂C0₃, or Na₂C0₃, or the like). Olefins 2-5a and 2-5 can be transformed to the corresponding chiral diols, 2-6b (or 2-6d, the enantiomer of 2-6b, or mixtures thereof) or 2-6a (or 2-6c, the enantiomer of 2-6a, or mixtures thereof), through exposure to Sharpless asymmetric dihydroxylation conditions: 1) commercially available AD- mix alpha or AD-mix beta with or without additional osmium oxidant and methanesulfonamide, 2) combination of a catalytic osmium oxidant (e.g., Os0₄ or K₂0sC>₂(OH)₄), a stoichiometric iron oxidant (e.g., K₃Fe(CN)₆), a base (e.g., KHCO₃, K2CO₃, Cs₂C0₃, or Na₂C0₃, or the like), and a chiral ligand (e.g., (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQD)₂AQN, (DHQ)₂AQN, (DHQD)₂PYR, or (DHQ)₂PYR; preferably (DHQ)₂PHAL, (DHQD)₂PHAL, (DHQD)₂AQN, and (DHQD)₂PYR), or 3) option 2) with methanesulfonamide. The primary alcohol of the resultant chiral diols, 2-6b (or 2-6d, the enantiomer of 2-6b, or mixtures thereof) or 2-6a (or 2-6c, the enantiomer of 2-6a, or mixtures thereof), can then be activated to afford compounds 2-7b (or 2-7d, the enantiomer of 2-7b, or mixtures thereof) or 2-7a (or 2-7c, the enantiomer of 2-7a, or mixtures thereof). For example, the mesylates can be prepared by exposing chiral diols, 2-6b (or 2-6d, the enantiomer of 2-6b, or mixtures thereof) or 2-6a (or 2-6c, the enantiomer of 2-6a, or mixtures thereof), to methanesulfonyl chloride and a base. Epoxide formation can be affected by the base-mediated (e.g., KHCO₃, K2CO₃, CS2CO₃, or Na₂CC>₃, or the like) ring closure of compounds 2-7b (or 2- 7d, the enantiomer of 2-7b, or mixtures thereof) or 2-7a (or 2-7c, the enantiomer of 2-7a, or mixtures thereof) to provide epoxides 4* (or 4c*, the enantiomer of 4*, or mixtures thereof) and 5* (or 5-b*, the enantiomer of 5*, or mixtures thereof). The epoxides can then be converted into amino-alcohols 4b (or 4c, the enantiomer of 4b, or mixtures thereof) and 1-6* (or 1-7*, the enantiomer of 1-6*, or mixtures thereof) through ammonia-mediated epoxide opening using ammonia in a suitable solvent (e.g., MeOH, EtOH, or water). Subsequent treatment with TMS-azide in the presence of trimethylorthoformate and sodium acetate in acetic acid would yield compounds 6 (or 6a, the enantiomer of 6, or mixtures thereof) or 1 (or la, the enantiomer of 1, or mixtures thereof) (US 4,426,531).Scheme 3. Synthesis of 1 via Asymmetric Dihydroxylation Method

Y is -OS02-alkyl, -OS02-substituted alkyl, -OS02-aryl, -OS02- substituted aryl, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, – 0(C=0)-aryl, -0(C=0)-substituted aryl, or halogen

R-i = halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S0₂)-alkyl, -0(S0₂)-substituted alkyl, -0(S0₂)-aryl, or -0(S0₂)-substituted aryl.Compound 1 (or la, the enantiomer of 1, or mixtures thereof) prepared by any of the methods presented herein can be converted to a sulfonic salt of formula IX (or IXa, the enantiomer of IX, or mixtures thereof), as shown in Scheme 4. This can be accomplished by a) combining compound 1 (or la, the enantiomer of 1, or mixtures thereof), a crystallization solvent or crystallization solvent mixture (e.g., EtOAc, i^‘PrOAc, EtOH, MeOH, or acetonitrile, or oZ-S-OHcombinations thereof), and a sulfonic acid o (e.g., Z = Ph, p-tolyl, Me, or Et), b) diluting the mixture with an appropriate crystallization co-solvent or crystallization co-solvent mixture (e.g., pentane, methyl i-butylether, hexane, heptane, or toluene, or combinations thereof), and c) filtering the mixture to obtain a sulfonic acid salt of formula IX (or IXa, the enantiomer of IX, or mixtures thereof). cheme 4. Synthesis of a Sulfonic Acid Salt of Compound 1 or la

The following describes the HPLC method used in assessing HPLC purity of the examples and intermediates presented below:Column: Waters XBridge Shield RP18, 4.6 x 150 mm, 3.5 μιηMobile Phase: A = 0.05% TFA/H₂0, B = 0.05% TFA/ACNAutosampler flush: 1 : 1 ACN/H₂0Diluent: 1:1 ACN/H₂0Flow Rate: 1.0 ml/minTemperature: 45 °CDetector: UV 275 nmPump Parameters:

EXAMPLE 1Preparation of ethyl 2-(5-bromopyridin-2-yl)-2,2-difluoroacetate (2-Br)

2-Br Dialkylated impurity In a clean multi-neck round bottom flask, copper powder (274.7 g, 2.05 eq) was suspended in dimethyl sulfoxide (3.5 L, 7 vol) at 20 – 35 °C. Ethyl bromodifluoroacetate (449 g, 1.05 eq) was slowly added to the reaction mixture at 20 – 25 °C and stirred for 1 – 2 h. 2, 5- dibromopyridine (500 g, 1 eq) was added to the reaction mixture and the temperature was increased to 35 – 40 °C. The reaction mixture was maintained at this temperature for 18 – 24 h and the reaction progress was monitored by GC.After the completion of the reaction, ethyl acetate (7 L, 14 vol) was added to the reaction mixture and stirring was continued for 60 – 90 min at 20 – 35 °C. The reaction mixture was filtered through a Celite bed (100 g; 0.2 times w/w Celite and 1L; 2 vol ethyl acetate). The reactor was washed with ethyl acetate (6 L, 12 vol) and the washings were filtered through a Celite bed. The Celite bed was finally washed with ethyl acetate (1 L, 2 vol) and all the filtered mother liquors were combined. The pooled ethyl acetate solution was cooled to 8 – 10 °C, washed with the buffer solution (5 L, 10 vol) below 15 °C (Note: The addition of buffer solution was exothermic in nature. Controlled addition of buffer was required to maintain the reaction mixture temperature below 15 °C). The ethyl acetate layer was washed again with the buffer solution until (7.5 L; 3 x 5 vol) the aqueous layer remained colorless. The organic layer was washed with a 1: 1 solution of 10 % w/w aqueous sodium chloride and the buffer solution (2.5 L; 5 vol). The organic layer was then transferred into a dry reactor and the ethyl acetate was distilled under reduced pressure to get crude 2-Br.The crude 2-Br was purified by high vacuum fractional distillation and the distilled fractions having 2-Br purity greater than 93 % (with the dialkylated not more than 2 % and starting material less than 0.5 %) were pooled together to afford 2-Br.Yield after distillation: 47.7 % with > 93 % purity by GC (pale yellow liquid). Another 10 % yield was obtained by re-distillation of impure fractions resulting in overall yield of ~ 55 – 60 %.*H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz): 8.85 (1H, d, 1.6 Hz), 8.34 (1H, dd, J = 2.0 Hz, 6.8 Hz), 7.83 (1H, d, J = 6.8 Hz), 4.33 (2H, q, J = 6.0 Hz), 1.22 (3H, t, J = 6.0 Hz). ¹³C NMR: 162.22 (i, -C=0), 150.40 (Ar-C-), 149.35 (t, Ar-C), 140.52 (Ar-C), 123.01 (Ar-C), 122.07 (Ar-C), 111.80 (t, -CF₂), 63.23 (-OCH₂-), 13.45 (-CH₂CH₃).EXAMPLE 2

Preparation of2-( 5-bromopyridin-2-yl )-l -(2,4-difluorophenyl )-2, 2-difluoroethanone ( 3-Br ) A. One-step Method

l-Bromo-2,4-difluorobenzene (268.7 g; 1.3 eq) was dissolved in methyl tert butyl ether (MTBE, 3.78 L, 12.6 vol) at 20 – 35 °C and the reaction mixture was cooled to -70 to -65 °C using acetone/dry ice bath. n-Butyl lithium (689 rriL, 1.3 eq; 2.5 M) was then added to the reaction mixture maintaining the reaction temperature below -65 °C (Note: Controlled addition of the n-Butyl Lithium to the reaction mixture was needed to maintain the reaction mixture temperature below – 65 °C). After maintaining the reaction mixture at this temperature for 30 – 45 min, 2-Br (300 g, 1 eq) dissolved in MTBE (900 rriL, 3 vol) was added to the reaction mixture below – 65 °C. The reaction mixture was continued to stir at this temperature for 60 – 90 min and the reaction progress was monitored by GC.The reaction was quenched by slow addition of 20 % w/w ammonium chloride solution (750 mL, 2.5 vol) below -65 °C. The reaction mixture was gradually warmed to 20 – 35 °C and an additional amount of 20 % w/w ammonium chloride solution (750 mL, 2.5 vol) was added. The aqueous layer was separated, the organic layer was washed with a 10 % w/w sodium bicarbonate solution (600 mL, 2 vol) followed by a 5 % sodium chloride wash (600 mL, 2 vol). The organic layer was dried over sodium sulfate (60 g; 0.2 times w/w), filtered and the sodium sulfate was washed with MTBE (300 mL, 1 vol). The organic layer along with washings was distilled below 45 °C under reduced pressure until no more solvent was collected in the receiver. The distillation temperature was increased to 55 – 60 °C, maintained under vacuum for 3 – 4 h and cooled to 20 – 35 °C to afford 275 g (73.6 % yield, 72.71 % purity by HPLC) of 3-Br as a pale yellow liquid.*H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz):8.63 (1H, d, 1.6 Hz, Ar-H), 8.07 – 8.01 (2H, m, 2 x Ar-H), 7.72 (1H, d, J = 6.8 Hz, Ar-H), 7.07 – 6.82 (1H, m, Ar-H), 6.81 – 6.80 (1H, m, Ar-H). ¹³C NMR: 185.60 (t, -C=0), 166.42 (dd, Ar-C-), 162.24 (dd, Ar-C),150.80 (Ar-C), 150.35 (Ar-C), 140.02 (Ar-C), 133.82 (Ar-C), 123.06 (Ar-C), 1122.33 (Ar-C), 118.44 (Ar-C), 114.07 (-CF₂-), 122.07 (Ar-C), 105.09 (Ar-C).

B. Two-step Method via 2b-Br

2-Br (147.0 g) was dissolved in n-heptane (1.21 L) and transferred to a 5-L reactor equipped with overhead stirrer, thermocouple, condenser and addition funnel. Morpholine (202 ml) was added. The solution was heated to 60 °C and stirred overnight. The reaction was complete by HPLC analysis (0.2% 2-Br; 94.7% 2b-Br). The reaction was cooled to room temperature and 1.21 L of MTBE was added. The solution was cooled to ~4 °C and quenched by slow addition of 30% citric acid (563 ml) to maintain the internal temperature <15 °C. After stirring for one hour the layers were allowed to settle and were separated (Aq. pH=5). The organic layer was washed with 30% citric acid (322 ml) and 9% NaHC0₃ (322 ml, aq. pH 7+ after separation). The organic layer was concentrated on the rotary evaporator (Note 1) to 454 g (some precipitation started immediately and increased during concentration). After stirring at room temperature the suspension was filtered and the product cake was washed with n-heptane (200 ml). The solid was dried in a vacuum oven at room temperature to provide 129.2 g (77%) dense powder. The purity was 96.5% by HPLC analysis.To a 1-L flask equipped with overhead stirring, thermocouple, condenser and addition funnel was added magnesium turnings (14.65 g), THF (580 ml) and l-bromo-2,4-difluorobenzene (30.2 g, 0.39 equiv). The mixture was stirred until the reaction initiated and self-heating brought the reaction temperature to 44 °C. The temperature was controlled with a cooling bath as the remaining l-bromo-2,4-difluorobenzene (86.1 g, 1.11 equiv) was added over about 30 min. at an internal temperature of 35-40 °C. The reaction was stirred for 2 hours while gradually cooling to room temperature. The dark yellow solution was further cooled to 12 °C.During the Grignard formation, a jacketed 2-L flask equipped with overhead stirring, thermocouple, and addition funnel was charged with morpholine amide 2b-Br (129.0 g) and THF (645 ml). The mixture was stirred at room temperature until the solid dissolved, and then the solution was cooled to -8.7 °C. The Grignard solution was added via addition funnel over about 30 min. at a temperature of -5 to 0 °C. The reaction was stirred at 0 °C for 1 hour and endpointed by HPLC analysis. The reaction mixture was cooled to -5 °C and quenched by slow addition of 2N HC1 over 1 hour at <10 °C. The mixture was stirred for 0.5 h then the layers were allowed to settle and were separated. The aqueous layer was extracted with MTBE (280 ml). The combined organic layers were washed with 9% NaHCC>3 (263 g) and 20% NaCl (258 ml). The organic layer was concentrated on the rotary evaporator with THF rinses to transfer all the solution to the distillation flask. Additional THF (100 ml) and toluene (3 x 100 ml) were added and distilled to remove residual water from the product. After drying under vacuum, the residue was 159.8 g of a dark brown waxy solid (>theory). The purity was approximately 93% by HPLC analysis.EXAMPLE 3Preparation of 3-amino-l-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-l,l-difluoropropan- -ol (±ib-Br)

4-Br (200g, 1 eq) was added into methanolic ammonia (8.0 L; 40 vol; ammonia content: 15 – 20 % w/v) in an autoclave at 10 – 20 °C. The reaction mixture was gradually heated to 60 – 65 °C and at 3 – 4 kg/cm² under sealed conditions for 10 – 12 h. The reaction progress was monitored by GC. After completion of the reaction, the reaction mixture was cooled to 20 – 30 °C and released the pressure gradually. The solvent was distilled under reduced pressure below 50 °C and the crude obtained was azeotroped with methanol (2 x 600 mL, 6 vol) followed by with isopropanol (600 mL, 2 vol) to afford 203 g (96.98 % yield, purity by HPLC: 94.04 %) of +4b-Br. EXAMPLE 4Preparation of3-amino-l-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-l,l-difluoropropan- -ol (4b-Br or 2c-Br)

Amino alcohol ±4b-Br (150 g, 1 eq) was dissolved in an isopropanol /acetonitrile mixture (1.5L, 8:2 ratio, 10 vol) and Di-p-toluoyl-L-tartaric acid (L-DPTTA) (84.05 g, 0.55 eq) was added into the reactor at 20 – 30 °C. The reaction mixture was heated to 45 – 50 °C for 1 – 1.5 h (Note: The reaction mixture becomes clear and then became heterogeneous). The reaction mixture was gradually cooled to 20 – 30 °C and stirred for 16 – 18 h. The progress of the resolution was monitored by chiral HPLC analysis.After the completion of the resolution, the reaction mixture was gradually cooled to 20 – 35 °C. The reaction mixture was filtered and the filtered solid was washed with a mixture of acetonitrile and isopropanol (8:2 mixture, 300 mL, 2 vol) and dried to afford 75 g of the L- DPTTA salt (95.37 % ee). The L-DPTTA salt obtained was chirally enriched by suspending the salt in isopropanol /acetonitrile (8:2 mixture; 750 mL, 5 vol) at 45 – 50 °C for 24 – 48 h. The chiral enhancement was monitored by chiral HPLC; the solution was gradually cooled to 20 – 25 °C, filtered and washed with an isoporpanol /acetonitrile mixture (8:2 mixture; 1 vol). The purification process was repeated and after filtration, the salt resulted in chiral purity greater than 96 % ee. The filtered compound was dried under reduced pressure at 35 – 40 °C to afford 62 g of the enantio-enriched L-DPPTA salt with 97.12% ee as an off-white solid. The enantio-enriched L-DPTTA salt (50 g, 1 eq) was dissolved in methanol (150 mL, 3 vol) at 20 – 30 °C and a potassium carbonate solution (18.05 g K2CO₃ in 150 mL water) was slowly added at 20 – 30 °C under stirring. The reaction mixture was maintained at this temperature for 2 – 3 h (pH of the solution at was maintained at 9). Water (600 mL, 12 vol) was added into the reaction mixture through an additional funnel and the reaction mixture was stirred for 2 – 3 h at 20 – 30 °C. The solids were filtered; washed with water (150 mL, 3 vol) and dried under vacuum at 40 – 45 °C to afford 26.5 g of amino alcohol 4b-Br or 4c-Br with 99.54 % chemical purity, 99.28 % ee as an off-white solid. (Water content of the chiral amino alcohol is below 0.10 % w/w).1H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz):8.68 (1H, d, J = 2.0 Hz, Ar- H), 8.16 (1H, dd, J = 8.0 Hz, 2.0 Hz, Ar-H), 7.49 – 7.43 (1H, m, Ar-H), 7.40 (1H, d, J = 8 Hz, Ar-H), 7.16 – 7.11 (1H, m, Ar-H), 7.11 – 6.99 (1H, m, Ar-H), 3.39 – 3.36 (1H, m, -OCH_AH_B– ), 3.25 – 3.22 (1H, m, -OCH_AH_B-).¹³C NMR: 163.87 -158.52 (dd, 2 x Ar-C-), 150.88 (Ar-C), 149.16 (Ar-C), 139.21 (Ar-C), 132.39 (Ar-C), 124.49 (Ar-C), 122.17 (Ar-C), 121.87 (d, Ar- C), 119.91 (t, -CF₂-), 110.68 (Ar-C), 103.97 (i, Ar-C), 77.41 (i,-C-OH), 44.17 (-CH₂-NH₂).EXAMPLE 5

Preparation of l-(5-bromopyridin-2-yl)-2-(2,4-difluorophenyl)-l,l-difluoro-3-(lH-tetrazol-l- yl)propan-2-ol (l-6*-Br or l-7*-Br)

4b-Br or 4c-Br (20.0 g, 1 eq.) was added to acetic acid (50 mL, 2.5 vol) at 25 – 35 °C followed by the addition of anhydrous sodium acetate (4.32 g, 1 eq), trimethyl orthoformate (15.08 g, 2.7 eq). The reaction mixture was stirred for 15 – 20 min at this temperature and trimethylsilyl azide (12.74 g, 2.1 eq) was added to the reaction mixture (Chilled water was circulated through the condenser to minimize the loss of trimethylsilyl azide from the reaction mixture by evaporation). The reaction mixture was then heated to 70 – 75 °C and maintained at this temperature for 2 -3 h. The reaction progress was monitored by HPLC. Once the reaction was complete, the reaction mixture was cooled to 25 – 35 °C and water (200 mL, 10 vol) was added. The reaction mixture was extracted with ethyl acetate (400 mL, 20 vol) and the aqueous layer was back extracted with ethyl acetate (100 mL, 5 vol). The combined organic layers were washed with 10 % potassium carbonate solution (3 x 200 mL; 3 x 10 vol) followed by a 10 % NaCl wash (1 x 200 mL, 10 vol). The organic layer was distilled under reduced pressure below 45 °C. The crude obtained was azeotroped with heptanes (3 x 200 mL) to get 21.5g (94 % yield, 99.26 5 purity) of tetrazole 1-6* or 1-7* compound as pale brown solid (low melting solid).1H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz NMR instrument): 9.13 (1H, Ar-H), 8.74 (1H, Ar-H), 8.22 – 8.20 (1H, m, Ar-H), 7.44 (1H, d, J = 7.2 Hz, Ar-H), 7.29 (1H„Ar-H), 7.23 – 7.17 (1H, m, Ar-H), 6.92 – 6.88 (1H, Ar-H), 5.61 (1H, d, J = 1 1.2 Hz, – OCHAHB-), 5.08 (1H, d, J = 5.6 Hz, -OCH_AH_B-).¹³C NMR: 163.67 -161.59 (dd, Ar-C-), 160.60 – 158.50 (dd, Ar-C-), 149.65 (Ar-C), 144.99 (Ar-C), 139.75 (Ar-C), 131.65 (Ar-C), 124.26 (Ar-C), 122.32 (d, Ar-C), 119.16 (t, -CF₂-), 118.70 (d, Ar-C), 1 11.05 (d, Ar-C) 104.29 (t, Ar-C), 76.79 (i,-C-OH), 59.72 (Ar-C), 50.23 (-OCH₂N-). EXAMPLE 6Preparation of 2-(2,4-difluorophenyl)-l , 1 -difluoro-3-( 1 H-tetrazol-1 -yl)-l -(5-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (1 or la)A. Preparation of 1 or la via l-6*-Br or l-7*-Br

Synthesis of 4,4,5, 5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-l,3,2-dioxaborolane Potassium carbonate (59.7 g, 2.2 eq.) was added to a slurry of DMF (190 mL, 3.8 Vol.), 4- Bromo phenol (37.4g, 1.1 eq.) and 2,2,2-trifluroethyl tosylate (50.0 g, 1.0 eq.) at 20 – 35 °C under an inert atmosphere. The reaction mixture was heated to 115 – 120 °C and maintained at this temperature for 15 – 18 h. The reaction progress was monitored by GC. The reaction mixture was then cooled to 20 – 35 °C, toluene (200 mL, 4.0 vol.) and water (365 mL, 7. 3 vol.) were added at the same temperature, stirred for 10 – 15 minutes and separated the layers. The aqueous layer was extracted with toluene (200 mL, 4.0 vol.). The organic layers were combined and washed with a 2M sodium hydroxide solution (175 mL, 3.5 vol.) followed by a 20 % sodium chloride solution (175 mL, 3.5 vol.). The organic layer was then dried over anhydrous sodium sulfate and filtered. The toluene layer was transferred into clean reactor, spurged with argon gas for not less than 1 h. Bis(Pinacolato) diborane (47 g, 1.1 eq.), potassium acetate (49.6 g, 3.0 eq.) and 1,4-dioxane (430 mL, 10 vol.) were added at 20 -35 °C, and spurged the reaction mixture with argon gas for at least 1 h. Pd(dppf)Cl₂ (6.88 g, 0.05eq) was added to the reaction mixture and continued the argon spurging for 10 – 15 minutes. The reaction mixture temperature was increased to 70 – 75 °C, maintained the temperature under argon atmosphere for 15 – 35 h and monitored the reaction progress by GC. The reaction mixture was cooled to 20 – 35 °C, filtered the reaction mixture through a Celite pad, and washed with ethyl acetate (86 mL, 2 vol.). The filtrate was washed with water (430 mL, 10 vol.). The aqueous layer was extracted with ethyl acetate (258 mL, 6 vol.) and washed the combined organic layers with a 10 % sodium chloride solution (215 mL, 5 vol.). The organic layer was dried over anhydrous sodium sulfate (43g, 1 time w/w), filtered and concentrated under reduced pressure below 45 °C to afford crude 4,4,5, 5-tetramethyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)-l,3,2-dioxaborolane (65 g; 71 % yield with the purity of 85.18 % by GC). The crude 4,4,5,5-tetramethyl-2-(4-(2,2,2-trifluoroethoxy)phenyl)-l,3,2-dioxaborolane (65 g, 1 eq.) was dissolved in 10 % ethyl acetate – n-Heptane (455 mL, 7 vol.) and stirred for 30 – 50 minutes at 20 – 35 °C. The solution was filtered through a Celite bed and washed with 10 % ethyl acetate in n-Heptane (195 mL, 3 vol.). The filtrate and washings were pooled together, concentrated under vacuum below 45 °C to afford 4,4,5, 5-tetramethyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)-l,3,2-dioxaborolane as a thick syrup (45.5 g; 70 % recovery). This was then dissolved in 3 % ethyl acetate-n-heptane (4 vol.) and adsorbed on 100 – 200 M silica gel (2 times), eluted through silica (4 times) using 3 % ethyl acetate – n- heptane. The product rich fractions were pooled together and concentrated under vacuum. The column purified fractions (> 85 % pure) were transferred into a round bottom flask equipped with a distillation set-up. The compound was distilled under high vacuum below 180 °C and collected into multiple fractions. The purity of fractions was analyzed by GC (should be > 98 % with single max impurity < 1.0 %). The less pure fractions (> 85 % and < 98 % pure fraction) were pooled together and the distillation was repeated to get 19g (32% yield) of 4,4,5, 5-tetramethyl-2-(4- (2,2,2-trifluoroethoxy)phenyl)-l,3,2-dioxaborolane as a pale yellow liquid.*H NMR: δ values with respect to TMS (DMSO-d⁶; 400 MHz):7.64 (2H, d, 6.8 Hz), 7.06 (2H, d, J = 6.4 Hz), 4.79 (2H, q, J = 6.8 Hz), 1.28 (12H, s).1³C NMR: 159.46 (Ar-C-O-), 136.24 (2 x Ar-C-), 127.77 – 120.9 (q, -CF₃), 122.0 (Ar-C-B), 114.22 (2 x Ar-C-), 64.75 (q, J = 27.5 Hz).Synthesis of 2-(2.4-difluorophenyl)-l.l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(4-(2.2.2- trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (1 or la)l-6*-Br or l-7*-Br (14 g, 0.03 mol, 1 eq) was added to tetrahydrofuran (168 mL, 12 vol) at 25 – 35 °C and the resulting solution was heated to 40 – 45 °C. The reaction mixture was maintained at this temperature for 20 – 30 min under argon bubbling. Sodium carbonate (8.59 g, 0.08 mol, 2.5 eq) and water (21 mL, 1.5 vol) were added into the reaction mixture and the bubbling of argon was continued for another 20 – 30 min. 4,4,5, 5-tetramethyl-2-(4-(2,2,2- trifluoroethoxy)phenyl)-l,3,2-dioxaborolane (10.76 g, 1.1 eq) dissolved in tetrahydrofuran (42 mL, 3 vol) was added into the reaction mixture and argon bubbling was continued for 20 – 30 min. Pd(dppf)Cl₂ (2.65 g, 0.1 eq) was added to the reaction mixture under argon bubbling and stirred for 20 – 30 min (Reaction mixture turned into dark red color). The reaction mixture was heated to 65 – 70 °C and maintained at this temperature for 3 – 4 h. The reaction progress was monitored by HPLC. The reaction mixture was cooled to 40 – 45 °C and the solvent was distilled under reduced pressure. Toluene (350 mL, 25 vol.) was added to the reaction mixture and stirred for 10 – 15 min followed by the addition of water (140 mL, 10 vol). The reaction mixture was filtered through Hyflo (42 g, 3 times), the layers were separated and the organic layer was washed with water (70 mL, 5 vol) and a 20 % w/w sodium chloride solution (140 mL, 10 vol). The organic layer was treated with charcoal (5.6 g, 0.4 times, neutral chalrcoal), filtered through Hyflo. (lS)-lO-Camphor sulfonic acid (7.2 g, 1 eq.) was added to the toluene layer and the resulting mixture was heated to 70 – 75 °C for 2 – 3 h. The reaction mixture was gradually cooled to 25 – 35 °C and stirred for 1 – 2 h. The solids were filtered, washed with toluene (2 x 5 vol.) and then dried under vacuum below 45 °C to afford 18.0 g of an off white solid. The solids (13.5 g, 1 eq.) were suspended in toluene (135 mL, 10 vol) and neutralized by adding 1M NaOH solution (1.48 vol, 1.1 eq) at 25 – 35 °C and stirred for 20 – 30 min. Water (67.5 mL, 5 vol) was added to the reaction mixture and stirred for 10 – 15 min, and then the layers were separated. The organic layer was washed with water (67.5 mL, 5 vol) to remove the traces of CSA. The toluene was removed under reduced pressure below 45 °C to afford crude 1 or la. Traces of toluene were removed by azeotroping with ethanol (3 x 10 vol), after which light brown solid of crude 1 or la (7.5 g, 80% yield) was obtained.The crude 1 or la (5 g) was dissolved in ethanol (90 mL, 18 vol.) at 20 – 35 °C, and heated to 40 – 45 °C. Water (14 vol) was added to the solution at 40 – 45 °C, the solution was maintained at this temperature for 30 – 45 min and then gradually cooled to 20 – 35 °C. The resulting suspension was continued to stir for 16 – 18 h at 20 – 35 °C, an additional amount of water (4 vol.) was added and the stirring continued for 3 – 4 h. The solids were filtered to afford 4.0 g (80% recovery) of 1 or la (HPLC purity >98%) as an off-white solid.1H NMR: δ values with respect to TMS (DMSO-d₆; 400 MHz):9.15 (1H, s, Ar-H), 8.93 (1H, d, J = 0.8 Hz, Ar-H), .8.22 – 8.20 (1H, m, Ar-H), 7.80 (2H, d, J = 6.8 Hz, Ar-H), 7.52 (1H, d, J = 6.8 Hz, Ar-H), 7.29 (1H, d,J = 3.2Hz, Ar-H), 7.27 – 7.21 (1H, m, Ar-H), 7.23 – 7.21 (2H, d, J = 6.8 Hz, Ar-H), 7.19 (1H, d, J = 6.8 Hz, Ar-H), 6.93 – 6.89 (1H, m, Ar-H), 5.68 (1H, / = 12 Hz, -CH_AH_B), 5.12 (2H, d, J = 11.6 Hz, -CH_AH_B), 4.85 (2H, q, J = 1.6 Hz).1³C NMR: 163.93 – 158.33 (m, 2 x Ar-C), 157.56 (Ar-C), 149.32 (i, Ar-C), 146.40 (Ar-C), 145.02 (Ar-C), 136.20 (Ar-C), 134.26 (2 x Ar-C), 131.88 – 131.74 (m, AR-C), 129.72 (Ar-C), 128.47 (2 x Ar-C), 123.97 (q, -CF₂-), 122.41 (Ar-C), 119.30 (-CF₃), 118.99 (Ar-C), 115.65 (2 x Ar-C), 110.99 (d, Ar-C), 104.22 (i, Ar-C), 77.41 – 76.80 (m, Ar-C), 64.72 (q, -OCH₂-CF₃), 50.54 (-CH₂-N-).B. Preparation of 1 or la via 4b-Br or 4c-Br

Synthesis of 3-amino-2-(2.4-difluorophenyl)-l.l-difluoro-l-(5-(4-(2.2.2- trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (8a or 8b)Potassium carbonate (30.4 g) and water (53.3 g) were charged to a 1-L flask equipped with overhead stirring, thermocouple, and nitrogen/vacuum inlet valve, and stirred until dissolved. The boronic acid (19.37 g), a solution of 4b-Br or 4c-Br in 2-butanol (103.5 g, 27.8 g theoretical 4b-Br or 4c-Br)) and 2-BuOH (147.1 g) were added and stirred to form a clear mixture. The flask was evacuated and refilled with nitrogen 3 times. Pd(d f)2Cl2 (0.30 g) was added and stirred to form a light orange solution. The flask was evacuated and refilled with nitrogen 4 times. The mixture was heated to 85 °C and stirred overnight and endpointed by HPLC analysis. The reaction mixture was cooled to 60 °C and the layers were allowed to settle. The aqueous layer was separated. The organic layer was washed with 5% NaCl solution (5 x 100 ml) at 30-40 °C. The organic layer was filtered and transferred to a clean flask with rinses of 2-BuOH. The combined solution was 309.7 g, water content 13.6 wt% by KF analysis. The solution was diluted with 2-BuOH (189 g) and water (10 g). Theoretically the solution contained 34.8 g product, 522 ml (15 volumes) of 2-BuOH, and 52.2 ml (1.5 volumes) of water. L-Tartaric acid (13.25 g) was added and the mixture was heated to a target temperature of 70-75 °C. During the heat-up, a thick suspension formed. After about 15 minutes at 70-72 °C the suspension became fluid and easily stirred. The suspension was cooled at a rate of 10 °C/hour to 25 °C then stirred at 25 °C for about 10 hours. The product was collected on a vacuum filter and washed with 10:1 (v/v) 2-BuOH/water (50 ml) and 2- butanol (40 ml). The salt was dried in a vacuum oven at 60 °C with a nitrogen purge for 2 days. The yield was 40.08 g of 8a or 8b as a fluffy, grayish-white solid. The water content was 0.13 wt% by KF analysis. The yield was 87.3% with an HPLC purity of 99.48%. Synthesis of 2-(2,4-difluorophenyl)-l,l-difluoro-3-(lH-tetrazol-l-yl)-l-(5-(4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)propan-2-ol (1 or la)To a 350 ml pressure bottle were charged acetic acid (73 ml), 8a or 8b (34.8 g), sodium acetate (4.58 g) and trimethylorthoformate (16.0 g). The mixture was stirred for 18 min. at room temperature until a uniform suspension was obtained. Azidotrimethylsilane (8.88 g) was added and the bottle was sealed. The bottle was immersed in an oil bath and magnetically stirred. The oil bath was at 52 °C initially, and was warmed to 62-64 °C over about ½ hour. The suspension was stirred at 62-64 °C overnight. After 20.5 hours the suspension was cooled to room temperature and sampled. The reaction was complete by HPLC analysis. The reaction was combined with three other reactions that used the same raw material lots and general procedure (total of 3.0 g additional starting material). The combined reactions were diluted with ethyl acetate (370 ml) and water (368 ml) and stirred for about ½ hour at room temperature. The layers were settled and separated. The organic layer was washed with 10% K₂C0₃ solution (370 ml/ 397 g) and 20% NaCl solution (370 ml/ 424 g). The organic layer (319 g) was concentrated, diluted with ethanol (202 g) and filtered, rinsed with ethanol (83 g). The combined filtrate was concentrated to 74 g of amber solution.The crude 1 or la solution in ethanol (74 g solution, containing theoretically 31.9 g 1 or la) was transferred to a 2-L flask equipped with overhead stirring, thermocouple, and addition funnel. Ethanol (335 g) was added including that used to complete the transfer of the 1 or la solution. The solution was heated to nominally 50 °C and water (392 g) was added over 12 minutes. The resulting hazy solution was seeded with 1 or la crystals and stirred at 50 °C. After about ½ hour the mixture was allowed to cool to 40 °C over about ½ hour during which time crystallization started. Some darker colored chunky solid separated out from the main suspension. The pH of the crystallizing mixture was adjusted from 4.5 to 6 using 41% KOH (1.7 g). After about 1 hour a good suspension had formed. Additional water (191 g) was added slowly over ½ hour. The suspension was heated to 50 °C and cooled at 5 °C/min to room temperature. After stirring overnight the suspension was cooled in a water bath to 16 °C and filtered after 1 hour. The wet cake was washed with 55:45 (v/v) water/ethanol (2 x 50 ml) and air-dried on the vacuum filter funnel overnight. Further drying at 40 °C in a vacuum oven with a nitrogen bleed resulted in no additional weight loss. The yield was 30.2 g of off-white fine powder plus some darker granular material. By in-process HPLC analysis there was no difference in the chemical purity of the darker and lighter materials. The purity was 99.4%. The water content was 2.16 wt% by KF analysis. The residual ethanol was 1.7 wt% estimated by ‘Ft NMR analysis. The corrected yield was 29.0 g, 91.0% overall yield for tetrazole formation and crystallization. The melting point was 65 °C by DSC analysis.

FDA Approves Mycovia Pharmaceuticals’ VIVJOA™ (oteseconazole), the First and Only FDA-Approved Medication for Recurrent Vulvovaginal Candidiasis (Chronic Yeast Infection)

– Approval of VIVJOA™ marks a significant therapeutic advancement for reducing the incidence of RVVC, a condition with substantial unmet need, in permanently infertile and postmenopausal women

– VIVJOA™ is the first FDA approval in Mycovia’s pipeline of novel treatments for fungal infections

– U.S. commercial launch of VIVJOA™ expected in Q2

April 28, 2022 07:55 AM Eastern Daylight Time

DURHAM, N.C.–(BUSINESS WIRE)–The U.S. Food and Drug Administration (FDA) approved VIVJOA™ (oteseconazole capsules), an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential. VIVJOA is the first and only FDA-approved medication for this condition and provides sustained efficacy demonstrated by significant long-term reduction of RVVC recurrence through 50 weeks versus comparators. VIVJOA is the first FDA-approved product for Mycovia Pharmaceuticals, Inc. (Mycovia), an emerging biopharmaceutical company dedicated to recognizing and empowering those living with unmet medical needs by developing novel therapies.

“We believe the market need for VIVJOA is strong, and we are eager to execute our commercial plans”Tweet this

RVVC, also known as chronic yeast infection, is defined by the Centers for Disease Control and Prevention (CDC) as three or more symptomatic acute episodes of yeast infection in 12 months. RVVC is a distinct condition from vulvovaginal candidiasis (VVC), and until now, there have been no FDA-approved medications specifically indicated for it. Nearly 75% of all adult women will have at least one yeast infection in their lifetime, with approximately half experiencing a recurrence. Of those women, up to 9% develop RVVC.

“After nearly two decades of living with chronic yeast infection and feeling like there was no hope from the itchiness, irritation and constant dread of when the next yeast infection would return, I was overjoyed to even be a part of this clinical trial,” said Leslie Ivey, RVVC patient and clinical trial participant. “It is gratifying to see RVVC finally get the attention it deserves.”

Symptoms of RVVC include vaginal itching, burning, irritation and inflammation. Some women may experience abnormal vaginal discharge and painful sexual intercourse or urination, causing variable but often severe discomfort and pain.

VIVJOA’s FDA approval is based upon the positive results from three Phase 3 trials of oteseconazole – two global, pivotal VIOLET studies and one U.S.-focused ultraVIOLET study, including 875 patients at 232 sites across 11 countries. In the two global VIOLET studies, 93.3% and 96.1% of women with RVVC who received VIVJOA did not have a recurrence for the 48-week maintenance period compared to 57.2% and 60.6% of patients who received placebo (p <0.001). In the ultraVIOLET study, 89.7% of women with RVVC who received VIVJOA cleared their initial yeast infection and did not have a recurrence for the 50-week maintenance period compared to 57.1% of those who received fluconazole followed by placebo (p <0.001). The most common side effects reported in Phase 3 clinical studies were headache (7.4%) and nausea (3.6%). VIVJOA is contraindicated in those with a hypersensitivity to oteseconazole, and based on data from rat studies, also in females who are of reproductive potential, pregnant, or lactating. Please see additional Important Safety Information below.

Patrick Jordan, CEO of Mycovia Pharmaceuticals and Partner at NovaQuest Capital Management, stated, “We celebrate this important milestone for Mycovia, as VIVJOA is the first antifungal in our pipeline to obtain FDA approval and achieves our goal to fulfill a previously unmet medical need among women suffering from RVVC. We are honored to lead this advancement in women’s health.”

“We believe the market need for VIVJOA is strong, and we are eager to execute our commercial plans,” Jordan continued. “As we enter a new chapter of our history as a commercial biopharmaceutical company, we will continue driving our mission forward to develop novel therapies for overlooked conditions.”

Oteseconazole is designed to inhibit fungal CYP51, which is required for fungal cell wall integrity, and this selective interaction is also toxic to fungi, resulting in the inhibition of fungal growth. Due to its chemical structure, oteseconazole has a lower affinity for human CYP enzymes as compared to fungal CYP enzymes. The FDA granted oteseconazole Qualified Infectious Disease Product and Fast Track designations.

“A medicine with VIVJOA’s sustained efficacy combined with the clinical safety profile has been long needed, as until now, physicians and their patients have had no FDA-approved medications for RVVC,” stated Stephen Brand, Ph.D., Chief Development Officer of Mycovia. “We are excited to be the first to offer a medication designed specifically for RVVC, a challenging and chronic condition that is expected to increase in prevalence over the next decade.”

Mycovia is planning its commercial launch of VIVJOA™ in the second quarter of 2022.

About Recurrent Vulvovaginal Candidiasis

RVVC is a debilitating, chronic infectious condition that affects 138 million women worldwide each year. RVVC, also known as chronic yeast infection, is a distinct condition from vulvovaginal candidiasis (VVC) and defined as three or more symptomatic acute episodes of yeast infection in 12 months. Primary symptoms include vaginal itching, burning, irritation and inflammation. Some women may experience abnormal vaginal discharge and painful sexual intercourse or urination, causing variable but often severe discomfort and pain.

About VIVJOA™

VIVJOA™ (oteseconazole) is an azole antifungal indicated to reduce the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are NOT of reproductive potential. VIVJOA is the first and only FDA-approved medication that provides sustained efficacy demonstrated by significant long-term reduction of RVVC recurrence through 50 weeks versus comparators. Oteseconazole is designed to inhibit fungal CYP51, which is required for fungal cell wall integrity, and this selective interaction is also toxic to fungi, resulting in the inhibition of fungal growth. Due to its chemical structure, oteseconazole has a lower affinity for human CYP enzymes as compared to fungal CYP enzymes. The FDA approved VIVJOA based upon the positive results from three Phase 3 clinical trials of oteseconazole – two global, pivotal VIOLET studies and one U.S.-focused ultraVIOLET study, including 875 patients at 232 sites across 11 countries.

https://www.businesswire.com/news/home/20220428005301/en/FDA-Approves-Mycovia-Pharmaceuticals%E2%80%99-VIVJOA%E2%84%A2-oteseconazole-the-First-and-Only-FDA-Approved-Medication-for-Recurrent-Vulvovaginal-Candidiasis-Chronic-Yeast-Infection

References

^ Jump up to:^a ^b https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215888s000lbl.pdf
^ “Vivjoa: FDA-Approved Drugs”. U.S. Food and Drug Administration (FDA). Retrieved 27 April 2022.
^ Jump up to:^a ^b “FDA Approves Mycovia Pharmaceuticals’ VIVJOA (oteseconazole), the First and Only FDA-Approved Medication for Recurrent Vulvovaginal Candidiasis (Chronic Yeast Infection)” (Press release). Mycovia Pharmaceuticals. 28 April 2022. Retrieved 28 April 2022 – via Business Wire.
^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 76”. WHO Drug Information. 30 (3). hdl:10665/331020.

External links

“Oteseconazole”. Drug Information Portal. U.S. National Library of Medicine.
Clinical trial number NCT03562156 for “A Study of Oral Oteseconazole for the Treatment of Patients With Recurrent Vaginal Candidiasis (Yeast Infection) (VIOLET)” at ClinicalTrials.gov
Clinical trial number NCT03561701 for “A Study of Oral Oteseconazole (VT-1161) for the Treatment of Patients With Recurrent Vaginal Candidiasis (Yeast Infection) (VIOLET)” at ClinicalTrials.gov
Clinical trial number NCT03840616 for “Study of Oral Oteseconazole (VT-1161) for Acute Yeast Infections in Patients With Recurrent Yeast Infections (ultraVIOLET)” at ClinicalTrials.gov

Clinical data

Trade names	Vivjoa
Other names	VT-1161
License data	US DailyMed: Oteseconazole
Routes of administration	By mouth
Drug class	Antifungal
ATC code	J02AC06 (WHO)
Legal status
Legal status	US: ℞-only ^[1]
Identifiers
show IUPAC name
CAS Number	1340593-59-0
PubChem CID	77050711
DrugBank	DB13055
ChemSpider	52083215
UNII	VHH774W97N
KEGG	D11785
ChEBI	CHEBI:188153
ChEMBL	ChEMBL3311228
ECHA InfoCard	100.277.989
Chemical and physical data
Formula	C₂₃H₁₆F₇N₅O₂
Molar mass	527.403 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

/////////OTESECONAZOLE, vt 1161, fungal infection, Candida albicans infection, onychomycosis, PHASE 3,

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C1=CC(=CC=C1C2=CN=C(C=C2)C(C(CN3C=NN=N3)(C4=C(C=C(C=C4)F)F)O)(F)F)OCC(F)(F)F

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Nangibotide

July 28, 2021 9:18 am / Leave a comment

Nangibotide

LQEEDAGEYGCM-amide

CAS 2014384-91-7

Molecular FormulaC₅₄H₈₂N₁₄O₂₂S₂
Average mass1343.439 Da
2014384‐91‐7

L-Leucyl-L-glutaminyl-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methioninamide
LR 12 peptide
LQEEDAGEYG CM

L-Leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-L-methionine
L-Methionine, L-leucyl-L-glutaminyl-L-glutaminyl-L-α-glutamyl-L-α-aspartyl-L-alanylglycyl-L-α-glutamyl-L-tyrosylglycyl-L-cysteinyl-нангиботидمانغيبوتيد南吉博肽

Sequence (one letter code)	LQEEDAGEYGCM-amide
Sequence (three letter code)	H-Leu-Gln-Glu-Glu-Asp-Ala-Gly-Glu-Tyr-Gly-Cys-Met-NH2

OriginatorInotrem
ClassAnti-infectives; Anti-inflammatories; Anti-ischaemics; Antivirals; Peptides
Mechanism of ActionTREML1 protein inhibitors

Phase II/IIICOVID 2019 infections
Phase IISeptic shock
Phase IMyocardial infarction

12 Jul 2021Inotrem has patents pending for nangibotide use in severe forms of COVID-19
12 Jul 2021Inotrem receives funding from French government by Bpifrance for nangibotide development in COVID-2019 infections
12 Jul 2021Inotrem receives authorization from both the French and Belgian authorities to proceed with clinical development of nangibotide up to registration in COVID-2019 infections

Nangibotide, also referred as LR12, is an antagonist of triggering receptor expressed on myeloid cells (TREM)-1, and was derived from residues 94 to 105 of TREM-like transcript-1 (TLT-1).

TREM-1 plays a crucial role in the onset of sepsis by amplifying the host immune response. TLT-1– and TLT-1–derived peptides therefore exhibit anti-inflammatory properties by dampening TREM-1 signalling. LR12 blocks TREM-1 by binding to the TREM-1 ligand and provides protective effects during sepsis such as inhibiting hyper-responsiveness, organ damage, and death, without causing deleterious effects. The protective effects of modulating TREM-1 signalling are also evident in other models of inflammation such as: pancreatitis; haemorrhagic shock; inflammatory bowel diseases and inflammatory arthritis

Inotrem is developing the peptide nangibotide, a triggering receptor expressed on myeloid cells 1 inhibitor, for treating sepsis and septic shock. In July 2021, this drug was reported to be in phase 3 clinical development.

Nangibotide is an inhibitor of TREM-1, a receptor found on certain white blood cells. Activation of TREM-1 stimulates inflammation. Nangibotide is therefore being investigated as a treatment for the overwhelming inflammation typically seen in severe sepsis.

Mode of action

TREM-1 is a receptor found on neutrophils, macrophages and monocytes, key elements of the immune system. Activation of TREM-1 results in expression of NF-κB, which promotes systemic inflammation. Nangibotide inhibits TREM-1, thereby preventing the inflammatory activation. Absence of TREM-1 results in vastly reduced inflammation without impairing the ability to fight infection.^[2]

Animal models

LR17, a mouse equivalent of nangibotide, improves survival in mouse models of severe sepsis.^[3] In a pig model of sepsis, LR12 – another animal equivalent of nangibotide – resulted in significantly improved haemodynamics and less organ failure.^[4] In monkeys, LR12 also reduced the inflammatory and hypotensive effects of sepsis.^[5]

Human studies

Nangibotide has demonstrated safety in Phase 1 (healthy volunteers)^[6] and Phase 2 (sick patients with septic shock)^[7] studies. The ASTONISH trial will examine clinical efficacy in 450 patients with septic shock.^[8]

Inotrem Receives Approval to Expand Nangibotide Clinical Trial in Critically Ill COVID-19 Patients and Receives Additional Public Funding of €45 Million

Inotrem’s phase 2/3 clinical trial “ESSENTIAL” will enroll up to 730 patients in Europe to demonstrate the safety and efficacy of nangibotide to treat critically ill COVID-19 patients with respiratory failure.
Recent preclinical studies have strengthened the body of evidence for targeting the TREM-1 pathway which is activated in a subset of patients suffering from severe COVID-19.

July 12, 2021 03:00 AM Eastern Daylight Time

PARIS–(BUSINESS WIRE)–Inotrem S.A., a biotechnology company specializing in the development of immunotherapies targeting the TREM-1 pathway, announces that it has obtained authorization to pursue the clinical development of nangibotide up to registration in COVID-19 patients from both the French and Belgian competent authorities.

As part of this program, Inotrem receives additional 45 million euros in public funding under the “Capacity Building” Call for Expression of Interest, operated on behalf of the French government by Bpifrance, the French national investment bank, as part of the Programme d’investissements d’avenir (PIA) and the France Recovery Plan, bringing French state support for the project to a total of 52,5 million euros. This public funding will support Inotrem’s clinical program including the phase 2/3 study “ESSENTIAL” which aims to demonstrate the efficacy and safety of nangibotide in treating patients in respiratory distress with severe forms of COVID-19.

The primary endpoint is evaluation of the impact of nangibotide on the progression of disease in patients receiving ventilatory support due to COVID-19 as well as on the severity of the respiratory failure, duration of mechanical ventilation, length of stay in intensive care and mortality. In “ESSENTIAL”, a Phase 2/3 clinical program, up to 730 patients will be enrolled initially in France and Belgium and, possibly in other European countries. Pre-defined interim analyses will be conducted by an independent Data Monitoring Board to test futility and to allow for the study design to be adapted as necessary. “ESSNTIAL” is the continuation of a 60 patients phase 2a evaluating the safety and efficacy of nangibotide in patients suffering from severe COVID-19. In July 2020, the CoviTREM-1 consortium, which includes the Nancy and Limoges university hospitals and Inotrem, obtained public funding of 7,5 million euros under the “PSPC-COVID” call for projects, operated on behalf of the French government by Bpifrance

New pre-clinical studies with nangibotide have demonstrated that the administration of nangibotide in murine models infected with SARS-CoV-2 was associated with a decrease in inflammatory mediators and an improvement of clinical signs, in particular respiratory function, and survival. Inotrem also confirmed in 3 different and independent cohorts that sTREM-1, a marker of the activation of the TREM-1 biological pathway, is associated with both severity and mortality in critically ill COVID-19 patients.

Leveraging the results of these preclinical studies and the implications for the role of the TREM-1 pathway in COVID-19, Inotrem has filed additional patents to cover nangibotide use in severe forms of COVID-19 as well as the use of sTREM-1 as a biomarker and companion diagnostic. This significantly strengthens Inotrem’s already broad patent estate.

Jean-Jacques Garaud, Executive Vice-President, Head of Scientific and Medical Affairs and Inotrem’s co-founder said :“We are eager to pursue the development of nangibotide in these severe forms of COVID-19. Nangibotide is a TREM-1 inhibitor which has already demonstrated a trend towards efficacy in septic shock patients and has the potential to modulate the dysregulated immune response in critically ill COVID-19 patients. With this large clinical study, we can demonstrate efficacy for nangibotide in a further indication with the goals of reducing the duration of hospitalization and mortality.”

Sven Zimmerman, CEO of Inotrem, also declared: “The size of the financial support awarded to us as part of the French government’s initiative against COVID-19 is a testimony to the relevance of targeting the TREM-1 pathway with nangibotide in these severely ill patients. We are delighted by the confidence placed in our technology and our team. Everyone at Inotrem is fully committed to deliver on this ambitious program alongside nangibotide’s ongoing Phase 2b trial in septic shock patients.”

About Inotrem
Inotrem S.A. is a biotechnology company specialized in immunotherapy for acute and chronic inflammatory syndromes. The company has developed a new concept of immunomodulation that targets the TREM-1 pathway to control unbalanced inflammatory responses. Through its proprietary technology platform, Inotrem has developed the first-in-class TREM-1 inhibitor, LR12 (nangibotide), with potential applications in a number of therapeutic indications such as septic shock and myocardial infarction. In parallel, Inotrem has also launched another program to develop a new therapeutic modality targeting chronic inflammatory diseases. The company was founded in 2013 by Dr. Jean-Jacques Garaud, a former head of research and early development at the Roche Group, Prof. Sébastien Gibot and Dr. Marc Derive. Inotrem is supported by leading European and North American investors.

www.inotrem.com

About TREM-1 pathway
TREM-1 pathway is an amplification loop of the immune response that triggers an exuberant and hyperactivated immune state which is known to play a crucial role in the pathophysiology of septic shock and acute myocardial infarction.

About Nangibotide
Nangibotide is the formulation of the active ingredient LR12, which is a 12 amino-acid peptide prepared by chemical synthesis. LR12 is a specific TREM-1 inhibitor, acting as a decoy receptor and interfering in the binding of TREM-1 and its ligand. In preclinical septic shock models, nangibotide was able to restore appropriate inflammatory response, vascular function, and improved animals’ survival post septic shock.

About ESSENTIAL study:
The Efficacy and Safety Study Exploring Nangibotide Treatment in COVID-19 pAtients with ventiLatory support, is a randomized, double-blind, placebo-controlled confirmatory study with adaptive features that will be performed in Europe. This is a pivotal study and it is expected that based on its results, nangibotide could be registered in this indication. The first part of the study (i.e.: 60 patients) has been already finalized and assessed by an independent data monitoring committee with excellent safety results. The study will recruit up to 730 patients in up to 40 sites. Several interim and futility analyses are foreseen as part of the adaptive design of the study.

About Bpifrance
Bpifrance is the French national investment bank: it finances businesses – at every stage of their development – through loans, guarantees, equity investments and export insurances. Bpifrance also provides extra-financial services (training, consultancy.). to help entrepreneurs meet their challenges (innovation, export…).

PATENT

WO-2021144388

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=B2A2A7E6609054F25F6B4F74CEA24A2A.wapp2nB?docId=WO2021144388&tab=PCTDESCRIPTION

Process for preparing nangibotide by solid phase synthesis, useful for treating acute inflammatory disorders such as septic shock. Also claims novel peptide fragments, useful in the synthesis of nangibotide.

Example 1

Preparation of nangibotide by full SPPS (Reference)

Step 1 : Loading of the first amino acid onto the Rink Amide Resin

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min. 2 eq Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin after 5 min. All the coupling steps were conducted in this way unless described differently. The loading step was carried out for 1.5 hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of 20% piperidine solution in DMF for two 10 min cycles. This step was performed analogously for all the amino acid residues. The loading, calculated by UV absorption for the peptidyl resin, was 0.8 mmol/g.

Step 2: peptide elongation

For the coupling of all the amino acids involved in the synthesis of nangibotide, 3 eq of each amino acid were activated by 3 eq of DIC and OxymaPure dissolved in DMF at 0.3 M cone. At the end of the peptide elongation, a final Fmoc deprotection, as already described, was performed before moving to the cleavage step.

Step 3: Cleavage and precipitation of crude nangibotide

The cleavage of nangibotide off the resin was carried out using a solution of 16 mL of TFA/DODT/TIPS/water in 90/4/3/3 ratio cooled at 0°C. The peptidyl resin was added portionwise in 30 min keeping the internal temperature under 25°C. The cleavage was run for 3.5 hours, then the resin was filtered and washed by 10 mL of TFA for 10 min.

DIPE was used for the precipitation of the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried under vacuum overnight. Molar yield 40%. Purity 61%.

Example 2

Preparation of nangibotide by three-fragment condensation

In the approach using three fragments, only the cysteine residue was coupled to the methionine on rink amide resin to prepare fragment 11-12, whereas protected peptide fragments 1-7 and 8-10 were synthesized using 2-CTC resin.

Step 1: Synthesis of fragment 11-12

addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH to obtain resin-attached Fmoc-deprotected fragment 11-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g.

Step 2: Synthesis of fragments 1-7 and 8-10

For the synthesis of both fragments the loading of 2-chloro trityl chloride resin was performed on 5 g (1.6 mmol/g) using 0.8 eq Fmoc-Gly-OH (6.40 mmol, 1.90 g) dissolved in 30 mL of DCM and addition of 3 eq DIPEA (24 mmol, 4.19 mL). The loading step was carried out for 1 hour, then the resin was washed by 30 mL DCM for three times and eventual Cl-groups were capped by two different capping solutions: first by 30 mL of methanol/DIPEA/DCM (1:2:7) and then by 30 mL AC2O/DIPEA/DCM in the same ratio. After the treatment with these solutions for 15 min and subsequent washing with DCM, the resin was washed three times with DMF, before deprotection of Fmoc and evaluation of the resin loading. Generally, this protocol gave a resin loaded with 1.1 mmol/g Fmoc-Gly-OH. The Fmoc deprotection and coupling step protocols were equally performed with all the amino acids in the respective sequences: Fmoc-Tyr(tBu)-OH and Fmoc-Glu(tBu)-OH for fragment 8-10, and Fmoc-Ala-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Glu(OtBu)-OH twice, Fmoc-Gln(Trt)-OH and Fmoc-Leu-OH for fragment 1-7.

For each coupling, 3 eq amino acid were activated by 3 eq DIC and 3 eq OxymaPure dissolved in DMF at 0.3 M cone.

Fragment Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The final solution was concentrated to 50 mL under vacuum then washed by water and brine. The organic layer was dried by anhydrous sodium sulphate, filtered and further concentrated before crystallization of the tripeptide with 5 volumes of petroleum ether at 0°C. The peptide was filtered, washed by petroleum ether and dried overnight in a vacuum oven at 37°C. Molar yield 65%. Purity 90%.

Fragment Fmoc-Leu-Gln(Trt)-Glu(OtBu)-Glu(OtBu)-Asp(OtBu)-Ala-Gly-OH (1-7) was obtained by cleavage off the resin using 6 volumes (30 mL) of a TFA 1.5 % solution in DCM, 5 times for 2 min. The final TFA solution was neutralized by 1.2 eq pyridine (15.89 mmol, 1.3 mL) diluted in 30 mL methanol. The DCM was evaporated and replaced by methanol, adding and evaporating 30 mL methanol a couple of times till one third of the volume. The peptide fragment was precipitated by adding 5 volumes (150 mL) water to the methanol solution at 0°C and filtered after stirring for 30 min. The full protected heptapeptide was washed by water and dried overnight in a vacuum oven at 37°C. Molar yield 85%. Purity 89%.

Step 3: Synthesis of fragment 8-12 (Fragment condensation 1)

The fragment condensation between Fmoc-Glu(tBu)-Tyr(tBu)-Gly-OH (8-10) and H-Cys(Trt)-Met-MBHA resin (11-12) was carried out activating 2 eq (1.6 mmol, 1.12 g) of fragment 8-10 dissolved in 6 mL of DMF at 40°C by using 2 eq OxymaPure (1.6 mmol, 0.22 g) and 2 eq DIC (1.6 mmol, 0.25 mL) for 10 min. The activated ester of tripeptide 8-10 was added to the resin-attached fragment 11-12 and stirred for 3 hours at 40°C. After filtration, the resin was washed three times by 15 mL DMF and then capped by 12 mL of AC2O 10% in DMF for 15 min. The resin was washed three timed by 12 mL DMF before deprotection of Fmoc to finally obtain resin-attached Fmoc-protected fragment 8-12. Molar yield 91%. Purity 89%.

Step 4: Synthesis of nanaibotide (Fragment condensation 2)

The fragment condensation between fragment 1-7 and H-Glu(OtBu)-Tyr(tBu)-Gly-Cys(Trt)-Met-MBHA resin (8-12) was carried out activating 1.5 eq (2.25 mmol, 2.64 g) of fragment 1-7 dissolved in 25 mL DMF at 40°C by using 2 eq OxymaPure (2.25 mmol, 0.32 g) and 2 eq DIC (2.25 mmol, 0.35 mL) for 15 min. The activated ester of fragment 1-7 was added to the resin-attached fragment 8-12 and stirred for 3.5 hours at 40°C. After filtration, the resin was washed three times by 12 mL DMF before deprotection of Fmoc with the standard procedure described above. After Fmoc deprotection, the resin was washed again by DMF and DCM and then dried at vacuum pump.

Step 5: Cleavage and precipitation of crude nanaibotide

DIPE was used to precipitate the peptide, adding 12 volumes (300 mL) dropwise to the peptide TFA solution, keeping the temperature under 20°C. The suspension with nangibotide was filtered on a gooch funnel, the peptide washed again with 100 mL of DIPE and then dried at vacuum pump overnight. Molar yield 61%. Purity 73%.

Example 3

Preparation of nangibotide by two-fragment condensation

In the approach using two fragments, the SPPS elongation onto MBHA resin, as described in Example 2, step 1, was continued until Glu⁸ was attached to provide fragment 8-12, then fragment 1-7, synthesized on 2-CTC resin as described in example 2, step 2, was coupled to the resin-attached fragment 8-12 as described in example 2, step 4.

Step 1: Synthesis of fragment 8-12

2 g of MBHA resin (1.0-1.3 mmol/g) was swelled using 16 mL of DMF for 30 min 2 eq of Fmoc-Met-OH (2.4 mmol, 2.67 g), 2 eq DIC (2.4 mmol, 1.136 mL) and 2 eq OxymaPure (2.4 mmol, 1.023 g) were dissolved in 8 mL of DMF at 0.3 M cone, and added to the resin. The loading step was carried out for 1 and half hour. After the loading, the resin was filtered and washed 3 times with 12 mL of DMF. The Fmoc deprotection step was carried out by addition of 12 mL of a 20% piperidine solution in DMF for two 10 min cycles. Same procedure was repeated for the coupling of Fmoc-Cys(Trt)-OH; Fmoc-Glu(OtBu)-OH; Fmoc-Tyr(tBu)-OH; Fmoc-Gly-OH to obtain fragment 8-12. The loading, calculated by UV absorption for the peptidyl resin relative to the first amino acid inserted, was 0.8 mmol/g. Molar yield 88%. Purity 83%.

Step 2: Synthesis of nanaibotide (Fragment condensation 2)

The final fragment condensation was performed as described in example 2, step 4.

Step 3: Cleavage and precipitation of crude nanaibotide

The cleavage of nangibotide off the resin was carried out as described in example 2, step 5. Molar yield 60%. Purity 70%.

PAPER

Methods in enzymology (2000), 312, 293-304

Journal of the American College of Cardiology (2016), 68(25), 2776-2793

PATENT

https://patents.google.com/patent/WO2011124685A1/en

Product pat, WO2011124685 ,protection in the EU states and the US April 2031

References

^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”. Br J Clin Pharmacol. 84 (10): 2270–2279. doi:10.1111/bcp.13668. PMC 6138490. PMID 29885068.
^ Weber B, Schuster S, Zysset D, Rihs S, Dickgreber N, Schürch C, Riether C, Siegrist M, Schneider C, Pawelski H, Gurzeler U, Ziltener P, Genitsch V, Tacchini-Cottier F, Ochsenbein A, Hofstetter W, Kopf M, Kaufmann T, Oxenius A, Reith W, Saurer L, Mueller C (2014). “TREM-1 deficiency can attenuate disease severity without affecting pathogen clearance”. PLOS Pathog. 10 (1): e1003900. doi:10.1371/journal.ppat.1003900. PMC 3894224. PMID 24453980.
^ Derive M, Bouazza Y, Sennoun N, Marchionni S, Quigley L, Washington V, Massin F, Max JP, Ford J, Alauzet C, Levy B, McVicar DW, Gibot S (1 June 2012). “Soluble TREM-like transcript-1 regulates leukocyte activation and controls microbial sepsis”. Journal of Immunology. 188 (11): 5585–5592. doi:10.4049/jimmunol.1102674. PMC 6382278. PMID 22551551.
^ Derive M, Boufenzer A, Bouazza Y, Groubatch F, Alauzet C, Barraud D, Lozniewski A, Leroy P, Tran N, Gibot S (Feb 2013). “Effects of a TREM-like transcript 1-derived peptide during hypodynamic septic shock in pigs”. Shock. 39 (2): 176–182. doi:10.1097/SHK.0b013e31827bcdfb. PMID 23324887. S2CID 23583753.
^ Derive M, Boufenzer A, Gibot S (April 2014). “Attenuation of responses to endotoxin by the triggering receptor expressed on myeloid cells-1 inhibitor LR12 in nonhuman primate”. Anaesthesiology. 120 (4): 935–942. doi:10.1097/ALN.0000000000000078. PMID 24270127. S2CID 10347527.
^ Cuvier V, Lorch U, Witte S, Olivier A, Gibot S, Delor I, Garaud JJ, Derive M, Salcedo-Magguilli M (2018). “A first-in-man safety and pharmacokinetics study of nangibotide, a new modulator of innate immune response through TREM-1 receptor inhibition”. Br J Clin Pharmacol. 84 (10): 2270–2279. doi:10.1111/bcp.13668. PMC 6138490. PMID 29885068.
^ François B, Wittebole X, Ferrer R, Mira JP, Dugernier T, Gibot S, Derive M, Olivier A, Cuvier V, Witte S, Pickkers P, Vandenhende F, Garaud JJ, Sánchez M, Salcedo-Magguilli M, Laterre PF (July 2020). “Nangibotide in patients with septic shock: a Phase 2a randomized controlled clinical trial”. Intensive Care Medicine. 46 (7): 1425–1437. doi:10.1007/s00134-020-06109-z. PMID 32468087. S2CID 218912723.
^ “Efficacy, Safety and Tolerability of Nangibotide in Patients With Septic Shock (ASTONISH)”. ClinicalTrials.gov. US National Library of Medicine. Retrieved 13 July 2020.

Derive et al (2013) Effects of a TREM-Like Transcript 1–Derived Peptide During Hypodynamic Septic Shock in Pigs. Shock39(2) 176 PMID: 23324887

Derive et al (2014) Attenuation of Responses to Endotoxin by the Triggering Receptor Expressed on Myeloid Cells-1 Inhibitor LR12 in Nonhuman Primate. Anesthesiology120(4) 935 PMID: 24270127

Derive et al (2012) Soluble Trem-like Transcript-1 Regulates Leukocyte Activation and Controls Microbial Sepsis. J. Immunol.188(11) 5585 PMID: 22551551

Clinical data

Routes of administration	Intravenous; intraperitoneal
Physiological data
Receptors	TREM-1
Metabolism	Enzymatic in bloodstream
Pharmacokinetic data
Metabolism	Enzymatic in bloodstream
Elimination half-life	3 minutes
Identifiers
show IUPAC name
CAS Number	2014384‐91‐7
ChemSpider	64835227
UNII	59HD7BLX9H
ChEMBL	ChEMBL4297793
Chemical and physical data
Formula	C54H82N14O22S2
Molar mass	1343.439
3D model (JSmol)	Interactive image
show SMILES
show InChI

//////////////Nangibotide, phase 3, нангиботид , مانغيبوتيد , 南吉博肽 , INOTREM, SEPTIC SHOCK, PEPTIDE

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Melarsoprol

July 23, 2021 9:19 am / Leave a comment

Melarsoprol

MelarsoprolCAS Registry Number: 494-79-1
CAS Name: 2-[4-[(4,6-Diamino-1,3,5-triazin-2-yl)amino]phenyl]-1,3,2-dithiarsolane-4-methanolAdditional Names:p-[(4,6-diamino-s-triazin-2-yl)amino]dithiobenzenearsonous acid 3-hydroxypropylene ester; 2-p-(4,6-diamino-s-triazin-2-ylamino)phenyl-4-hydroxymethyl-1,3,2-dithiarsoline; 2-(4-melamin-2-ylphenyl)-4-hydroxymethyl-1,3-dithia-2-arsolaneTrademarks: Mel B; Arsobal (Specia)
Molecular Formula: C12H15AsN6OS2Molecular Weight: 398.34
Percent Composition: C 36.18%, H 3.80%, As 18.81%, N 21.10%, O 4.02%, S 16.10%Literature References: Prepn: Friedheim, US2659723 (1953); US2772303 (1956).Properties: Practically insol in water, cold ethanol, methanol. Sol in propylene glycol.
Therap-Cat: Antiprotozoal (Trypanosoma).Keywords: Antiprotozoal (Trypanosoma).

Melarsoprol is a medication used for the treatment of sleeping sickness (African trypanosomiasis).^[1] It is specifically used for second-stage disease caused by Trypanosoma brucei rhodesiense when the central nervous system is involved.^[1] For Trypanosoma brucei gambiense, eflornithine or fexinidazole is usually preferred.^[1] It is effective in about 95% of people.^[3] It is given by injection into a vein.^[2]

Melarsoprol has a high number of side effects.^[4] Common side effects include brain dysfunction, numbness, rashes, and kidney and liver problems.^[2] About 1-5% of people die during treatment.^[3] In those with glucose-6-phosphate dehydrogenase (G6PD) deficiency, red blood cell breakdown may occur.^[2] It has not been studied in pregnancy.^[2] It works by blocking pyruvate kinase, an enzyme required for aerobic metabolism by the parasite.^[2]

Melarsoprol has been used medically since 1949.^[1] It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.^[5] In regions of the world where the disease is common, melarsoprol is provided for free by the World Health Organization.^[4] It is not commercially available in Canada or the United States.^[2] In the United States, it may be obtained from the Centers for Disease Control and Prevention, while in Canada it is available from Health Canada.^[1]^[2]

Medical uses

People diagnosed with trypanosome-caused disease should be treated with an anti-trypanosomal. Treatment is based on stage, 1 or 2, and parasite,T. b. rhodesiense or T. b. gambiense. In stage 1 disease, trypanosomes are present only in the peripheral circulation. In stage 2 disease, trypanosomes have crossed the blood-brain barrier and are present in the central nervous system.^[6]

The following are considerable treatment options:^[6]

Melarsoprol is a treatment used during the second stage of the disease. So far, it is the only treatment available for late-stage T. b. rhodesiense.^[7]

Due to high toxicity, melarsoprol is reserved only for the most dangerous cases. Other agents associated with lower toxicity levels are used during stage 1 of the disease.^[8] The approval of the nifurtimox-eflornithine combination therapy (NECT) in 2009 for the treatment of T. b. gambiense limited the use of melarsoprol to the treatment of second-stage T. b. rhodesiense.^[9]

Failure rates of 27% in certain African countries have been reported.^[10] This was caused by both drug resistance and additional mechanisms that have not yet been elucidated. Resistance is likely due to transport problems associated with the P2 transporter, an adenine-adenosine transporter. Resistance can occur with point mutations within this transporter.^[11] Resistance has been present since the 1970s.^[12]

Mechanism of action

Melarsoprol is a prodrug, which is metabolized to melarsen oxide (Mel Ox) as its active form. Mel Ox is an phenylarsonous acid derivative that irreversibly binds to sulfhydryl groups on pyruvate kinase, which disrupts energy production in the parasite. The inability to distinguish between host and parasite PK renders this drug highly toxic with many side effects.

Mel Ox also reacts with trypanothione (a spermidine-glutathione adduct that replaces glutathione in trypanosomes). It forms a melarsen oxide-trypanothione adduct (Mel T) that competitively inhibits trypanothione reductase, effectively killing the protist.^[11]

Pharmacokinetics

The half-life of melarsoprol is less than one hour, but bioassays indicate a 35-hour half-life. This is commonly associated with pharmacologic agents that have active metabolites. One such metabolite, Mel Ox, reaches maximum plasma levels about 15 minutes after melarsoprol injection. Melarsoprol clearance is 21.5 ml/min/kg and the Mel Ox half-life is approximately 3.9 hours.^[13]

Dosage

Two arsenic-containing stereoisomers exist in a 3:1 molar ratio. Since melarsoprol is insoluble in water, dosage occurs via a 3.6% propylene glycol intravenous injection.^[11] To avoid the risk of injection site reactions, melarsoprol must be given slowly.^{[citation needed]}

Melarsoprol used for the treatment of African trypanosomiasis with CNS involvement is given under a complicated dosing schedule. The dosing schedule for children and adults is 2–3.6 mg/kg/day intravenously for three days, then repeated every seven days for a total of three series.^[6] To monitor for relapse, follow-up is recommended every six months for at least two years.^[3]

Side effects

Although melarsoprol cures about 96% of people with late stage disease, its toxicity limits its use.^[7] About 1-5% of people die during treatment.^[3] As a toxic organic compound of arsenic, melarsoprol is a dangerous treatment that is typically only administered by injection under the supervision of a licensed physician. Notable side effects are similar to arsenic poisoning. Among clinicians, it is colloquially referred to as “arsenic in antifreeze”.^[14] Severe and life-threatening adverse reactions are associated with melarsoprol. It is known to cause a range of side effects including convulsions, fever, loss of consciousness, rashes, bloody stools, nausea and vomiting. In approximately 5-10% of cases, it causes encephalopathy. Of those, about 50% die due to encephalopathy-related adverse reactions.^[6] Additional potentially serious side effects of melarsoprol include damage to the heart, presence of albumin in the urine that could be associated with kidney damage, and an increase in blood pressure.^[3]

Cautions

Numerous warnings must be examined before melarsoprol treatment can be initiated. Prior to initiation, the following must be noted: glucose-6-phosphate dehydrogenase deficiency, kidney or liver disease, cardiac problems (high blood pressure, irregular beating of the heart or arrhythmias, any damage to the heart muscles and potential signs of heart failure), preexisting nervous system disorders, and any signs of leprosy.

Routine laboratory testing is needed before and after melarsoprol initiation. Laboratory parameters for both therapeutic effects and toxic effects need to be evaluated.

Blood analysis is used to detect the presence of trypanosomes. An evaluation of the cerebrospinal fluid via a lumbar puncture is also used to determine an individual’s white blood count and level of protein. These are diagnostic criteria such that the presence of trypanosomes, an elevated white blood count greater than five per microliter, or a protein content greater than 40 mg are considered abnormal and initiation should be considered. Continuous cerebrospinal fluid evaluation should be repeated every six months for at least three years in individuals that have undergone melarsoprol treatment.

To assess potential concerns related to toxicity, the following should be completed: a complete blood count, an assessment of electrolyte levels, liver and kidney function tests, and a urinalysis to detect the appearance, concentration and content of the urine.

Melarsoprol should be given using glass syringes (if they can be reliably sterilised). The propylene glycol it contains is capable of dissolving plastic.^[15]

Pregnancy and breastfeeding

Currently, melarsoprol is not recommended for use in pregnant women. The World Health Organization suggests that treatment be deferred until immediately after delivery since the effects of the medication on the developing fetus have not yet been established.^[3]

Lactation guidelines associated with melarsoprol have not yet been established.

Society and culture

Melarsoprol is produced by Sanofi-Aventis and under an agreement with the WHO, they donate melarsoprol to countries where the disease is common.^{[medical citation needed]}

Melarsoprol was used to treat a patient with African trypanosomiasis on season 1 episode 7 “Fidelity” of the medical drama House MD.^[16]

PAPER

Journal of Organometallic Chemistry (2006), 691(5), 1081-1084.

https://www.sciencedirect.com/science/article/abs/pii/S0022328X05009344

Graphical abstract

(2-Phenyl-[1,3,2]dithiarsolan-4-yl)-methanol derivatives were tested on K562 and U937 human leukemia cell lines. Their systemic toxicity was estimated by the corresponding LD₅₀ on mice. The cytotoxic activity of each derivative was significantly better than that of arsenic trioxide and the therapeutic index (T.I. = LD₅₀/IC₅₀) was improved.

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Our Formulary Infectious Diseases Laboratories CDC”. http://www.cdc.gov. 22 September 2016. Archived from the original on 16 December 2016. Retrieved 7 December 2016.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Melarsoprol Drug Information, Professional”. http://www.drugs.com. 20 December 1994. Archived from the original on 30 December 2016. Retrieved 7 December 2016.
^ Jump up to:^a ^b ^c ^d ^e ^f “WHO Model Prescribing Information: Drugs Used in Parasitic Diseases – Second Edition: Protozoa: African trypanosomiasis: Melarsoprol”. WHO. 1995. Archived from the original on 2016-11-10. Retrieved 2016-11-09.
^ Jump up to:^a ^b “Trypanosomiasis, human African (sleeping sickness)”. World Health Organization. February 2016. Archived from the original on 4 December 2016. Retrieved 7 December 2016.
^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ Jump up to:^a ^b ^c ^d CDC (2013). “Disease Control and Prevention: Parasites – African Trypanosomiasis”. Archived from the original on 2017-06-19.
^ Jump up to:^a ^b “Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (African Trypanosomiasis) – Infectious Disease and Antimicrobial Agents”. http://www.antimicrobe.org. Archived from the original on 2016-11-28. Retrieved 2016-11-17.
^ Bisser S, N’Siesi FX, Lejon V, et al. (2007). “Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei rhodesiense sleeping sickness”. J. Infect. Dis. 195 (3): 322–9. doi:10.1086/510534. PMID 17205469.
^ Farrar J (2014). “Manson’s Tropical Diseases: Expert Consult-Online”. 23: 616.
^ Kioy, D.; Jannin, J.; Mattock, N. (March 2004). “Human African trypanosomiasis”. Nature Reviews Microbiology. 2 (3): 186–187. doi:10.1038/nrmicro848. PMID 15751187. S2CID 36525641.
^ Jump up to:^a ^b ^c Brunton L (2011). “Goodman & Gillman’s The Pharmacological Basis of Therapeutics”. McGraw Hill Medical: 1427–28.
^ Brun, Reto; Schumacher, Reto; Schmid, Cecile; Kunz, Christina; Burri, Christian (November 2001). “The phenomenon of treatment failures in Human African Trypanosomiasis”. Tropical Medicine and International Health. 6 (11): 906–914. doi:10.1046/j.1365-3156.2001.00775.x. PMID 11703845. S2CID 21542129.
^ Keiser J.; Ericsson O; Burri C (2000). “Investigations of the metabolites of the trypanocidal drug melarsoprol”. Clinical Pharmacology. 67 (5): 478–88. doi:10.1067/mcp.2000.105990. PMID 10824626. S2CID 24326873.
^ Hollingham R (2005). “Curing diseases modern medicine has left behind”. New Scientist. 2005 (2482): 40–41. Archived from the original on 2015-05-11.
^ “MELARSOPROL injectable – Essential drugs”. medicalguidelines.msf.org. Retrieved 6 December 2019.
^ Holtz, Andrew (2006). The Medical Science of House, M.D.Penguin. p. 272. ISBN 1440628734. Retrieved 25 March 2020.

External links

“Melarsoprol”. Drug Information Portal. U.S. National Library of Medicine.

Clinical data


Trade names	Arsobal^[1]
Other names	Mel B, Melarsen Oxide-BAL^[2]
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Routes of administration	IV
ATC code	P01CD01 (WHO) QP51AD04 (WHO)
Pharmacokinetic data
Elimination half-life	35 hours
Excretion	Kidney
Identifiers
show IUPAC name
CAS Number	494-79-1
PubChem CID	10311
ChemSpider	9889
UNII	ZF3786Q2E8
KEGG	D00832
ChEMBL	ChEMBL166
CompTox Dashboard (EPA)	DTXSID90862033
ECHA InfoCard	100.007.086
Chemical and physical data
Formula	C₁₂H₁₅AsN₆OS₂
Molar mass	398.33 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI
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/////////Melarsoprol

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Rilzabrutinib

July 19, 2021 11:57 am / Leave a comment

(R)-2-(3-(4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile.png

PRN 1008, Rilzabrutinib

CAS 1575591-66-0

リルザブルチニブ;

C36H40FN9O3,

MW 665.7597

2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-1-yl]pent-2-enenitrile

Anti-inflammatory disease, Autoimmune disease treatment

Fda 2025, approvals 2025 8/29/2025, Wayrilz, To treat persistent or chronic immune thrombocytopenia that has not sufficiently responded to immunoglobulins, anti-D therapy, or corticosteroids

OriginatorPrincipia Biopharma
Class2 ring heterocyclic compounds; Amines; Anti-inflammatories; Fluorobenzenes; Nitriles; Phenyl ethers; Piperazines; Piperidines; Pyrazoles; Pyrimidines; Skin disorder therapies; Small molecules
Mechanism of ActionAgammaglobulinaemia tyrosine kinase inhibitors
Orphan Drug StatusYes – Idiopathic thrombocytopenic purpura; Pemphigus vulgaris

Phase IIIIdiopathic thrombocytopenic purpura; Pemphigus vulgaris
Phase IIAutoimmune disorders

02 Jun 2021Efficacy data from a phase IIa trial in Ankylosing spondylitis presented at the 22^nd Annual Congress of the European League Against Rheumatism (EULAR-2021)
07 Apr 2021Sanofi initiates enrollment in a phase I pharmacokinetics trial in healthy volunteers in Australia (PO, Tablet, Capsule) (NCT04748926)
31 Mar 2021Sanofi announces intention to seek regulatory approval for Idiopathic thrombocytopenic purpura in 2023 (Sanofi pipeline, May 2021)

Rilzabrutinib, sold under the brand name Wayrilz, is an anti-cancer medication used for the treatment of immune thrombocytopenia.^[1] Rilzabrutinib is a tyrosine kinase inhibitor.^[1] It is taken by mouth.^[1]

Rilzabrutinib may increase the risk of serious infections (including bacterial, viral, or fungal).^[2] The most common side effects include diarrhea, nausea, headache, abdominal pain, and COVID-19.^[2]

Rilzabrutinib was approved for medical use in the United States in August 2025.^[2]

CLIP

https://cen.acs.org/pharmaceuticals/drug-development/Sanofi-acquire-BTK-inhibitor-firm/98/web/2020/08

Sanofi to acquire BTK inhibitor firm Principia for $3.7 billion

Principia is testing its small-molecule compounds in multiple sclerosis and immune system diseases

Sanofi will pay $3.7 billion to acquire Principia Biopharma, a San Francisco-based biotech firm developing small molecules that inhibit Bruton tyrosine kinase (BTK). The price represents about a 75% premium over Principia’s stock market value in early July, before reports surfaced that Sanofi was interested in buying the firm.

BTK is a protein important for both normal B cell development and the proliferation of lymphomas, which are B cell cancers. AbbVie, AstraZeneca, and BeiGene all market BTK inhibitors for treating specific kinds of lymphomas. Sales of AbbVie’s inhibitor, Imbruvica, approached $4.7 billion in 2019.

Other drug firms have been eager to get in on the action as well. In January, Merck & Co. spent $2.7 billion to acquire ArQule, whose experimental noncovalent BTK inhibitor is designed to overcome resistance that some cancers develop after treatment with current covalent BTK inhibitors. Eli Lilly and Company’s $8 billion acquisition of Loxo Oncology in 2019 also included a noncovalent BTK inhibitor.

BTK is also linked to inflammation, and Principia focuses on developing BTK inhibitors for immune system diseases and multiple sclerosis. Its compound rilzabrutinib is currently in clinical trials for pemphigus and immune thrombocytopenia. In 2017, Sanofi struck a deal to develop Principia’s brain-penetrant BTK inhibitor, SAR442168, for multiple sclerosis.

Sanofi announced in April of this year that the inhibitor reduced formation of new lesions—the scarred nervous tissue that gives multiple sclerosis its name—by 85% in a Phase II clinical trial. A Phase III trial of the compound began in June.

Upon announcing its deal to acquire Principia, Sanofi said that both rilzabrutinib and SAR442168 have the potential to become a “pipeline in a product,” indicating they can be used for many immune-related and neurological diseases, respectively.

The anti-inflammatory effects of BTK inhibitors have raised interest in the drugs as treatments for people hospitalized with COVID-19. Notably, the US National Cancer Institute conducted a small study suggesting acalabrutinib may help reduce the respiratory distress and inflammation in people with COVID-19. Based on that preliminary study, AstraZeneca—which markets acalabrutinib as Calquence—is conducting a 60-person randomized trial of the drug for COVID-19.

Sanofi has not indicated interest in investigating Principia’s BTK inhibitors as COVID-19 treatments.Chemical & Engineering NewsISSN 0009-2347
PATENT

WO 2021127231https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021127231&tab=PCTDESCRIPTION&_cid=P20-KRA0I9-18818-1

SOLID FORMS OF 2-[3-[4-AMTNO-3-(2-FT,TTORO-4-PHENOXY- PHEN¥L)PYRAZOLO[3,4 D]PYRIMIDIN l~YL]PIPERIDINE~l~CARBON¥L] 4~

METHYL-4-[4-(OXETAN-3-YL)PIPERAZIN-l-YLjPENT-2-ENENITRILE

[11 This application claims the benefit of priority to U.S. Provisional Application

No 62/951,958, filed December 20, 2019, and U.S Provisional Application No. 63/122,309, filed December 7, 2020, the contents of each of which are incorporated by reference herein in their entirety.

[2] Disclosed herein are solid forms of 2-[3-[4~amino-3~(2~fluoro-4-phenoxy-plienyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l Carbonyl]~4-nietliyl-4~[4-(oxetaii~3-yl)piperazin-!~yi]pent-2~enenitriie (Compound (I)), methods of using the same, and processes for making Compound (I), including its solid forms. The solid forms of Compound (I) may be inhibitors of Bruton’s tyrosine kinase (BTK) comprising low residual solvent content.

[3| The enzyme BTK is a member of the Tec family non-receptor tyrosine kinases.

BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages BTK plays a role in the development and activation of B cells. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cell-related hematological cancers (e.g., non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g., rheumatoid arthritis, Sjogren’s syndrome, pemphigus, IBD, lupus, and asthma).

[4] Compound (I), pharmaceutically acceptable salts thereof, and solid forms of any of the foregoing may inhibit BTK and be useful in the treatment of disorders and conditions mediated by BTK activity. Compound (I) is disclosed in Example 31 of WO 2014/039899 and has the following structure:

where *C is a stereochemical center. An alternative procedure for producing Compound (!) is described in Example 1 of WO 2015/127310.

[5] Compound (I) obtained by the procedures described in WO 2014/039899 and WO 2015/127310 comprises residual solvent levels well above the limits described in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines. In general, manufacturing processes producing residual solvent levels near or above the ICH limits are not desirable for preparing active pharmaceutical ingredients (APIs).

Example 1: Spray Drying Process A

[311] A solution of Compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO 2014/039899) was washed with pH 3 phosphate buffer to remove basic impurities that are more soluble than Compound (I) in the aqueous layer. The dichloromethane solution was then washed with pH 7 buffer and solvent exchanged into isopropyl acetate. The isopropyl acetate solution was then washed with pH 3 phosphate buffer, bringing Compound (I) into the aqueous layer and removing non-basic impurities. The pH of the aqueous layer was adjusted to pH 9 with 10% sodium hydroxide, and the aqueous layer was extracted with isopropyl acetate. Upon concentration under vacuum, Compound (I) was precipitated from heptane at 0 °C, filtered and dried to give a white amorphous solid as a mixture of the (E) and (Z) isomers, as wet Compound (I). Wet Compound (I) was dissolved in methanol and spray dried at dryer inlet temperature of 125 °C to 155 °C and dryer outlet temperature of 48 to 58 °C to obtain the stable amorphous Compound (I) free base with levels of isopropyl acetate and heptane below 0.5% and 0.05%, respectively.

Example 2: Spray Drying Process B
intermediate A

Compound (!)

[241] A jacketed reactor with overhead stirrer, condenser, nitrogen line, temperature probe, and recirculating fluid chiller/heater was charged with Intermediate A (20.2 kg) and Intermediate B (13.6 kg, 1.5 equiv). DCM (361.3 kg, 14.5 vol) was charged to the reactor. The mixture was agitated, and the batch cooled to 0 °C to 5 °C. The reactor was charged with pyrrolidine (18.3 kg, 6 equiv) and then charged with TMSC1 (18.6 kg, 4 eq). Stirring was continued at 0 °C to 5 °C for 0.5 to 1 hour

[242] At 0 °C to 5 °C, acetic acid (2.0 equiv) was charged to the reactor followed by water (5 equiv). Stirring was continued at 0 °C to 5 °C for 1 to 1.5 hours. Water (10 equiv) was charged to the reactor, and the solution was adjusted to 20 °C to 25 °C. The internal temperature was adjusted to 20 °C to 25 °C and the biphasic mixture was stirred for 15 to 20 mins. Stirring was stopped and phases allowed to separate for at least 0.5 h. The lower aqueous layer was removed.

[243] Water (7 vol) was charged to the reactor. The pH was adjusted to 2.8-3.3 with a 10 wt. % solution of citric acid. Stirring was continued at 0 to 5 °C for 1 to 1.5 hours. Stirring was stopped and phases allowed to separate for at least 0.5 h. The lower aqueous layer was removed.

[244] A jacketed reactor with overhead stirrer, condenser, nitrogen line, temperature probe, and recirculating fluid chiller/heater was charged with an approximately 9% solution of NaHCCri (1 vol) and the organic layer. The internal temperature was adjusted to 20 °C to 25 °C, and the biphasic mixture was stirred for 15 to 20 mins. Stirring was stopped and phases allowed to separate for at least 0.5 h. The lower aqueous layer was removed. The aqueous layer was measured to have a pH greater than 7.

[245] A jacketed reactor with overhead stirrer, condenser, nitrogen line, temperature probe and recirculating fluid chiller/heater was charged with the organic layer. The organic phase ¾s distilled under vacuum at less than 25 °C to 4 total volumes. IP AC (15 vol) was charged to the reactor. The organic phase was distilled under vacuum at less than 25 °C to 10 total volumes. Water (15 vol) followed by pH 2.3 phosphate buffer were charged to the reactor at an internal temperature of 20 °C to 25 °C. The pH adjusted to 3 Stirring was stopped and phases allowed to separate for at least 0.5 h. The organic phase was removed.

[246] The following steps were repeated twice: IP AC (5 vol) was charged to the reactor containing the aqueous layer. Stirring was continued for 0.25 to 0.5 hours. Stirring was stopped and phases allowed to separate for at least 0.5 h. The organic phase was removed. [247] IP AC (15 vol) was charged to the reactor containing the aqueous layer. A pH 10 phosphate buffer was charged to the reactor and the pH adjusted to 10 with 14% NaOH solution. Stirring was continued for 1.5 to 2 hours. Stirring was stopped and phases allowed to separate for at. least 0.5 h. The aqueous layer was discarded. The organic layer was dried over brine.

[248] The organic solution was distilled under vacuum at less than 25 °C to 5 total volumes.

[249] A jacketed reactor with overhead stirrer, condenser, nitrogen line, temperature probe and recirculating fluid chiller/heater was charged with n-heptane (20 vol). The internal temperature was adjusted to 0 to 5 °C, and the IP AC solution was added.

[250] The suspension was filtered. The filter cake was washed with n-heptane and the tray was dried at 35 °C. Compound (I) (24.6 kg) was isolated in 86% yield.

[251] Compound (1) was dissolved in methanol (6 kg) and spray dried to remove residual IP AC and n-heptane.

Example 3: Precipitation Process A

[252] A solution of Compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO 2014/039899) was quenched with acetic acid and water, followed by washing with pH 3 aqueous solution to remove basic impurities that are more soluble than Compound (1) in the aqueous layer. Washing was repeated as needed to reduce impurities. Methanesulfonic acid was added to the dichloromethane solution, and the dichloromethane solution was concentrated by distillation under reduced pressure, followed by addition of 1% NaCi aqueous solution and isopropyl acetate before adjustment of pH to approximately 3 with potassium hydroxide. The isopropyl acetate layer was removed and discarded. The aqueous layer containing Compound (I) was washed with isopropyl acetate to remove hydrophobic impurities. Washing was repeated as needed to reduce related substance impurities. Residual isopropyl acetate was removed by distillation under reduced pressure. The aqueous solution containing Compound (I) was cooled to 0 to 5°C before adjusting the pH to approximately 9 with potassium hydroxide. The free base of Compound (I) was allowed to precipitate and maturate at 20 °C for 20 hours. The mixture temperature was then adjusted to 20 °C to 25 °C, and the hydrate impurity was verified to be less than 0.3% (< 0.3%). The cake of the free base of Compound (I) was filtered and washed as needed to reduce conductivity. The cake was then allowed to dry on the filter under vacuum and nitrogen swept to reduce water content by Karl-Fischer (KF < 50%) before transferring to the oven for drying. The wet cake of the free base of Compound (1) was dried under vacuum at 25 °C until water content by Karl -Fischer was less than 1.5% (KF < 1.5%), and then dehmiped by milling to yield a uniform white amorphous solid as a mixture of the (E) and (Z) isomers, with no detectible levels of isopropyl acetate or heptane.

Example 4: Precipitation Process 3B

[253] A solution of Compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO 2014/039899) was quenched with acetic acid and water, followed by washing with pH 3 aqueous solution to remove basic impurities that are more soluble than Compound (I) in the aqueous layer. The washing was repeated as needed to reduce residual solvents and impurities. The dichloromethane solution was then washed with saturated sodium bicarbonate (pH > 7). Dichloromethane was removed by distillation under reduced pressure, followed by addition of water and isopropyl acetate. The pH of the aqueous layer was adjusted to pH to 2.8 – 3.3 with 2 M aqueous sulfuric acid (H2SQ4) at 0 – 5 °C, and the mixture rvas stirred and settled. After phase separation removal of the organic layer, the aqueous layer was washed with isopropyl acetate three times and the residual isopropyl acetate in aqueous layer was distilled out under vacuum at a temperature below 25 °C and the solution was basitied with 5% aqueous KOFI to pH 9 – 10 to a slurry . The resulting suspension was stirred and warmed up to 20 °C to 25 °C and aged for 20 h. The product was filtered and washed with water and dried to give white solid in 86% yield.

Example 5: Precipitation Process C

[254] A solution of Compound (I) in dichloromethane (prepared according to Example 31 on pages 86-87 of WO 2014/039899) was quenched with acetic acid and water, followed by washing to remove basic impurities that are more soluble than Compound (I) in the aqueous layer. Washing was repeated as needed to reduce impurities. Methanesulfonic acid was added to the d chloromethane solution, and the dichloromethane solution was concentrated under reduced pressure to obtain a thin oil. The concentrated oil was cooled to approximately 5°C before washing with an aqueous solution of sodium chloride. The organic phase was discarded. Washing of the aqueous layer was repeated as needed with dichloromethane to remove low level impurities. The pH of the aqueous solution was adjusted to approximately 3 with an aqueous solution of potassium hydroxide. Residual dichloromethane was removed

under reduced pressure. The level of residual acetic acid was determined by, for example, titration. The aqueous solution containing Compound (I) was cooled to a temperature between 0°C and 5°C. Acetic acid was present at 0 wt % to 8 wt. %. Acetic acid level was 0 wt % if the aqueous acid solution was washed with aqueous sodium bicarbonate or another aqueous inorganic base. Optionally, additional acetic acid was added to achieve a 0 wt.% to 8 wt. % acetic acid level. An aqueous solution of potassium hydroxide was constantly charged to the aqueous solution to obtain a pH to approximately 9.5. The free base of Compound (I) was allowed to precipitate and maturate at approximately 20 °C for least 3 hours. The cake (wet solid) of the free base of Compound (I) was filtered and washed with water. The wet cake was then dried under reduced vacuum with slight heat. Alternatively, instead of washing the wet cake with water, the wet cake was reslurried with water at approximately 15 °C for at least 1 hour before filtering. The free base of Compound (I) in the fomi of a wet cake was dried under vacuum with slight heat at 25°C.

[255] FIGs. 12-15 are example SEM images showing the variable morphologies of particles of Compound (I) during the filtration step to isolate Compound (I) based on the amount acetic acid added during the initial step in the precipitation of Compound (Ϊ) (FIG. 12: at 0 wt. % acetic acid; FIG 13: at 3 wt. % acetic acid; FIG. 14: at 5 wt. % acetic acid; FIG 15: at 8 wt. % acetic acid). Filtration speed depended on the morphology and was the fastest for 0 wt. % acetic acid. At 1 wt. % acetic acid, the filtration speed diminished considerably, improving at 2 wt. % to 3 wt. % acetic acid. Morphologies with more open holes (such as, e.g., more porous particles) resulted in improved filtration speeds, whereas more compact particles resulted in decreased filtration speed.

Example 6: Conversion of a Crystalline Form of Compound (Ϊ) to an Amorphous Form

[256] 9.8 grams of a crystalline form of Compound (I) were dissolved in approximately 20 mL of dichloromethane and approximately 120 ml. of brine solution. Then, approximately 1 equivalent of methanesulfonic acid was added. The pH w¾s approximately 2. The layers were separated. The aqueous layer was concentrated at a temperature between 0°C and 5°C to remove residual dichloromethane before slowly adding aqueous KOI I solution (approximately 5%) to adjust the pH to a value between 9 and 10. During aqueous KOH addition, an amorphous form of Compound (I) precipitated out. The slurry was slowly warmed to room temperature and then was stirred for approximately 24 hours before filtering and rinsing the wet cake with water. The wet cake was dried under vacuum with slight heat at approximately 30°C to provide 7 grams of a white to an off-white solid (87% yield and 98 4% purity). XRPD showed that the product was an amorphous solid form of Compound (I).

Example 7: Micronization of Compound (I) Particles Obtained by Precipitation Processes

[257] A fluid jet mill equipment was used during lab scale jet milling trials. The fluid jet mill equipment includes a flat cylindrical chamber with 1.5” diameter, fitted with four symmetric jet nozzles winch are tangentially positioned in the inner wall. Prior to feeding material to the fluid jet mill in each trial, the material was sieved in a 355 iim screen to remove any agglomerates and avoid blocking of the nozzles during the feed of material to the micronization chamber. The material to be processed was drawn into the grinding chamber through a vacuum created by the venturi (P vent ~ 0 5 – 1 0 bar above P grind). The feed flow rate of solids (F_feed) was controlled by a manual valve and an infinite screw volumetric feeder. Compressed nitrogen was used to inject the feed material; compressed nitrogen was also used for the jet nozzles in the walls of the milling chamber. Compressed fluid issuing from the nozzles expands from P grind and imparts very’ high rotational speeds in the chamber. Accordingly, material is accelerated by rotating and expanding gases and subjected to centrifugal forces. Particles move outward and are impacted by high velocity jets, directing the particles radially inward at very high speeds. Rapidly moving particles impact the slower moving path of particles circulating near the periphery of the chamber. Attrition takes place due to the violent impacts of particles against each other. Particles with reduced size resulting from this sequence of impacts are entrained in the circulating stream of gas and swept against the action of centrifugal force toward the outlet at the center. Larger particles in the gas stream are subjected to a centrifugal force and returned to the grinding zone. Fine particles are carried by the exhaust gas to the outlet and pass from the grinding chamber into a collector.

[258] The feeder has continuous feed rate control; however, to more precisely control the feed rate, the full scale of feed rates was arbitrary divided in 10 positions. To calibrate F feed, the feeder was disconnected from milling chamber and 10 g of Compound (I) powder was fed through the feeder operating at various feed rate positions. The mass of powder flowing through the feeder over 6 minutes was marked. The resulting feed rate was directly proportional to feeder position. After processing each of the four trials, the jet mill was stopped, micronized product removed from the container, and the milling chamber checked for any powder accumulation.

Variables/Parameters

F_feed Feed flow rate of solids [kg/h]

P grind Grinding pressure inside the

drying chamber [bar]

P vent Feed pressure in the venturi [bar]

Example 8: Residual Solvent Levels

[251] Retention of process solvents (/.<?., res dual solvents) depends on van der Waal s’ forces that are unique to and an inherent property of each molecule. Additionally, solvent retention depends how the API solid is formed, isolated, washed, and dried (i.e., during the manufacturing process). Because residual solvents may pose safety risks, pharmaceutical processes should be designed to minimize residual solvent levels (e.g , to result in residual solvent levels below the limits established in the ICH guidelines).

[252] Residual solvent analysis was performed using gas chromatography-mass spectrometry. The residual solvent levels in solid forms of Compound (I) prepared by spray drying processes described herein and precipitation processes described herein are provided in Table 2. The residual solvent levels in crude Compound (I) listed in Table 2 are comparable to the residual solvent levels in crude Compound (I) prepared according to the procedures detailed in Example 31 of WO 2014/039899 and Example 1 of WO 2015/127310.

Table 2: Residual solvent levels in solid forms of Compound (I)

PATENT

WO 2015127310

https://patents.google.com/patent/WO2015127310A1/enExample 1Synthesis of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]-piperidine-l-carbonyl]-4-m iperazin-l-yl]pent-2-enenitrile

Step 1To a solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l -yl]-l-piperidyl]-3-oxo-propanenitrile (15 g, 3.12mmol), 2-methyl-2-[4- (oxetan-3-yl)piperazin-l-yl]propanal (794.25mg, 3.74mmol) in DCM (40mL), pyrrolidine (1.54mL,18.71mmol) at 0-5 °C was added, which is followed by TMS-Cl (1.58mL,12.47mmol). The reaction mixture was stirred at 0-5 °C for 3 h and was quenched with 1 M potassium phosphate buffer (pH 3). Layers were separated and the organic layer was washed once more with 1 M potassium phosphate buffer (pH 3). The organic layer was extracted withl M potassium Phosphate buffer at pH 1.5. Layers were separated. The aqueous phase contained the desired product while the impurities stayed in the organic phase. The aqueous phase was neutralized with 1 M potassium phosphate (pH 7) and was extracted with isopropylacetate (10 volumes). Upon concentration 2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile was obtained as a foam having >99% HPLC purity. MS (pos. ion) m/z: 666 (M+l ).The foam containing high levels of residual solvent was dissolved in 2 M HC1 and the resulting solution was placed under vacuum to remove residual organic solvents. pH of the solution was then adjusted to ~ 7 and the resulting paste was filtered and dried in vacuum without heat. This resulted in isolation of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin- l-yl]pent-2-enenitrile containing residual water up to 10%. Drying under vacuum without heat reduces the water level but lead to generation of impurities.Step 1AAlternatively, the isopropylacetate solution of 2-[(3R)-3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l -yl]pent-2-enenitrile can be concentrated to 4 vol and added to heptane (20 volume) at 0 °C. The resulting suspension was stirred at 0 °C overnight and the product was filtered, washed twice with heptane and dried at 45 °C for 2 days under vacuum to give 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l – yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile in 85 – 90 % yield as a free flowing solid. However, the solids obtained by this method contained high residual solvents (3.9 wt% isopropylacetate and 1.7 wt% heptane). In addition, the free base form was not very stable as degradation products were observed during the drying process at less than 45 °C.Salt formationExample 2Preparation of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin- l-yl]-piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)-piperazin-l-yl]pent-2-enenitrile hemisulfate and sulfate saltHemisulfate: To the solution of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4- d]pyrimidin-l-yl]-piperidine -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)-piperazin-l-yl]pent-2- enenitrile (4.2 g) in EtOAc (60 mL, 15 vol) was added sulfuric acid (0.31 g, 0.17 mL, 0.5 eq) in EtOAc (20 mL, 5 vol) at ambient temperature. The suspension was stirred at ambient temperature for ~ 2 hr and then 40 °C for 4 hr and then at ambient temperature for at least 1 hr. After filtration and drying at ambient temperature under vacuum, 1.5 g of white powder was obtained. Solubility of the hemi-sulfate at ambient temperature was > 100 mg/mL in water.Sulfate saltTo the solution of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4- d]pyrimidin-l-yl]-piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)-piperazin-l-yl]pent-2- enenitrile (810 mg) in EtOAc (8 mL, 10 vol) was added sulfuric acid (0.06 mL, 1.0 equiv.) in EtOAc (2.5 mL, 5 vol) at ambient temperature. The resulting suspension was stirred at 40 °C for 2 hr and then cooled to ambient temperature for at least 1 hr. After filtration, solids were dried by suction under Argon for 1 h to give a white powder (0.68 g) in 69% yield.

Example 3Preparation of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4- d]pyrimidin- 1 -yl]-piperidine- 1 -carbonyl] -4-methyl-4-[4-(oxetan-3-yl)-piperazin- 1 -yl]pent-2- enenitrile hydrochlorideTo a solution of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- 1 -yl]pent-2- enenitrile (100 mg, 0.15 mmol) in CH2CI2 (1ml) at ambient temperature was added 2 equivalent of HC1 (0.3 mmol, 0.15 ml of 2M HC1 in 1 : 1 dioaxane:CH₂Cl₂). The resulting homogeneous solution was stirred at ambient temperature for 1 h and was added dropwise to 15 volumes of ethylacetate (as compared to CH₂C1₂) resulting in formation of a white solid. The mixtures was aged at ambient temperature for lh and placed at 2-8 C for 19 h. Upon filtration and washing of the filter cake with ethylacetate and drying a white solid was obtained. Analysis by XRPD indicated formation of an amorphous solid. Both Ή-NMR and IC analysis indicated formation of the salt. IC indicated formation mono-HCl salt.

Example 4General procedure for preparation of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]-piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)- piperazin-l-yl]pent-2-enenitrile mono- and di-mesylate saltsTo a solution of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4- d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2- enenitrile (100 mg, 0.15 mmol) in CH₂C1₂ (1 ml) at ambient temperature was added either 1 equivalent of methanesulfonic acid (0.15 mmol, 0.2 ml of 74 mg/ml solution in CH₂C1₂) or 2 equivalent of methanesulfonic acid (0.3 mmol, 0.4 ml of 74 mg/ml solution in CH₂C1₂). The resulting homogeneous solution was stirred at ambient temperature for 1 h and was added dropwise to 10 volumes of antisolvents (ethylacetate, methyl tert-butylether (MTBE), or cyclohexane) (10 ml as compared to CH₂C1₂) resulting in formation of a white solid. The mixture was aged at ambient temperature for lh and placed at 2-8 °C for 19 h. Upon filtration and washing of the filter cake with the antisolvent and drying, a white solid was obtained. Analysis by XRPD indicated formation of an amorphous solid. Both Ή-NMR and IC analysis indicated formation of the salt as well as counterion ratio.Alternatively 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]- pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- 1 -yl]pent-2- enenitrile can be dissolved in 4 volumes of isopropylacetate and added to 2 equivalent of methanesulfonic acid in 6 volumes of isopropylacetate at 0 °C to generate the dimesylate salt.

1. Theoretical mesylate content, monomesylate=12.6% and dimesylate=22.4%, NO- not determinedExample 5 General procedure for the preparation of carboxylate salt Approximately 20 mg of the compound (I) was dissolved in minimum amount of the allocated solvent system. These were then mixed with the appropriate number of equivalents of counterion dissolved or slurried in the allocated solvent.If compound (I) was insoluble in the selected solvent, slurry of the sample was used after adding 300 μί.If the acid was insoluble in the selected solvent, slurry of the acid was used after adding 300 xL.If the acid was a liquid, the acid was added to the dissolved/slurried compound (I) from a stock solution in the allocated solvent.The suspensions/ precipitates resulting from the mixtures of compound (I) were temperature cycled between ambient (ca. 22°C) and 40°C in 4 hour cycles for ca. 48 hrs (the cooling/heating rate after each 4 hour period was ca. 1 °C/min). The mixtures were visually checked and any solids present were isolated and allowed to dry at ambient conditions prior to analysis. Where no solid was present, samples were allowed to evaporate at ambient. Samples which produced amorphous material, after the treatment outlined above, were re- dissolved and precipitated using anti-solvent (ter/-butylmethylether) addition methods at ambient conditions (ca. 22°C). i.e. the selected anti-solvent was added to each solution, until no further precipitation could be observed visually or until no more anti-solvent could be added. The solvents used in this preparation were acetonitrile, acetone, isopropyl acetate, THF and MTBE. The acid used were oxalic acid, L-aspartic acid, maleic acid, malonic acid, L-tartaric acid, and fumaric acid.Example 6General procedure for preparation of 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]-piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)- piperazin-l-yl]pent-2-enenitrile hemicitrate saltTo a solution 2-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]- pyrimidin- 1 -yl]piperidine- 1 -carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- 1 -yl]pent-2- enenitrile (5 g, 7.5 mmol) in ethanol (50 ml) was added citric acid (720.5 mg, 3.76 mmol) dissolved in 2 ml of water. Mixture was stirred at ambient temperature for 15 min, additional 0.5 ml of water was added and the mixture was stirred for 1 h, concentrated in vacuo to a gum. Ethanol was added and the mixture was concentrated. This process was repeated twice more and then CH2CI2 was added to the mixture. Upon concentration a white solid was obtained which was tumble dried under reduced pressure at 40 C for 4 h, then in a vacuum oven for 19h to give 5.4 g of a solid. Analysis by XRD indicated formation of an amorphous solid

PATENT

WO2014039899, Example 31

Rilzabrutinib (PRN1008) is an oral, reversible covalent inhibitor of Bruton’s tyrosine kinase (BTK) [1].

https://patents.google.com/patent/WO2014039899A1/enExample 31Synthesis of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl)piperidine- 1 -carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin- 1 -yl)pent-2-enenitrile

Step 1A solution of 2-bromo-2-methyl-propanal (696.6 mg, 4.61 mmol) in DCM (10 mL) was cooled with an ice bath and l -(oxetan-3-yl)piperazine (328 mg, 2.31 mmol), diluted with 5-10 mL of DCM, was slowly added via addition funnel over a 15 min period. Next, Hunig’s base (0.4 mL, 2.31 mmol) was added and then the cooling bath was removed. The reaction mixture was stirred at room temperature overnight and the DCM layer was washed three times with 0.5N HC1. The combined aqueous layer was neutralized with NaOH to pH 10-11 and extracted with DCM. The combined organic layer was washed with brine and dried over Na?S0₄. Filtration and removal of solvent afforded 2-methyl-2-[4-(oxetan-3-yl)piperazin-l- yl]propanal as a light yellow liquid, which was used directly in the next step without further purification.Step 2To a cooled (0 °C) solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)- pyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidyl]-3-oxo-propanenitrile (80 mg, 0.17 mmol), was added 2-methyl-2-[4-(oxetan-3-yl)piperazin-l-yl]propanal (-108 mg, 0.51 mmol) in DCM (10 mL) followed by pyrrolidine (0.08 mL, 1.02 mmol) and TMS-C1 (0.09 raL, 0.68 mmol.) The ice bath was removed, and the reaction stirred 1 hour. Most of the solvent was removed and the residues were purified by chromatography, using 95:5 CH₂Cl₂:MeOH to obtain 79 mg of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-lH-pyrazolo[3,4-d]-pyrimidin-l- yl)piperidine- 1 -carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin- 1 -yl)pent-2-enenitrile as a white solid. MS (pos. ion) m/z: 666 (M+l).

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0223523421001781?dgcid=rss_sd_all

Therapy based on Bruton’s tyrosine kinase (BTK) inhibitors one of the major treatment options currently recommended for lymphoma patients. The first generation of BTK inhibitor, Ibrutinib, achieved remarkable progress in the treatment of B-cell malignancies, but still has problems with drug-resistance or off-target induced serious side effects. Therefore, numerous new BTK inhibitors were developed to address this unmet medical need. In parallel, the effect of BTK inhibitors against immune-related diseases has been evaluated in clinical trials. This review summarizes recent progress in the research and development of BTK inhibitors, with a focus on structural characteristics and structure-activity relationships. The structure-refinement process of representative pharmacophores as well as their effects on binding affinity, biological activity and pharmacokinetics profiles were analyzed. The advantages and disadvantages of reversible/irreversible BTK inhibitors and their potential implications were discussed to provide a reference for the rational design and development of novel potent BTK inhibitors.

Research

Rilzabrutinib is an oral, reversible covalent inhibitor of Bruton’s tyrosine kinase, that may increase platelet counts in people with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)–mediated platelet destruction and reduced production of pathogenic autoantibodies.^[5]

References

https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219685s000lbl.pdf
“FDA Approves Drug to Treat Adults with Persistent or Chronic Immune Thrombocytopenia”. U.S. Food and Drug Administration. 2 September 2025. Retrieved 5 September 2025. This article incorporates text from this source, which is in the public domain.
“Press Release: Sanofi’s Wayrilz approved in US as first BTK inhibitor for immune thrombocytopenia” (Press release). Sanofi. 29 August 2025. Retrieved 5 September 2025 – via GlobeNewswire.
World Health Organization (2020). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83”. WHO Drug Information. 34 (1). hdl:10665/339768.
Kuter DJ, Efraim M, Mayer J, Trněný M, McDonald V, Bird R, et al. (April 2022). “Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia”. The New England Journal of Medicine. 386 (15): 1421–1431. doi:10.1056/NEJMoa2110297. PMID 35417637.

External links

“Rilzabrutinib ( Code – C174769 )”. EVS Explore.
Clinical trial number NCT04562766 for “Study to Evaluate Rilzabrutinib in Adults and Adolescents With Persistent or Chronic Immune Thrombocytopenia (ITP) (LUNA 3)” at ClinicalTrials.gov

Clinical data

Trade names	Wayrilz
Other names	PRN-1008
AHFS/Drugs.com	Wayrilz
License data	US DailyMed: Rilzabrutinib
Routes of administration	By mouth
Drug class	Antineoplastic
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
IUPAC name
CAS Number	1575591-66-0
PubChem CID	73388818
DrugBank	DB17709
ChemSpider	58893525
UNII	NWN58M4F5T
KEGG	D11873
ChEMBL	ChEMBL3702854
Chemical and physical data
Formula	C₃₆H₄₀FN₉O₃
Molar mass	665.774 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES
InChI

///////////////PRN-1008, PRN 1008, Rilzabrutinib, リルザブルチニブ, Fda 2025, approvals 2025 8/29/2025, Wayrilz,
N#CC(=CC(N(C1COC1)C)(C)C)C(=O)N1CCCC1Cn1nc(c2c1ncnc2N)c1ccc(cc1F)Oc1ccccc1

PAT

Example 31 [WO2014039899]

PAT

US8940744, 31

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PRN 473, SAR 444727

July 18, 2021 2:45 am / Leave a comment

2-[(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carbonyl]-4,4-dimethylpent-2-enenitrile.png

SAR-444727

1414354-91-8C₃₀ H₃₀ F N₇ O_{2 Molecular Weight539.60}1-Piperidinepropanenitrile, 3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-(2,2-dimethylpropylidene)-β-oxo-, (3R)-

(3R)-3-[4-Amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-α-(2,2-dimethylpropylidene)-β-oxo-1-piperidinepropanenitrile

2-(3-(4-amino~3-(2-fiuoro~4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile

OriginatorPrincipia Biopharma
ClassSmall molecules
Mechanism of ActionAgammaglobulinaemia tyrosine kinase inhibitors

Phase IAutoimmune disorders
DiscontinuedArthritis

28 Sep 2020Principia Biopharma has been acquired by Sanofi
22 Jun 2020Principia Biopharma plans a pharmacokinetic phase I trial (In volunteers) for Hypersensitivity (for Immunoglobulin E-mediated allergies) in Australia (Topical) (ACTRN12620000693921)
10 Mar 2020Phase-I clinical trials in Autoimmune disorders (In volunteers) in Australia (Topical)
US 8957080
US 8673925
WO 2014022569
WO 2013191965
WO 2012158764

Useful for treating pemphigus vulgaris, immune thrombocytopenia, inflammatory bowel disease, Sjogren’s syndrome, multiple sclerosis, chronic lymphocytic leukemia and ankylosing spondylitis. Principia Biopharma is developing a topical formulation PRN-473 (presumed to be SAR-444727), a reversible covalent bruton’s (BTK) tyrosine kinase inhibitor, developed based on Principia’s reversible, tailored covalency platform, for treating immune-mediated diseases [phase I, July 2021]. Principia Biopharma was also investigating BTK inhibitors , developed based on Principia’s reversible, tailored covalency platform, for treating hematologic malignancies [no development reported since July 2019]. At the time of publication, Zhu was also affiliated with Nurix Therapeutics , while By and Phiasivongsa were based at Rain Therapeutics and Kronos Bio , respectively.

PATENT

WO-2021142131

Novel crystalline polymorphic forms (I to V) of PRN-473 and their preparation method.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021142131&_cid=P22-KR7EAJ-62766-1

CRYSTALLINE FORMS OF 2- [3- [4- AMINO-3-(2- FLUORO-4-PHENOXY- PHENYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-1-YL]PIPERIDINE-1-CARBONYL]- 4,4-DIMETHYLPENT-2-ENENITRILE

This application claims the benefit of priority to U.S. Provisional Application No. 62/958,389, filed January 8, 2020, the contents of which are incorporated by reference herein in their entirety.

Disclosed herein are crystalline forms of 2-(3-(4-amino~3-(2-fiuoro~4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile (Compound (I)), methods of using the same, and processes for making Compound (I), including its various crystalline forms. The crystalline forms of Compound (I) are inhibitors of Bruton’s tyrosine kinase (BTK). The enzyme BTK is a member of the Tec family non-receptor tyrosine kinases.

BTK is expressed in most hematopoietic cells, including B cells, mast cells, and macrophages. BTK plays a role in the development and activation of B cells and has been implicated in multiple signaling pathways across a wide range of immune-mediated diseases. BTK activity has been implicated in the pathogenesis of several disorders and conditions, such as B cel1-related hematological cancers (e.g,, non-Hodgkin lymphoma and B cell chronic lymphocytic leukemia) and autoimmune diseases (e.g, rheumatoid arthritis,

Sjogren’s syndrome, pemphigus, IBD, lupus, and asthma).

Compound (I) and various solid forms thereof may inhibit BTK and be useful in the treatment of disorders and conditions mediated by BTK activity. Compound (I) is disclosed as, e.g., Compound 125A in Table 1 of WO 2012/158764 and has the following structure:

Example 1: Preparation of Crystalline Form (I) of Compound (I)

Methyl isobutyl ketone (MIBK; 6 mL) was added to amorphous (R)-2-(3-(4-amino-3- (2-fluoro-4-phenoxyphenyJ)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4- dimethylpent-2-enenitrile (1,0 g) and stirred to fonn a solution. After approximately five minutes of agitation, a precipitate began to form. Additional MIBK (10 mL) was charged, and the slurry was stirred. After approximately ten days, the solid was filtered and rinsed with MIBK (10 mL). The solid was dried under vacuum with heating to afford approximately 0.5 g of crystalline Form (I) of Compound (I) as a white solid.

PATENT

WO2012158764 , claiming BTK tyrosine kinase inhibitors, useful for treating cancer.

https://patents.google.com/patent/WO2012158764A1/en

WO 2012/158764 125A

PATENT

US20210205313

PATENT

US20210205312 ,

for concurrently published filings, claiming a gel composition comprising PRN-473 and use of another BTK tyrosine kinase inhibitor ie PRN1008 , respectively.

PATENT

WO2016100914 , claiming use of a BTK inhibitor ie PRN-473, alone or in combination with corticosteroid therapy, for treating pemphigus vulgaris.

PATENT

WO 2014022569

https://patents.google.com/patent/WO2014022569A1/en

//////// PRN-473, PRN 473, SAR 444727, PHASE 1

CC(C)(C)C=C(C#N)C(=O)N1CCC[C@H](C1)n1nc(c2c(N)ncnc21)c1ccc(Oc2ccccc2)cc1F

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