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Rezivertinib

July 3, 2021 6:40 am / Leave a comment

BPI-7711, Rezivertinib

1835667-12-3

C27H30N6O3, 486.576

N-[2-[2-(dimethylamino)ethoxy]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide

Beta Pharma in collaboration Chinese licensee CSPC Pharmaceuticals Group , is developing BPI-7711

In June 2021, this drug was reported to be in phase 3 clinical development.

APPROVALS 2024, CHINA 2024

OriginatorBeta Pharma
ClassAmides; Amines; Antineoplastics; Indoles; Phenyl ethers; Pyrimidines; Small molecules
Mechanism of ActionEpidermal growth factor receptor antagonists
Phase IIINon-small cell lung cancer

30 Dec 2020Chemical structure information added
09 Apr 2020Beta Pharma initiates a phase I trial for Non-small cell lung cancer (In volunteers) in China (PO) (NCT04135833)
25 Mar 2020Beta Pharma completes a phase I pharmacokinetic trial for Non-small cell lung cancer (In volunteers) in China (NCT04135820)

GTPL10628

2-Propenamide, N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-

N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl)amino)phenyl)-2-propenamideThe epidermal growth factor receptor (EGFR, Herl, ErbB l) is a principal member of the ErbB family of four structurally-related cell surface receptors with the other members being Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its primary cellular functions though its intrinsic catalytic tyrosine protein kinase activity. The receptor is activated by binding with growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-a), which transform the catalytically inactive EGFR monomer into catalytically active homo- and hetero- dimers. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to the autophosphorylation of specific EGFR tyrosine residues and elicits the downstream activation of signaling proteins. Subsequently, the signaling proteins initiate multiple signal transduction cascades (MAPK, Akt and JNK), which ultimately mediate the essential biological processes of cell growth, proliferation, motility and survival.EGFR is found at abnormally high levels on the surface of many types of cancer cells and increased levels of EGFR have been associated with advanced disease, cancer spread and poor clinical prognosis. Mutations in EGFR can lead to receptor overexpression, perpetual activation or sustained hyperactivity and result in uncontrolled cell growth, i.e. cancer. Consequently, EGFR mutations have been identified in several types of malignant tumors, including metastatic lung, head and neck, colorectal and pancreatic cancers. In lung cancer, mutations mainly occur in exons 18 to 21, which encode the adenosine triphosphate (ATP)-binding pocket of the kinase domain. The most clinically relevant drug- sensitive EGFR mutations are deletions in exon 19 that eliminate a common amino acid motif (LREA) and point mutations in exon 21, which lead to a substitution of arginine for leucine at position 858 (L858R). Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations have perpetual tyrosine kinase activity and as a result they are oncogenic. Biochemical studies have demonstrated that these mutated EGFRs bind preferentially to tyrosine kinase inhibitor drugs such as erlotinib and gefitinib over adenosine triphosphate (ATP).Erlotinib and gefitinib are oral EGFR tyrosine kinase inhibitors that are first line monotherapies for non-small cell lung cancer (NSCLC) patients having activating mutations in EGFR. Around 70% of these patients respond initially, but unfortunately they develop resistance with a median time to progression of 10-16 months. In at least 50% of these initially responsive patients, disease progression is associated with the development of a secondary mutation, T790M in exon 20 of EGFR (referred to as the gatekeeper mutation). The additional T790M mutation increases the affinity of the EGFR kinase domain for ATP, thereby reducing the inhibitory activity of ATP- competitive inhibitors like gefitinib and erlotinib.Recently, irreversible EGFR tyrosine kinase inhibitors have been developed that effectively inhibit the kinase domain of the T790M double mutant and therefore overcome the resistance observed with reversible inhibitors in the clinic. These inhibitors possess reactive electrophilic functional groups that react with the nucleophilic thiol of an active-site cysteine. Highly selective irreversible inhibitors can be achieved by exploiting the inherent non-covalent selectivity of a given scaffold along with the location of a particular cysteine residue within the ATP binding site. The acrylamide moieties of these inhibitors both undergo a Michael reaction with Cys797 in the ATP binding site of EGFR^T790M to form a covalent bond. This covalent mechanism is thought to overcome the increase in ATP affinity of the T790M EGRF double mutant and give rise to effective inhibition. However, these inhibitors may cause various undesired toxicities. Therefore, development of new inhibitors for treatment of various EGFR-related cancers is still in high demand.
PatentCN201580067776) N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound of formula I) can be prepared by the following synthetic route:

PATENT

WO2016094821A2

https://patents.google.com/patent/WO2016094821A2/enExample 1N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide (1) Sche

N-(4-(2-(Dimethylamino)ethoxy)-2-methoxy-5-nitrophenyl)-4-(l-methyl-lH- indol-3-yl)pyrimidin-2-amine (Scheme 1, Intermediate B). To a slurry of NaH (30 mmol, 60% oil dispersion prewashed with hexanes) and 50 mL of 1,4-dioxane was added 2-dimethylaminoethanol (27 mmol, 2.7 mL) dropwise with stirring under N₂. After stirring for 1 h, a slurry of A (5.4 mmol) in 50 mL of 1,4-dioxane was added portion-wise over 15 min under a stream of N₂. The resulting mixture was stirred overnight, then poured into water and the solid was collected, rinsed with water, and dried under vacuum to yield 2.6 g of product as a yellow solid. A purified sample was obtained from chromatography (silica gel; CH₂C1₂-CH₃0H gradient). 1H NMR (300 MHz, DMSO) δ 2.26 (s, 6H), 2.70 (t, 2H, J = 6 Hz), 3.87 (s, 3H), 4.01 (s, 3H), 4.32 (t, 2H, J = 6 Hz), 7.00-7.53 (m, 5H), 8.18-8.78 (m, 5H); C₂₄H₂6N₆04 m/z MH⁺ 463.4-(2-(Dimethylamino)ethoxy)-6-methoxy-Nl-(4-(l-methyl-lH-indol-3- yl)pyrimidin-2-yl)benzene-l,3-diamine (Scheme 1, Intermediate C). A suspension of 2.6 g of Intermediate B, 1.6 g of Fe°, 30 mL of ethanol, 15 mL of water, and 20 mL of cone. HC1 was heated to 78 °C for 3 h. The solution was cooled to room temperature, adjusted to pH 10 with 10% NaOH (aq) and diluted with CH₂C1₂. The mixture was filtered through Dicalite, and the filtrate layers were separated. The aqueous phase was extracted with CH₂C1₂ twice, and the combined organic extracts were dried over Na₂S0₄ and concentrated. Column chromatography (silica gel, CH₂Cl₂-MeOH gradient) afforded 1.2 g of Intermediate C as a solid. C₂₄H₂₈N₆0₂ m/z MH⁺ 433.N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(l-methyl-lH-indol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide (1). To a solution of Intermediate C (2.8 mmol) in 50 mL of THF and 10 mL of water was added 3-chloropropionychloride (2.8 mmol) dropwise with stirring. After 5 h of stirring, NaOH (28 mmol) was added and the mixture was heated at 65°C for 18 h. After cooling to room temperature, THF was partially removed under reduced pressure, and the mixture was extracted with CH₂C1₂, dried over Na₂S0₄, and concentrated. Chromatography of the crude product (silica gel, CH₂Cl₂-MeOH) afforded 0.583 g of Example 1 as a beige solid. 1H NMR (300 MHz, DMSO) δ 2.28 (s, 6H), 2.50-2.60 (m, 2H), 3.86 (s, 3H), 3.90 (s, 3H), 4.19 (t, 2H, = 5.5 Hz), 5.73-5.77 (m, IH), 6.21-6.27 (m, IH), 6.44-6.50 (m, IH), 6.95 (s, IH), 7.11-7.53 (overlapping m, 3H), 7.90 (s, IH), 8.27-8.30 (overlapping m, 3H), 8.55 (s, IH), 8.84 (s, IH), 9.84 (s, IH) ppm; C₂₇H₃₀N₆O₃ m/z MH⁺ 487

PATENT WO2021115425

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021115425&tab=FULLTEXT&_cid=P20-KQN9F3-73566-1Epidermal growth factor receptors (EGFR, Her1, ErbB1) are the main members of the ErbB family of four structurally related cell surface receptors, and the other members are Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its main cellular functions through its inherent catalytic tyrosine protein kinase activity. The receptor is activated by binding to growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). The catalytically inactive EGFR monomer is transformed into a catalytically active homopolymer and Heterodimer. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to autophosphorylation of specific EGFR tyrosine residues and elicits downstream activation of signaling proteins. Subsequently, the signal protein initiates multiple signal transduction cascades (MAPK, Akt, and JNK), which ultimately regulate the basic biological processes of cell growth, proliferation, motility, and survival.

EGFR has been found to have abnormally high levels on the surface of many types of cancer cells, and elevated EGFR levels have been associated with advanced disease, cancer spread, and poor clinical prognosis. Mutations in EGFR can lead to overexpression of the receptor, permanent activation or continuous hyperactivity, leading to uncontrolled cell growth, which is cancer. Therefore, EGFR mutations have been identified in several types of malignant tumors, including metastatic lung cancer, head and neck cancer, colorectal cancer, and pancreatic cancer. In brain cancer, mutations mainly occur in exons 18-21, which encode the adenosine triphosphate (ATP)-binding pocket of the kinase domain. The most clinically relevant drug-sensitive EGFR mutations are deletions in exon 19 and point mutations in exon 21. The former eliminates a common amino acid motif (LREA), and the latter results in position 858 (L858R). The arginine is replaced by leucine. Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations have permanent tyrosine kinase activity, so they are carcinogenic. In at least 50% of patients who initially responded to current therapies, the progression of the disease is related to the development of a secondary mutation, T790M (also known as the goalkeeper mutation) in exon 20 of EGFR.
BPI-7711 is a third-generation EGFR-TKI compound developed by Beida Pharmaceuticals and disclosed in International Patent No. WO2017/218892. It is the N-(2-(2-(dimethylamino) )Ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonic acid salt:

Need to develop improved properties containing N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indole-3 -Yl)pyrimidin-2-yl)amino)phenyl)acrylamide pharmaceutically acceptable salt, in particular the pharmaceutical composition of BPI-7711 and its use, and the preparation of said pharmaceutical composition suitable for large-scale production method.

PATENT

WO2021061695 , for another filing, assigned to Beta Pharma, claiming a combination of an EGFR inhibitor (eg BPI-7711) and a CDK4/6 inhibitor, useful for treating cancer.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021061695&tab=PCTDESCRIPTION&_cid=P20-KQN9IQ-74298-1

PATENT

WO-2021121146

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021121146&tab=FULLTEXT&_cid=P20-KQN9K4-74458-1

Novel crystalline polymorphic form A of rezivertinib – presumed to be BPI-7711 – useful for treating diseases mediated by EGFR mutations eg lung cancer, preferably non-small cell lung cancer (NSCLC).Epidermal growth factor receptor (EGFR) is a type of transmembrane receptor tyrosine kinase in the human body. The activation (ie phosphorylation) of this kinase is of great significance to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis. EGFR kinase is involved in the disease process of most cancers, and these receptors are overexpressed in many major human tumors. Overexpression, mutations, or high expression of ligands associated with these family members can lead to some tumor diseases, such as non-small cell lung cancer, colorectal cancer, breast cancer, head and neck cancer, cervical cancer, bladder cancer, and thyroid. Cancer, stomach cancer, kidney cancer, etc.
In recent years, epidermal growth factor receptor tyrosine kinase has become one of the most attractive targets in current anti-tumor drug research. In 2003, the US FDA approved the first epidermal growth receptor tyrosine kinase inhibitor (EGFR-TKI) drug (gefitinib) for the treatment of advanced non-small cell lung cancer (NSCLC). Development of a generation of EGFR inhibitors. Numerous clinical trials have confirmed that for patients with EGFR-positive non-small cell lung cancer, the therapeutic effect of molecular targeted drugs is significantly better than traditional chemotherapy.
Although the first-generation EGFR-inhibiting targeted drugs responded well to the initial treatment of many non-small cell lung cancer (NSCLC) patients, most patients will eventually develop disease progression due to drug resistance (such as EGFR secondary T790M mutation). The emergence of drug resistance is caused by various mechanisms based on the mutations in the original EGFR pathway activity. In the drug resistance research on the first generation of EGFR inhibitors, the research frontier is the irreversible third generation EFGR inhibitor.
But so far, the third-generation EGFR inhibitors worldwide, in addition to AstraZeneca O’Higgins imatinib developed, there is no other effective against T790M resistance mutations in patients with drug approved for clinical use; Several drug candidates for the T790M mutation are in clinical development. The chemical structure of this third-generation EGFR inhibitor is completely different from that of the first-generation. The main difference from the first-generation EGFR inhibitors is that they both use a highly selective core structure to replace the low-selective aminoquinoline core structure of the first and second-generation EGFR-TKIs. Compared with wild-type EGFR, these third-generation compounds are highly specific and selective for the T790M mutation after EGFR positive resistance.
Chinese Patent Application No. CN201580067776.8 discloses a compound of the following formula I, which also belongs to the third-generation EGFR-TKI class of small molecule targeted drugs. The compound has a high inhibitory effect on non-small cell lung cancer (NSCLC) cells with single-activity mutation and T790M double-mutant EGFR, and its effective inhibitory concentration is significantly lower than the concentration required to inhibit the activity of wild-type EGFR tyrosine kinase. It has good properties, low side effects and good safety.

Chinese Patent Application No. CN201780050034.3 also discloses various salts and corresponding crystal forms of the compound of the above formula I. Example 2 discloses two crystal forms of the methanesulfonate of the compound of formula I, 2A and 2B, respectively.In the following examples, the “room temperature” can be 15-25°C.[0041](1) N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine -2-yl)amino)phenyl)acrylamide (compound of formula I)[0042]

[0043]Known (for example, see CN201580067776.8) N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound of formula I) can be prepared by the following synthetic route:[0044]

[0045]Step 1-Preparation of Intermediate J:[0046]

[0047]Preparation: In a 10L reaction flask, add 6L of anhydrous tetrahydrofuran solvent, protected by nitrogen, and cool to 0°C. While stirring, slowly add 101 g of sodium hydride (101 g, 2.52 mol), and the internal temperature does not exceed 10° C., and add 234 g of dimethylaminoethanol (234 g, 2.62 mol). After the addition, the temperature is adjusted to room temperature to prepare a sodium alkoxide solution.[0048]In a 30L reaction flask, add N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)-2-pyrimidinamine ( Starting material B) (430g, 1.10mol), then add 9L of tetrahydrofuran, start stirring, dissolve it, control the temperature at 10±10°C, slowly add the prepared sodium alkoxide solution dropwise. Control the temperature at 10±10℃ and keep it for 5.0h. When the raw material content is ≤0.5%, the reaction ends. Control the temperature at 10±10°C, slowly add 3% hydrochloric acid solution dropwise, adjust the pH of the solution to 6-7, stir for 1.5h and then stand for stratification, separate the organic phase, and concentrate to 15-20L. After cooling to 20±5°C, 4.3 kg of water was slowly added dropwise, filtered, and dried to obtain 497 g of yellow powder intermediate J with a yield of 98.0% and an HPLC purity of 99.3%. MS m/z: 463.2 [M+1].[0049]Nuclear magnetic data: ¹ HNMR (d ₆ -DMSO): δ ppm: 8.78 (s, 1H); 8.42-8.28 (m, 3H); 8.16 (s, 1H); 7.53 (d, 1H, J = 8.28); 7.29- 7.20 (m, 2H); 7.13-7.07 (m, 1H); 7.01 (s, 1H); 4.33 (t, 2H, J = 5.65); 4.02 (s, 3H); 3.88 (s, 3H); 2.71 ( t, 2H, J = 5.77); 2.27 (s, 6H).[0050]Step 2-Preparation of Intermediate K:[0051]

[0052]Preparation: Add 5L of tetrahydrofuran and Intermediate J (350g, 108mmol) to a 10L hydrogenation reactor, add 17.5g of wet palladium charcoal, replace the hydrogenation reactor with hydrogen, adjust the pressure value to 0.2MPa, control the temperature at 25°C, and keep the temperature for reaction. At 9h, HPLC monitors the progress of the reaction, and stops the reaction when the substrate is ≤0.5%. Filter, concentrate the filtrate under reduced pressure until the solvent volume is about 2L, adjust the internal temperature to room temperature, slowly add 4L n-heptane dropwise within 4-7 hours, filter and dry the solid under reduced pressure to obtain 285g of white powder intermediate K The yield was 86%, and the HPLC purity was 99.60%. MS m/z: 433.3 [M+1].

Nuclear magnetic data: ¹ HNMR (CDCl ₃ ): δ ppm: 8.42 (d, 1H, J = 7.78), 8.28 (s, 1H), 8.26-8.23 (m, 1H), 7.78 (s, 1H), 7.51 (d, 1H,J=8.28),7.41(s,1H),7.26-7.23(m,1H),7.19- 7.11(m,2H),6.72(s,1H), 4.38(br,2H),4.06(t, 2H,J=5.77), 3.88(s,3H), 3.75(s,3H), 2.63(t,2H,J=5.77), 2.26(s,6H).

Step 3-Preparation of compound of formula I:

Add 250 mL of anhydrous tetrahydrofuran solvent and Intermediate K (14 g, 32 mmol) to the reaction flask and stir, cool to 0-5° C., add 10% hydrochloric acid (12 ml), and stir for 20 minutes. At 0-5°C, slowly drop 3-chloropropionyl chloride (5.6 g, 45 mmol) into the reaction flask. Stir for 3 hours, after sampling test (K/(U+K)≤0.5%) is qualified, add 36% potassium hydroxide aqueous solution (75ml, 480mmol), heat to 23-25°C, and stir for 12 hours. Raise the temperature to 50-60°C and stir for 4 hours. After the sampling test (U/(U+L)≤0.1%) is qualified, stand still for liquid separation. Separate the organic phase, wash with 10% brine three times, dry, filter, and concentrate the organic phase to 150 ml. The temperature was raised to 40° C., 150 ml of n-heptane was slowly added dropwise, and the temperature was lowered to room temperature to precipitate crystals. Filtered and dried to obtain 10.71 g of light brown solid (compound of formula I), yield 68%, HPLC purity: 99.8% (all single impurities do not exceed 0.15%). MS m/z: 487.3 [M+1].[0057]Nuclear magnetic data (Figure 1): ¹ HNMR (d ₆ -DMSO): δppm: 9.84 (s, 1H), 8.90 ~ 8.82 (m, 1H), 8.32-8.25 (m, 2H), 7.89 (s, 1H) ,7.51(d,1H,J＝8.25), 7.27～7.10(m,1H), 6.94(s,1H), 6.49(dd,1H,J＝16.88,10.13), 6.25(dd,1H,J＝16.95 ,1.81),5.80～5.75(m,1H),4.19(t,2H,J＝5.57),3.88(d,6H,J＝14.63,6H),3.34(s,3H),2.58(d,2H, J=5.5), 2.28 (s, 6H).

(2) N-(2-(2-(Dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidine -2-yl)amino)phenyl)acrylamide methanesulfonate (Form A) preparation
Example 1

The compound of formula I (3 g, 6.1 mmol) was dissolved in 24 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 65° C., and the mixture was stirred and dissolved. Add an equivalent amount of methanesulfonic acid (0.59 g, 6.1 mmol) to the system. The temperature was lowered to 50°C, and 12ml of isopropyl acetate IPAc was slowly added. Stir at 50°C for 1 hour, then lower the temperature to 15°C. 21ml IPAc was added in 4 hours. The solution was stirred and crystallized at 15°C, filtered under reduced pressure, the filter cake was washed with isopropyl acetate, and washed with acetone to reduce the residual DMSO solvent. Blow drying at 50°C (or vacuum drying at 50°C) to obtain 3.16 g of a pale yellow solid (crystal form A). HPLC purity is 100%, yield is 88%, DMSO: <100ppm; IPAc: <100ppm. MS m/z: 487.2 [M+1-MsOH]. Melting point: 242-244°C.
Nuclear magnetic data (figure 2): ¹ HNMR(d ₆ -DMSO): δppm: 9.57(brs,1H), 9.40(s,1H), 8.71(s,1H), 8.48(s,1H), 8.32(d ,1H,J=7.9),8.29(d,1H,J=5.3),7.96(s,1H),7.51(d,1H,J=8.2),7.23(ddd,1H,J=7.9,7.1,0.8 ), 7.19 (d, 1H, J = 5.4), 7.15 (ddd, 1H, J = 7.8, 7.3, 0.5), 6.94 (s, 1H), 6.67 (dd, 1H, J = 16.9, 10.2), 6.27 ( dd, 1H, J = 16.9, 1.8), 5.57 (dd, 1H, J = 16.9, 1.7), 4.44 (t, 2H, J = 4.6), 3.89 (s, 3H), 3.88 (s, 3H), 3.58 (t, 2H, J=4.6), 2.93 (s, 6H), 2.39 (s, 3H).
After testing, the powder X-ray diffraction pattern of crystal form A obtained in this example has diffraction angle 2θ values of 11.06±0.2°, 12.57±0.2°, 13.74±0.2°, 14.65±0.2°, 15.48±0.2°, 16.58±0.2°, 17.83±0.2°, 19.20±0.2°, 19.79±0.2°, 20.88±0.2°, 22.05±0.2°, 23.06±0.2°, 24.23±0.2°, 25.10±0.2°, 25.71±0.2°, 26.15±0.2°, 27.37±0.2°, 27.42±0.2° has a characteristic peak; its XRPD spectrum is shown in Figure 3 and the attached table, DSC diagram is shown in Figure 4, TGA diagram is shown in Figure 5, and infrared spectrum IR diagram is shown in Figure 6. Show.
Example 2

[0066]The compound of formula I (28.25 g, 58.1 mmol) was dissolved in 224 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 15-35° C., and the mixture was stirred to clear. 0.97 equivalents of methanesulfonic acid (5.4 g, 0.97 mmol) were added to the system in batches. Slowly add 448 ml of methyl isobutyl ketone (MIBK). Stir for 1 hour, then lower the temperature to 10-15°C. The solution was reacted with salt formation at 10-15°C, sampled, and HPLC detected the residue of the compound of formula I in the mother liquor (≤0.4%). After the reaction was completed, vacuum filtration was performed to obtain 32 g of the crude methanesulfonate of the compound of formula I.Add 3g of the crude methanesulfonate of the compound of formula I into 24ml of dimethyl sulfoxide DMSO solvent, stir to clear at 65°C, cool down, slowly add 48ml of methyl isobutyl ketone (MIBK) dropwise, stir and crystallize 6-8 After hours, vacuum filtration, drying at 60° C. (or 60° C. vacuum drying) to obtain the target crystal form A. Melting point: 242-244°C. The XRPD pattern of the crystal form is consistent with Figure 3 (Figure 7), and all characteristic peaks are within the error range.

SYN

European Journal of Medicinal Chemistry 291 (2025) 117643

Rezivertinib, also known as BPI-7711, is a third-generation epidermal growth factor receptor (EGFR) TKI, developed by Beta Pharm. Rezivertinib selectively targets both EGFR-sensitizing mutations
and the T790 M resistance mutation, thereby addressing resistance mechanisms associated with first- and second-generation EGFR-tyrosine kinase inhibitors. In 2024, the NMPA approved Rezivertinib mesylate capsules (trade name: Ruibida) for the treatment of adult patients with locally advanced or metastatic NSCLC who have progressed during or after EGFR-TKI therapy and have confirmed EGFR T790 M mutation-positive status. Rezivertinib exerts its antitumor activity by forming covalent bonds with mutant EGFR, particularly the T790 M mutation, which effectively blocks the downstream signaling pathways responsible for promoting tumor cell proliferation and survival [21]. The mechanism of Rezivertinib effectively inhibits tumor growth in patients harboring T790M-mediated resistance to first- and second-generation EGFR-TKIs. In a Phase IIb clinical trial (NCT03812809), Rezivertinib demonstrated significant clinical efficacy among patients with EGFR T790 M mutation-positive NSCLC who had experienced disease progression following prior EGFR-TKI therapy. The trial reported an ORR of
64.6 % and a median PFS of 12.2 months, highlighting its potent antitumor activity in this specific patient cohort. In terms of safety, Rezivertinib exhibited a favorable tolerability profile [22]. The most
frequently observed treatment-related adverse events were rash, diarrhea, and elevated liver enzymes, predominantly of mild to moderate severity (grade 1 or 2). No dose-limiting toxicities were noted, and its safety profile aligned with those of other third-generation EGFR-TKIs.
The synthesis of Rezivertinib, illustrated in Scheme 5, initiates with nucleophilic substitution reaction between Rezi-001 and Rezi-002,affording Rezi-003 [23]. Fe-mediated reduction of Rezi-003 yields
Rezi-004, followed by amidation with Rezi-005 to deliver Rezivertinib [20] J.J. Cui, E.W. Rogers, Preparation of Fluorodimethyltetrahydroethenopyrazolobenzoxatriazacyclotridecinone
Derivatives for Use as Antitumor Agents, 2017. US20180194777A1.

[21] Y. Shi, Y. Zhao, S. Yang, J. Zhou, L. Zhang, G. Chen, J. Fang, B. Zhu, X. Li, Y. Shu,
J. Shi, R. Zheng, D. Wang, H. Yu, J. Huang, Z. Zhuang, G. Wu, L. Zhang, Z. Guo,
M. Greco, X. Li, Y. Zhang, Safety, efficacy, and pharmacokinetics of rezivertinib
(BPI-7711) in patients with advanced NSCLC with EGFR T790M mutation: a phase
1 dose-escalation and dose-expansion study, J. Thorac. Oncol. 17 (2022) 708–717.

//////////// BPI-7711, BPI 7711, rezivertinib, phase 3, CHINA 2024, APPROVALS 2024

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Uprifosbuvir

June 28, 2021 2:54 am / Leave a comment

Uprifosbuvir

MK 3682, IDX 21437

ウプリホスブビル;

Formula	C22H29ClN3O9P
CAS	1496551-77-9
Mol weight	545.9071

уприфосбувир [Russian] [INN]أوبريفوسبوفير [Arabic] [INN]乌磷布韦 [Chinese] [INN]

propan-2-yl (2R)-2-[[[(2R,3R,4R,5R)-4-chloro-5-(2,4-dioxopyrimidin-1-yl)-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate

Isopropyl (2R)-2-{[(R)-{[(2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-3-hydroxy-4-methyltetrahydro-2-furanyl]methoxy}(phenoxy)phosphoryl]amino}propanoate

IDX-21437, DB15206, SB18784, D10996, Q27281714

Uprifosbuvir (MK-3682) is an antiviral drug developed for the treatment of Hepatitis C. It is a nucleotide analogue which acts as an NS5B RNA polymerase inhibitor. It is currently in Phase III human clinical trials.^[1]^[2]^[3]

Uprifosbuvir is under investigation in clinical trial NCT02332707 (Efficacy and Safety of Grazoprevir (MK-5172) and Uprifosbuvir (MK-3682) With Elbasvir (MK-8742) or Ruzasvir (MK-8408) for Chronic Hepatitis C Genotype (GT)1 and GT2 Infection (MK-3682-011)).Hepatitis C viruss (HCV) have the newly-increased patients of 3-4 million every year, and World Health Organization (WHO) is estimated in global sense More than 200,000,000, in China more than 10,000,000 patients, HCV belongs to flaviviridae hepatovirus virus to dye person.Long-term hepatitis C virus Gently to inflammation, weight is to liver cirrhosis, hepatocarcinoma for poison infection.And during hepatitis C cirrhosis patients in decompensation, can there are various complication, such as abdomen Water abdominal cavity infection, upper gastrointestinal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, liver failure etc. are showed.The side of HCV infection is treated initially Method is interferon and interferon and ribavirin combination therapy, and only 50% therapist has reaction, and interferon to the method With obvious side effect, such as flu-like symptoms, body weight lower and fatigue and weak, and interferon and ribavirin Conjoint therapy then produces sizable side effect, including haemolysis, anemia and tired etc..U.S. FDA have approved multiple HCV medicines, including the polymerization of protease inhibitor, ucleosides and non-nucleoside in recent years Enzyme inhibitor and NS5A inhibitor etc..The protease inhibitor class medicine of FDA approvals has three：VX‐950 (Telaprevir), SCH-503034 (Boceprevir) and TMC435 (Simeprevir), the shortcoming of protease inhibitor is It is also easy to produce that mutation, toxicity is big, poor bioavailability, it is effective to individual other gene type.Eggs of the Telaprevir as the first generation White enzyme inhibitor has logged out market.The second filial generation and third generation protease inhibitor of high activity and wide spectrum is mainly used as and other One of component of drug combination of hepatitis C medicine.NS5A inhibitor is the highly active anti-HCV medicament of a class.The most representative Daclatasive for having BMS, The Ombitasvir of the Ledipasvir and AbbVie of Gilead, as this kind of medicine independent medication is easy to produce drug resistance, They treat one of drug component of HCV primarily as drug combination.The AG14361 of hepatitis C is generally divided into two kinds of ucleosides and non-nucleoside.At present, clinically only Suo Feibu One ucleosides hepatitis C medicine of Wei is listed by FDA approvals, and other are still in the anti-hepatitis C virus medicine of ucleosides of clinical experimental stage Thing also has the MK-3682 (IDX21437) of Mo Shadong, the AL-335 of the ACH-3422 and Alios of Achillion drugmakers.Third Hepatitis virus have the features such as Multi-genotype and fast variation, and single medicine treatment hepatitis C has generation drug resistance fast, to part Genotype cure rate is low and the various defects such as course for the treatment of length.In order to overcome these defects, the treatment of drug combination is primarily now taken Scheme, in order to overcome these defects, primarily now takes the therapeutic scheme of drug combination, the Sovaldi conducts of FDA approval listings The key component of drug combination, for the patient of 4 type of 1 type of gene and gene be Suo Feibuwei, profit Ba Wei woodss and Polyethylene Glycol-α- The drug combination of interferon three, the course for the treatment of are 12 weeks；For 1 type of gene and the patient of 3 types, the big woods joints of Suo Feibuwei and Li Ba Medication, the course for the treatment of are respectively 12 weeks and 24 weeks.- 2016 years 2013, FDA ratified Suo Feibuwei and NS3 protein inhibitors again in succession Simeprevir shares the patient of 1 type of therapeutic gene；The NS5A inhibitor Daclatavir therapeutic genes 1 of Suo Feibuwei and BMS With the patient of 3 types.Harvoni is the patient that Suo Feibuweijia NS5A inhibitor Ledipasvir is used for 1 type of gene.Even if using Same nucleoside, the NS5A inhibitor and/or NS3 protease inhibitor for sharing varying strength can effectively extend composition of medicine Clinical application range and Shorten the Treatment Process.In June, 2016, FDA have approved Suo Feibuwei and more potent secondary NS5A inhibitor Velpatasvir shares the hepatitis C patient suitable for all gene types, it is not necessary to carry out genetic test.Just in three phases clinic Suo Feibuwei, NS5A inhibitor Velpatasvir and NS3 protease inhibitor Voxilaprevir goes for all of disease People, is try to the course for the treatment of and shortened to 8 weeks from 12 weeks.Suo Feibuwei just in clinical trial target spots different with hepatitis C virus are directed to Drug regimen (such as Suo Feibuweijia new type NS 5A inhibitor Velpatasvir and/or protease inhibitor GS5816), its knot Fruit show than single drug more wide spectrum, effectively, and can be with Shorten the Treatment Process.MSD Corp. is by MK-3682 and NS5A inhibitor Grazoprevir and/or protease inhibitor Elbasvir is used as new drug regimen, effective for all genotype of HCV, And further shorten to the course for the treatment of of 8 weeks.New deuterated nucleoside phosphoric acid ester compound disclosed in patent of the present invention, especially The double deuterated compound such as VI-1b2 in 5 ‘-position, shows than the more preferable bioavailability of former compound MK-3682 and longer partly declines Phase.In addition, this kind of novel nucleoside phosphoramidate is significantly superior to the Suo Feibuwei of clinical practice in terms of anti-hepatitis C activity, On sugared ring, chlorine atom replaces fluorine atom, and cytotoxicity is significantly reduced in surveyed cell line.By to base, sugared ring With the transformation and optimization of prodrug moiety system, the anti-hepatitis C activity of partial synthesis compound is higher than Suo Feibuwei 2-10 times, meanwhile, In the optimization of metabolism key position, synthesis compound shows that in blood plasma the higher metabolic stabilities of peso Fei Buwei and chemistry are steady It is qualitative.Therefore this kind of new deuterated nucleotide phosphate and NS5A inhibitor and/or egg as shown in formula a, a1, a2, b, b1, b2 The newtype drug combination constituted by white enzyme inhibitor is with extremely wide application prospect.Deuterium is the naturally occurring hydrogen isotope of nature, the deuterated isotopic body in common drug all containing trace.Deuterium without It is malicious, “dead”, it is safe to human body, C-D keys are more stable (6-9 times) than c h bond, hydrogen is replaced with after deuterium, can extend medicine Half-life, while pharmacologically active (shape difference of H and D is little, J Med Chem.2011,54,2529-2591) is not affected, in addition Deuterated medicine usually shows more preferable bioavailability and less toxicity, and the active ribonucleoside triphosphote of its metabolism is more stable, So deuterated nucleoside phosphoramidate will be better than corresponding nucleoside medicine in the curative effect of clinical practice.For example, 2013 It is exactly a deuterated compound that the nucleoside anti hepatitis C virus drug ACH-3422 of clinical trial is in the approval of year FDA, with non-deuterium (WO2014169278, WO are 2014169280) than having higher bioavailability and longer half-life for the former compound phase in generation.
Based on above-mentioned present Research, we design and are prepared for the new deuterated nucleoside that compound VI-1b2 is representative Phosphoramidate.Below we will be described in the architectural feature of deuterated nucleoside phosphoramidate of our inventions, preparation method, Antiviral activity experimental result and it as anti-hepatitis c virus drug combination key component and NS5A inhibitor and/ Or the drug regimen of protease inhibitor is in the application of anti-virus aspect.

The EPA awarded the greener reaction conditions to the pharmaceutical company Merck & Co. for building a prodrug synthesis that eliminated the use of toxic reagents. Prodrugs are molecules that get metabolized by our bodies into an active pharmaceutical. Some hepatitis C and HIV medications are prodrugs and get synthesized through a method call pronucleotide (ProTide) synthesis. The method uses toxic and corrosive thionyl chloride, plus an excess of expensive pentafluorophenol that generates a lot of waste. Merck’s new method creates their target compounds in 90 to 92% yields without these reagents and eliminates the need for halogenated solvents entirely through strategic catalyst loading and the use of different starting materials from the traditional route.

The design of greener chemicals award went to the development of more environmentally friendly versions of chemicals called thermoset binders, which can serve as carpet adhesives and are involved in the manufacture of mineral and fiberglass products. Generally, these chemicals are based on formaldehyde or polycarboxylic acids, and they can give off toxic formaldehyde and often use small amounts of sulfuric and hypophosphorous acid as catalysts to activate them. The insulation and commercial roofing company Johns Manville created a new binder based on the reaction between renewable dextrose, fructose, and other simple sugars, bound together by the α-carbon-containing cross-linking agent glyoxal. The reaction also uses a biodegradable acid in water as a catalyst. The binder can be made in just one step instead of the traditional multistep synthesis. Also, the synthesis can be done directly at the manufacturing site, instead of beforehand like with the traditional approach, meaning this new binder creates fewer of the health and environmental hazards that come from storage and transportation.

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US 20170226146,

Paper

Organic Process Research & Development (2021), 25(3), 661-667.

https://pubs.acs.org/doi/10.1021/acs.oprd.0c00487

A novel application of the synthesis of pronucleotide (ProTide) 5′-phosphoramidate monoesters promoted by aluminum-based Lewis acids is described. In the multikilogram synthesis of uprifosbuvir (MK-3682, 1), a clinical candidate for the treatment of hepatitis C, this methodology provided >100:1 diastereoselectivity at the phosphorus stereocenter and >100:1 selectivity for the 5′-mono phosphorylation over undesired bisphosphorylation side products. The high diastereoselectivity and mono/bis ratio achieved enabled elimination of the tedious workup associated with the tert-butyl magnesium chloride protocol commonly used to install this functionality in similar nucleotide prodrugs, achieving a near doubling of the isolated yield from 45% to 81%. The process development and purity control strategy of MK-3682, as well as handling of the pyrophoric reagent on scale, will also be discussed.

PAPER

Science (Washington, DC, United States) (2020), 369(6504), 725-730.

Science (Washington, DC, United States) (2017), 356(6336), 426-430.

Chemical Science (2017), 8(4), 2804-2810.

PATENT

CN 106543253

https://patents.google.com/patent/CN106543253A/zh

PATENT

WO 2014058801

https://patents.google.com/patent/WO2014058801A1/enExample 1Preparation of 2′-Chloro Nucleoside Analogs

Scheme 1

Ethyl (3R)-2-chloro-3-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-hydroxy-2- methylpropanoate (A2):

[00273] A 5 L flange flask was fitted with a thermometer, nitrogen inlet, pressure equalizing dropping funnel, bubbler, and a suba^»seal. Methyl lithium solution (1.06 L, 1.6 M in diethylether, 1.7 equiv.) was added, and the solution was cooled to about -25 °C.Diisopropyl amine (238 ml, 1.7 equiv.) was added using the dropping funnel over about 40 minutes. The reaction was left stirring, allowing to warm to ambient temperature overnight. C02_(s)/acetone cooling was applied to the LDA solution, cooling to about -70 °C.[00274] i?-Glyceraldehyde dimethylacetal solution (50% in DCM) was evaporated down to -100 mbar at a bath temp of 35 °C, to remove the DCM, then azeotroped with anhydrous hexane (200 ml), under the same Buchi conditions. 1H NMR was used to confirm that all but a trace of DCM remained.[00275] The fresh aldehyde (130 g, 1 mol) and ethyl 2-chloropropionionate (191 ml, 1.5 equiv.) were placed in a 1 L round bottom flask, which was filled with toluene (800 ml). This solution was cooled in a C0_2(s)/acetone bath, and added via cannula to the LDA solution over about 50 minutes, keeping the internal temperature of the reaction mixture cooler than -60 °C. The mixture was stirred with cooling (internal temp, slowly fell to ~ -72 °C) for 90 min, then warmed to room temperature over 30 minutes using a water bath. This solution was added to a sodium dihydrogen phosphate solution equivalent to 360 g of NaH₂P0₄ in 1.5 L of ice/water, over about 10 minutes, with ice-bath cooling. The mixture was stirred for 20 minutes, then transferred to a sep. funnel, and partitioned. The aqueous layer was further extracted with EtOAc (2 x 1 L), and the combined organic extracts were dried over sodium sulfate. The volatiles were removed in vacuo (down to 20 mbar). The resultant oil was hydrolyzed crude.

(3R,4R,5R)-3-chIoro-4-hydroxy-5-(hydroxymethyI)-3-methyIoxoIan-2-one (A4):

H O CI[00276] The crude oil A2 was taken up in acetic acid (1.5 L, 66% in water) and heated to 90 °C over one hour, then at held at that temperature for one hour. Once the mixture had cooled to room temperature, the volatiles were removed in vacuo, and azeotroped with toluene (500 ml). The resultant oil was combined with some mixed material from an earlier synthesis and columned in two portions (each -1.25 L of silica, 38→ 75% EtOAc in DCM). The lower of the two main spots is the desired material; fractions containing this material as the major component were combined and the solvent removed in vacuo to give 82 g of orange solid whose ¹ H NMR showed the material to be of about 57% purity (of the remainder 29% was the indicated epimer). This material was recrystallized fromtoluene/butanone (600 ml / -185 ml), the butanone being the ‘good’ solvent. The resultant solid was filtered washing with toluene and hexane, and dried in vacuo to give product of about 92% purity (30 g).(2R,3R,4R)-2-[(benzoyIoxy)methyI]-4-chIoro-4-methyI-5-oxooxoIan-3-yI benzoate(A5):

[00277] A 2 L 3 -neck round bottom flask was fitted with an overhead stirrer, thermometer and pressure equalizing dropping funnel (→N₂). The intermediate A4 (160 mmol) in acetonitrile (1 L) was added, followed by 4-dimethylaminopyridine (3.2 mmol) and benzoyl chloride (352 mmol). Finally triethylamine (384 mmol) was added over 10 minutes using the dropping funnel. The addition of the triethylamine is accompanied by a mild exotherm, which obviated the addition of a cold water bath to keep the internal temperature below 25 °C. The reaction was stirred at ambient temperature for 2.5 hours. The reaction mixture was transferred to a sep. funnel with EtOAc (2 L) and half saturated brine (2 L), and partitioned. The aqueous layer was re-extracted with EtOAc (1 L). The combined organic layers were washed with 50%> sodium bicarbonate/25%) brine (1.5 L) and dried over sodium sulfate, to give 62 g of solid. This was recrystallized from 1.8 L of 1 : 1 toluene/trimethylpentane (95 °C), to give 52.4 g of product.[00278] 1H NMR (CDCls, 400 MHz): δ (ppm) 1.91 (s, 3H), 4.57 (dd, J= 5.12Hz and J = 12.57Hz, 1H), 4.77 (dd, J= 3.29Hz and J= 12.68Hz, 1H), 4.92-4.96 (m, 1H), 5.60 (d, J = 8.36Hz, 1H), 7.38-7.66 (m, 6H), 7.97-7.99 (m, 2H), 8.08-8.10 (m, 2H); MS (ESI) m/z= 411.1(MNa ).

3,5-Di-0-benzoyl-2-C-chloro-2-C-methyl-D-ribofuranose (A6):

[00279] To a solution of A5 (14.48 mmol) in anhydrous tetrahydrofurane (70 ml) was added under inert atmosphere at -35°C, LiAlH(OtBu)₃ (1M in tetrahydrofurane, 21.7 mmol) over a 30 min period. The reaction mixture was stirred for 1 hour at -20 °C and quenched by addition of a saturated NH₄C1 solution, keeping the temperature bellow 0 °C. Ethyl acetate was added and the white suspension was filtered through a pad of celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 0 to 20%). The product was dried in vacuum (50 °C) overnight to afford expected intermediate as a colorless oil in 96% yield (mixture α/β: 45/55).[00280] 1H NMR (CDC1₃, 400 MHz): δ (ppm) 1.74 (s, 1.75H_P), 1.76 (s, 1.25H_a), 4.42-4.69 (m, 3H), 5.30 (d, J= 12.8Hz, 0.55H_P), 5.43-5.47 (m, 0.45H_a), 5.60 (d, J= 7.0Hz, 0.55H_P), 5.78 (d, J= 7.0Hz , 0.45H_a), 7.35-7.41 (m, 2H), 7.45-7.56 (m, 3H), 7.59-7.65 (m, 1H), 7.96- 8.04 (m, 2H), 8.06-8.14 (m, 2H); MS (ESI) m/z= 413 (MNa⁺).3,5-Di-0-benzoyl-2-C-chloro-2-C-methyl-D-arabinofuranosyl bromide (A7):

[00281] To a solution of A6 (12.80 mmol) in anhydrous dichloromethane (80 ml) was added under inert atmosphere at -20 °C, triphenylphosphine (18.0 mmol). The reaction mixture was stirred for 15 minutes at -20 °C and CBr₄ (19.20 mmol) was added. The reaction mixture was then stirred for 1 hour at -20 °C. The crude was partially concentrated under reduced pressure (bath temperature bellow 30 °C) and directly purified by chromatography on silica gel (eluent: petroleum ether/ethyl acetate 0 to 30%) to afford a mixture of β sugar A7a (1.67 g) and a sugar A7b (2.15 g) as a colorless gum in 66%> global yield.[00282] 1H NMR (CDC1₃, 400 MHz): β sugar δ (ppm) 1.93 (s, 3H), 4.60-4.88 (m, 3H), 6.08 (d, J= 7.9 Hz, 1H), 6.62 (s, 1H), 7.31-7.38 (m, 2H), 7.41-7.55 (m, 3H), 7.59-7.65 (m, 1H), 8.00-8.05 (m, 2H), 8.06-8.12 (m, 2H); a sugar δ (ppm) 1.88 (s, 3H), 4.66-4.89 (m, 3H), 5.37 (d, J= 4.88Hz, 1H), 6.44 (s, 1H), 7.41-7.55 (m, 4H), 7.54-7.65 (m, 2H), 8.00-8.05 (m, 2H), 8.14-8.20 (m, 2H); MS (ESI) m/z= 476/478 (MNa⁺).3 ,5′-Di-0-benzoyl-2′-C-chloro-2′-C-methyl-4-benzoyl-cytidine (A8):

[00283] To a suspension of N-benzoyl cytosine (9.48 mmol), and a catalytic amount of ammonium sulfate in 4-chlorobenzene (24 ml) was added HMDS (28.44 mmol). The reaction mixture was heated during 2 hours at 140 °C. The solvent was removed under inert atmosphere and the residue was taken in 4-chlorobenzene (15 ml). Then, A7b (4.74 mmol) in chlorobenzene (10 ml) was added dropwise to the reaction mixture followed by SnCl₄ (14.22 mmol) dropwise. The reaction mixture was stirred at 70 °C overnight, cooled to room temperature and diluted with dichloromethane and a saturated NaHC0₃ solution. The white suspension was filtered through a pad of celite and washed with dichloromethane. The filtrate was extracted with dichloromethane twice. The combined organic layers were dried over anhydrous Na₂S0₄, filtered and evaporated under reduced pressure to afford expected intermediate as a white solid in 89% yield.[00284] 1H NMR (DMSO, 400 MHz): δ (ppm) 1.58 (s, 3H), 4.68-4.81 (m, 3H), 5.68 (brs, 1H), 6.55 (brs, 1H), 7.36 (d, J= 7.84 Hz, 1H), 7.39-7.76 (m, 9H), 7.88-8.07 (m, 6H), 8.30 (d, J= 7.84 Hz, 1H); MS (ESI) m/z= 588 (MH⁺).3′,5′-Di-0-benzoyl-2^,-C-chloro-2^,-C-methyluridine (A9):

[00285] A suspension of A8 (4.19 mmol) in an acetic acid/water mixture (67 ml/17 ml, v/v), was heated at 110 °C for 3 hours. The reaction mixture was evaporated to dryness and co-evaporated with toluene (three times) to afford expected intermediate in quantitative yield as an oil which was directly used for the next step; MS (ESI) m/z= 485 (MH⁺). 2 -C-Chloro-2 -C-methyluridine (301):

H O CI[00286] Intermediate A9 (4.19 mmol) in 7 N methanolic ammonia (80 ml) was stirred at room temperature for 24 hours. The mixture was evaporated to dryness, diluted with water and transferred into a separatory funnel. The aqueous layer was extracted withdichloromethane and water was removed under reduced pressure. The residue was purified by flash RP18 gel chromatography (eluent: water/acetonitrile 0 to 40%) to afford pure expected compound as a white foam in 79% yield.[00287] 1H NMR (DMSO, 400 MHz): δ (ppm) 1.44 (s, 3H), 3.60-3.68 (m, 1H), 3.80-3.94 (m, 3H), 5.39 (t, J= 4.45 Hz, 1H), 5.63 (d, J= 8.26 Hz, 1H), 5.93 (d, J= 5.72 Hz, 1H), 6.21 (s, 1H), 8.16 (d, J= 8.90 Hz, 1H), 11.44 (m, 1H); MS (ESI) m/z= 277 (MH⁺).2′-C-Chloro-2′-C-methyl-3-benzyloxymethyluridine (Al 1):

H O CI[00288] To a solution of 301 (0.361 mmol) in anhydrous DMF (4 ml) was added at -5 °C, DBU (0.723 mmol) followed by benzyloxymethylchloride (0.542 mmol). The reaction mixture was stirred for 45 minutes between -5 °C and 5 °C. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 0 to 10%) to afford pure expected intermediate as a white solid in 80% yield.[00289] 1H NMR (DMSO, 400 MHz): δ (ppm) 1.41 (s, 3H), 3.61-3.69 (m, 1H), 3.82-3.95 (m, 3H), 4.57 (s, 2H), 5.32 (s, 2H), 5.43 (t, J= 4.46Hz, 1H), 5.80 (d, J= 8.08Hz, 1H), 5.96 (d, J= 4.46 Hz, 1H), 6.23 (s, 1H), 7.22-7.36 (m, 5H), 8.25 (d, J= 8.22Hz, 1H); MS (ESI) m/z= 397 (MH⁺). Isopropyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate (A12a):

2,2-Dimethylpropyl (2S)-2-[[chloro(phenoxy)phosphoryl]amino]propanoate (A12b):

[00290] To a solution of aminoester, HC1 salt (0.434 mmol) in anhydrous dichloromethane (or acetonitrile) (4 ml) (3 times vacuo/nitrogen) under nitrogen was added at -30°C phenyldichlorophosphate (0.434 mmol) followed by N-methylimidazole (2.90 mmol)(or only 1.45 mmol for A12b). The reaction mixture was stirred at -30°C during 1 hour. The reaction was monitored by LC/MS (the sample was quenched by methanol or water) to check the complete formation of expected intermediate A12a [MS (ESI) m/z= 302 (MH⁺)(-OMe compounder A12b [MS (ESI) m/z= 314 (MH^~)].Compound (A13a), (A13b) or (83ii):[00291] To the previous reaction mixture containing A12 was added All (or 302) (0.29 mmol) at -25°C under nitrogen. The reaction mixture was allowed to warm up slowly to room temperature overnight, and then diluted with dichloromethane and water (or with NaHCC”3 and EtOAc). The organic layer was extracted, dried, filtered and evaporated under reduced pressure. The crude residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 0 to 10%) (followed by preparative HPLC for A29).Compound (A13a):

[00292] Mixture of diastereoisomers; MS (ESI) m/z= 666 (MH⁺). Compound (A13b):

[00293] Mixture of diastereoisomers; MS (ESI) m/z= 692.3 (MH ).Compound (83ii):

[00294] Glassy solid; 1H NMR (CDCI3, 400MHz): δ (ppm) 1.19-1.24 (m, 9H), 1.35 (d, J = 7.1Hz, 3H), 3.95-4.05 (m, 1H), 4.31 (d, J= 8.1Hz, 2H), 4.41 (d, J= 9.0Hz, 1H), 4.59 (d, J = 7.1Hz, 2H), 4.98 (heptuplet, J= 6.28Hz, 1H), 6.38 (brs, 1H), 6.52 (s, 1H), 7.08-7.15 (m, 1H), 7.23-7.30 (m, 4H), 8.07 (s, 1H), 8.31 (s, 1H); ³¹P NMR (CDC1₃, 161.98 MHz): δ (ppm) 3.96 (s, IP); MS (ESI) m/z= 569.20 (MH⁺).Compounds (40iia) and (40iib):

[00295] To a solution of A13 (0.29 mmol) in anhydrous ethanol (6 ml) was added trifluoroacetic acid (2.9 mmol) dropwise (then 3 times vacuo/nitrogen purges), followed by Palladium hydroxide (20% on Carbon). The reaction mixture was purged 3 timesvacuo/nitrogen, and 3 times vacuo/hydrogen and then stirred under hydrogen for 5 hours. The reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The filtrate was evaporated under reduced pressure, and the crude compound was purified by preparative MS/HP LC to afford two pure compounds in 48% global yield.[00296] Compound 40ii (diastereoisomer 1): white solid; 1H NMR (CDC1₃, 400 MHz): δ (ppm) 1.22-1.26 (m, 6H), 1.37 (d, J= 7.08 Hz, 3H), 1.51 (s, 3H), 3.71-3.88 (m, 2H), 3.97- 4.06 (m, 1H), 4.16-4.18 (m, 1H), 4.45-4.57 (m, 2H), 4.97-5.07 (m, 1H), 5.57 (d, J= 8.20 Hz, 1H), 6.39 (s, 1H), 7.18-7.37 (m, 5H), 7.44 (d, J= 8.20 Hz, 1H), 8.40 (s, 1H); ³¹P NMR (CDC1₃, 161.98 MHz): δ (ppm) 4.20 (s, IP); MS (ESI, El⁺) m/z= 546 (MH⁺).[00297] Compound 40ii (diastereoisomer 2): white solid; 1H NMR (CDC1₃, 400 MHz): δ (ppm) 1.24-1.26 (m, 6H), 1.36 (d, J= 7.04 Hz, 3H), 1.59 (s, 3H), 3.69-3.77 (m, 1H), 3.91- 3.99 (m, 2H), 4.17-4.19 (m, 1H), 4.43-4.59 (m, 2H), 5.01-5.06 (m, 1H), 5.68 (d, J= 8.20 Hz, 1H), 6.42 (s, 1H), 7.21-7.39 (m, 5H), 7.60 (d, J=8.20 Hz, 1H), 8.14 (s, 1H); ³¹P NMR (CDC1₃, 161.98 MHz): δ (ppm) 3.47 (s, IP); MS (ESI) m/z= 546 (MH⁺).Compound 42ii:

[00298] Compound 42ii was synthesized from compound A13b (0.144 mmol) as described for compound 40ii.[00299] White solid; 1H NMR (MeOD, 400 MHz) δ (ppm) 0.94 (s, 9H), 1.40 (d, J= 7.10 Hz, 3H), 1.53 (s, 3H), 3.76 (d, J= 10.43 H, 1H), 3.86 (d, J= 10.44 H, 1H), 3.98-4.06 (m, 2H), 4.18-4.22 (m, 1H), 4.39-4.44 (m, 1H), 4.52-4.57 (m, 1H), 5.62 (d, J= 8.18 Hz, 1H), 6.40 (s, 1H), 7.20-7.29 (m, 3H), 7.36-7.41 (m, 2H), 7.74 (d, J= 8.18 Hz, 1H); ³¹P NMR (MeOD, 161.98 MHz) δ (ppm) 3.68 (s, IP); MS (ESI) m/z = 574.08 (MH⁺).

PAPER

US 20170226146

https://patents.google.com/patent/US20170226146A1/en

[0250]
[0251]
A 3-neck 100 mL jacketed round bottom flask with nitrogen inlet and mechanical stirrer was charged with compound 4 (3.0 g, 10.8 mmol), compound 13 (0.484 g, 2.17 mmol, 0.20 equiv), 2-butanone (21 mL), and 2,6-lutidine (2.53 mL, 21.7 mmol, 2.0 equiv). The resulting slurry was cooled to −15° C., then a solution of compound 12 (7.96 g, 13.0 mmol) in 2-butanone (3 mL) was added over 14 hours. The reaction mixture was allowed to stir at −15° C. for an additional 25 hours and then warmed to 20° C. n-Heptane (16 mL) was added with stirring over a 1 hour period then the mixture was allowed to stir at 25° C. for 3 hours, then filtered through a fitted funnel. The filter cake was slurry-washed with a 3:2 mixture of 2-butanone and n-heptane (10 mL and then 15 mL), then dried by pulling nitrogen stream through the fritted funnel. The filter cake was slurried in a 10:1 mixture of water and 2-butanone (21 mL) and then filtered. This slurrying and filtration sequence was repeated two more times. The resulting filter cake was dried with nitrogen stream through the fritted funnel to provide compound 6.

Example 21Alternate Preparation of Compound A

[0252]
[0253]
Compound 6 (0.072 mmol, 1 equiv), K₂HPO₄(63.0 mg, 0.361 mmol) and compound 14 (5.45 mg, 0.018 mmol) were added to a 1 dram vial with 4 A mol sieves (40 mg). To the resulting mixture was added DCM (800 μl), then the resulting reaction was allowed to stir for 5 minutes. To the reaction mixture was then added compound 14 (28.7 mg, 0.094 mmol, 1.3 equiv) and the resulting reaction was allowed to stir for about 15 hours at room temperature to provide Compound A.

[0256]
[0257]
A 100 mL reactor with nitrogen inlet and mechanical stirrer was charged with compound 4 (7.00 g, 25.3 mmol), compound 15 (0.225 g, 0.506 mmol, 0.020 equiv), 1,3-dioxolane (42 mL), and 2,6-lutidine (4.42 mL, 38.0 mmol, 1.5 equiv). The mixture was cooled to −10° C. and a 33 wt % solution of compound 12 in isopropyl acetate (29 mL, 30 mmol) was added over 1 hour. The reaction mixture was allowed to stir at −10° C. for additional 40 hours, then isopropyl acetate (28 mL) was added, and the resulting mixture was warmed to 0° C. A 10 wt % aqueous NaHSO₄solution was added (14 mL), and the mixture was allowed to stir at 30° C. for 30 minutes, then the layers were separated. To the organic layer was added an aqueous solution containing 5 wt % NaHCO₃and 5 wt % Na₂SO₄(21 mL). The mixture was allowed to stir at 50° C. for 6 h. The layers were separated. To the organic layer was added 10 wt % aqueous NaCl solution (21 mL). The mixture was allowed to stir at 50° C. for 30 min. The organic layer was separated, combined with isopropyl acetate (5 mL) and concentrated in vacuo to half volume at 20000 pa in a 50° C. bath. The resulting solution was solvent-switched with isopropanol (4×35 mL) to 60 g weight. The mixture was seeded with 100 mg of compound A at 60° C. The resulting slurry was allowed to stir at 55° C. for 30 minutes, then n-Heptane (35 mL) was added over 1 hour at 55° C. The resulting slurry was allowed to stir for an additional 1 hour at 55° C., then cooled to room temperature and filtered. The filter cake was washed with a 1:1 mixture of isopropanol and n-heptane (3×14 mL), followed by n-heptane (14 mL), then dried under nitrogen to provide Compound A.

PAPER

https://pubs.rsc.org/en/content/articlelanding/2021/sc/d1sc01978c#!divAbstract

Uprifosbuvir is an antiviral agent developed for treatment of chronic hepatitis C infections. Its original synthesis route requires twelve steps with an overall yield of only 1 %. Such a difficult and time-consuming synthesis approach is acceptable for the early trial phase of a new drug, but impractical for broad application as hepatitis C treatment or for repurposing against novel viral diseases.

Artis Klapars, John Y. L. Chung, and colleagues, Merck & Co., Inc., Rahway, NJ, USA, and WuXi STA, Shanghai, China, have developed a synthesis route for uprifosbuvir requiring only five steps and starting from readily available uridine. Initially, uridine is selectively oxidized after OH-acylation with pivaloyl chloride in an acyl migration/oxidation process driven by complexation with the Lewis acid BF₃*OEt₂ in toluene. In the second step, methylation is achieved by MeMgBr/MgCl₂ in a toluene/anisole mixture where a more reactive methyl-manganese species is formed in-situ from the Grignard reagent, providing high yield and a good diastereomeric ratio (dr). Subsequently, the tertiary chloride group is introduced. Due to the high functional-group density, a cyclodehydration step is required before chlorination to avoid side reactions. The chlorination is carried out using dichlorodimethylsilane with FeCl₃*6H₂O and tetramethyldisiloxane as additives which avoids the hazardous use of HCl gas under pressure required in the initial synthesis. In the final step, the regioselective phosphoramidation is achieved using a chlorophosphoramidate precursor and a dimeric chiral imidazole carbamate catalyst which led to a dr of 97:3 starting from a 1:1 diastereomeric mixture of the chlorophosphoramidate reagent.

Uprifosbuvir was synthesized with an overall yield of 50 %, a vast improvement compared to the 1 % of the original synthesis route. Additionally, the newly developed synthesis steps have the potential to provide easier access to other nucleoside-based antiviral agents.

Efficient Synthesis of Antiviral Agent Uprifosbuvir Enabled by New Synthetic Methods,
Artis Klapars, John Chung, John Limanto, Ralph Calabria, Louis-Charles Campeau, Kevin Campos, Wenyong Chen, Stephen M Dalby, Tyler A Davis, Daniel DiRocco, Alan Hyde, Amude M Kassim, Mona Utne Larsen, Guiquan Liu, Peter Maligres, Aaron Moment, Feng Peng, Rebecca Ruck, Michael Shevlin, Bryon L Simmons, Zhiguo Jake Song, Lushi Tan, Timothy J Wright, Susan Zultanski,
Chemical Science 2021.
https://doi.org/10.1039/D1SC01978C

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods†

Artis Klapars, *^a

This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry

Abstract

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl₃/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

Scheme 1 Synthetic approaches to uprifosbuvir 1 with the two main challenges highlighted. (a) Me₂NH, AcOH, EtOH/MeOH, 80 °C, 1.5 h; (b) Ca(OH)₂, water, 70 °C, 24 h, 19% over 2 steps.⁹

Scheme 3 Complexation-driven selective acyl migration/oxidation to access 12. (a) PivCl, pyridine, 0 °C, 16 h; (b) BF₃·OEt₂, PhMe, 40 °C, 10 h; (c) TEMPO, Bu₄NBr, AcOOH, dioctyl sulphide, PhMe, −10 °C to 20 °C, 24 h, 83% from 5.

Scheme 6 Completion of uprifosbuvir synthesis. (a) TMS-Cl, iPrOH, 70 °C, 12 h; (b) NEt₃, iPrOAc, wiped film evaporation, 80%; (c) PhOP(O)Cl₂, NEt₃, iPrOAc, −20 °C, 2 h, 90%; (d) C₆F₅OH, NEt₃, iPrOAc, −5 °C to 10 °C, 18 h, 76%;²⁶ (e) 4, 3 mol% 24, 2,6-lutidine, 1,3-dioxolane, −10 °C, 24 h, 88%; (f) 4, tBuMgCl, THF, −5 °C to 5 °C, 15 h, 50%;²⁷ (g) 4, Me₂AlCl, 2,6-lutidine, THF, 35 °C, 16 h, 81%.²⁷

Scheme 7 Summary of uprifosbuvir synthesis. AY = assay yield; IY = isolated yield.

https://www.rsc.org/suppdata/d1/sc/d1sc01978c/d1sc01978c1.pdf

PAPERhttps://www.sciencedirect.com/science/article/abs/pii/S0960894X17308314

References

^ Soriano V, Fernandez-Montero JV, de Mendoza C, Benitez-Gutierrez L, Peña JM, Arias A, Barreiro P (August 2017). “Treatment of hepatitis C with new fixed dose combinations”. Expert Opinion on Pharmacotherapy. 18 (12): 1235–1242. doi:10.1080/14656566.2017.1346609. PMID 28644739. S2CID 205819421.
^ Borgia G, Maraolo AE, Nappa S, Gentile I, Buonomo AR (March 2018). “NS5B polymerase inhibitors in phase II clinical trials for HCV infection”. Expert Opinion on Investigational Drugs. 27 (3): 243–250. doi:10.1080/13543784.2018.1420780. PMID 29271672. S2CID 3672885.
^ Lawitz E, Gane E, Feld JJ, Buti M, Foster GR, Rabinovitz M, et al. (September 2019). “Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6”. Journal of Viral Hepatitis. 26 (9): 1127–1138. doi:10.1111/jvh.13132. PMID 31108015. S2CID 160014275.

Clinical data

Trade names	Uprifosbuvir
Legal status
Legal status	US: Investigational New Drug
Identifiers
show IUPAC name
CAS Number	1496551-77-9
PubChem CID	90055716
DrugBank	DB15206
ChemSpider	57427403
UNII	JW31KPS26S
KEGG	D10996
ChEMBL	ChEMBL3833371
Chemical and physical data
Formula	C₂₂H₂₉ClN₃O₉P
Molar mass	545.9 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

References

^ Soriano V, Fernandez-Montero JV, de Mendoza C, Benitez-Gutierrez L, Peña JM, Arias A, Barreiro P (August 2017). “Treatment of hepatitis C with new fixed dose combinations”. Expert Opinion on Pharmacotherapy. 18 (12): 1235–1242. doi:10.1080/14656566.2017.1346609. PMID 28644739. S2CID 205819421.
^ Borgia G, Maraolo AE, Nappa S, Gentile I, Buonomo AR (March 2018). “NS5B polymerase inhibitors in phase II clinical trials for HCV infection”. Expert Opinion on Investigational Drugs. 27 (3): 243–250. doi:10.1080/13543784.2018.1420780. PMID 29271672. S2CID 3672885.
^ Lawitz E, Gane E, Feld JJ, Buti M, Foster GR, Rabinovitz M, et al. (September 2019). “Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6”. Journal of Viral Hepatitis. 26 (9): 1127–1138. doi:10.1111/jvh.13132. PMID 31108015. S2CID 160014275.

//////////uprifosbuvir, MK 3682, ウプリホスブビル, уприфосбувир, أوبريفوسبوفير , 乌磷布韦 , IDX-21437, DB15206, SB18784, D10996, Q27281714, IDX 21437, PHASE 3
CC(C)OC(=O)C(C)NP(=O)(OCC1C(C(C(O1)N2C=CC(=O)NC2=O)(C)Cl)O)OC3=CC=CC=C3

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Sitravatinib

March 22, 2021 12:17 pm / Leave a comment

Sitravatinib

1-N‘-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1-N’-[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

MG-91516

1,1-Cyclopropanedicarboxamide, N-[3-fluoro-4-[[2-[5-[[(2-methoxyethyl)amino]methyl]-2-pyridinyl]thieno[3,2-b]pyridin-7-yl]oxy]phenyl]-N’-(4- fluorophenyl)-

N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

シトラバチニブ; ситраватиниб , سيترافاتينيب , 司曲替尼 ,

Formula	C33H29F2N5O4S
Cas	1123837-84-2
Mol weight	629.6763

MG-516

Sitravatinib (MGCD516)

UNII-CWG62Q1VTB

CWG62Q1VTB

MGCD-516

MGCD516

Antineoplastic, Receptor tyrosine kinase inhibitor

Sitravatinib (MGCD516) is an experimental drug for the treatment of cancer. It is a small molecule inhibitor of multiple tyrosine kinases.

Sitravatinib is being developed by Mirati Therapeutics.^[1]

Ongoing phase II trials include a trial for liposcarcoma,^[2] a combination trial for non-small cell lung cancer,^[3] and a combination trial with nivolumab for renal cell carcinoma.^[4]

Mirati Therapeutics and licensee BeiGene are developing sitravatinib, an oral multitargeted kinase inhibitor which inhibits Eph, Ret, c-Met and VEGF-1, -2 and -3, DDR, Trk, Axl kinases, CHR4q12, TYRO3 and Casitas B-lineage, in combination with immune checkpoint inhibitors, for treating advanced solid tumors.

In March 2021, sitravatinib was reported to be in phase 3 clinical development.

PDT PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009026717

WO2009026717 , in which sitravatinib was first disclosed, claiming heterocyclic compounds as multi kinase inhibitors.

Scheme 10

Example 52
N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide

Step 1 : tert-Butyl (6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno [3 ,2-b]pyridin-2-yl)pyridin-3 -y l)methyl(2-methoxyethyl)carbamate (146)
To aniline 126 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF

(20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarbpxylic acid (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol) and the mixture was stirred at r.t. for 18 h. It was then partitioned between ethyl acetate and water, the organic phase was washed with water, IM NaOH, brine, dried (MgSO₄), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded title compound Ϊ46 (0.60 g, 74 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J = 8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.65 (d, J = 5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Step 2. N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-blpyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (147)
To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1 M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with IM NaOH, brine, dried (MgSO₄), filtered, and concentrated to afford title compound 147 (0.35 g, 69 % yield).

1H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).

PATENT

WO 2009026720

https://patents.google.com/patent/WO2009026720A1

PATENT

WO-2021050580

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021050580&tab=PCTDESCRIPTION&_cid=P12-KMKJ94-73521-1

Novel, stable crystalline polymorphic forms (form D) of sitravatinib , useful for treating a multi tyrosine kinase-associated cancer eg sarcoma, glioma, non-small cell lung, bladder, kidney, ovarian, gastric, breast or liver cancer.

International publication No. W02009/026717A disclosed compounds with the inhibition activities of multiple protein tyrosine kinases, for example, the inhibition activities of VEGF receptor kinase and HGF receptor kinase. In particular, disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4ql2, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression.

[003]

Compound 1

[004] Compound 1 shows tumor regression in multiple human xenograft tumor models in mice, and is presently in human clinical trials as a monotherapy as well as in combination for

treating a wide range of solid tumors. Compound 1 is presently in Phase 1 clinical trial for patients with advanced cancer, in Phase 2 studies for patients with advanced liposarcoma and non-small cell lung cancer (NSCLC).

[005] The small scale chemical synthesis of the amorphous Compound 1 had been disclosed in the Example 52 (compound 147) of W02009/026717A, however, in order to prepare the API of Compound 1 with high quality and in large quantity, crystalline forms of Compound 1 would be normally needed so the process impurities could be purged out by recrystallization.

Practically, it is difficult to predict with confidence which crystalline form of a particular compound will be stable, reproducible, and suitable for phamaceutical processing. It is even more difficult to predict whether or not a particular crystalline solid state form will be produced with the desired physical properties for pharmaceutical formulations.

[006] For all the foregoing reasons, there is a great need to produce crystalline forms of Compound 1 that provide manufacturing improvements of the pharmaceutical composition.

The present invention advantageously addresses one or more of these needs.

EXAMPLE 1

Preparation of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2- yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide (Compound 1)

[0085] This Example illustrates the preparation ofN-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1).

[0086] Step 1: N-(Y6-bromopyridin-3-vDmethvD-2-methoxyethan-l-amine (Compound 1A)

Compound 1A

[0087] To a stirred solution of 2-Methoxyethylamine (3.0 eq) in dichloromethane (DCM) (12 vol) was added Molecular sieves (0.3 w/w) and stirred for 2 hours at 25±5°C under nitrogen atmosphere. The reaction mass water content was monitored by Karl Fischer analysis until the water content limit reached 0.5 % w/w. Once the water content limit was reached, the reaction mass cooled to 5±5°C and 6-bromonicotinaldehyde (1.0 eq) was added lot wise over period of 30 minutes to the above reaction mass at 5±5°C. The reaction mass was stirred for 30±5 minutes at 5±5°C and acetic acid (1.05 eq) was added drop wise at 5±5°C. After completion of the addition, the mass was slowly warmed to 25±5°C and stirred for 8 h to afford Compound 1 A. The imine formation was monitored by HPLC.

[0088] Step 2: tert-butyl (Y6-brom opyri din-3 -vQmethvO(2-m ethoxy ethvDcarbamate (Compound

IB)

Compound 1B

[0089] Charged Compoud 1A (1.0 eq) in THF (5.0 vol) was added and the reaction mass was stirred for 30 minutes at 25±5°C under nitrogen atmosphere. The reaction mass was cooled to temperature of about 10±5°C. Di-tert- butyl dicarbonate (1.2 eq) was added to the reaction mass at 10±5°C under nitrogen atmosphere and the reaction mass temperature was raised to 25±5°C and the reaction mass for about 2 hours. The progress of the reaction was monitored by HPLC. After IPC completion, a prepared solution of Taurine (1.5 eq) in 2M aq NaOH (3.1 vol) was charged and stirred at 10±5°C for 16 h to 18 h. The reaction mass was further diluted with 1M aq.NaOH solution (3.7 vol) and the layers were separated. The aqueous layer was extracted with DCM (2 x 4.7vol) and the extract combined with the organic layer. The combined organic layers were washed with 1M aq.NaOH solution (3.94 vol), followed by water (2×4.4 vol), and dried over sodium sulfate (2.0 w/w) . The filtrate was concentrated under reduced pressure below 40° C until no distillate was observed. Tetrahydrofuran (THF) was sequentially added (1×4 vol and lx 6vol) and concentrated under reduced pressure below 40°C until no distillate was observed to obtained Compound IB as light yellow colored syrup liquid.

[0090] Step 3: tert-butyl 7-chlorothieno[3.2-b1pyridin-2-yl)pyridin-3-yl )methyl)(2-

methoxyethvDcarbamate (Compound 1C)

Compound 1C

[0091] To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.05 eq) in tetrahydrofuran (7 vol) was added n-butyl lithium (2.5 M in hexane) drop wise at -15±10°C and stirred for 90 minutes at same temperature under nitrogen atmosphere. Zinc chloride (1.05 eq) was added to the reaction mass at -15±10°C. The reaction mass was slowly warmed to 25±5°C and stirred for 45 minutes under nitrogen atmosphere to afford Compound 1C. The progress of the reaction was monitored by HPLC.

[0092] Step 4: tert-butyl (Y6-(7-(4-amino-2-fluorophenoxy)thieno[3.2-b1pyridin-2-v0pyridin-3-vDmethvD(2-methoxyethvDcarbamate (Compound ID)

Compound 1D

[0093] 3-fluoro-4-hydroxybenzenaminium chloride (1.2 eq) in DMSO (3.9 vol) at 25±5°C was charged under nitrogen atmosphere and the reaction mass was stirred until observance of a clear solution at 25±5°C. t-BuOK was added lot wise under nitrogen atmosphere at 25±10°C. The reaction mass temperature was raised to 45±5°C and maintained for 30 minutes under nitrogen atmosphere. Compound 1C was charged lot-wise under nitrogen atmosphere at 45±5°C and stirred for 10 minutes at 45± 5°C.The reaction mixture was heated to 100± 5°C and stirred for 2 hrs. The reaction mass is monitored by HPLC.

[0094] After reaction completion, the reaction mass was cooled to 10± 5°C and quenched with chilled water (20 vol) at 10±5°C. The mass temperature was raised to 25± 5°C and stirred for 7-8 h. The resulting Compound ID crude was collected by filtration and washed with 2 vol of water. Crude Compound ID material taken in water (10 vol) and stirred for up to 20 minutes at 25±5°C. The reaction mass was heated to 45±5°C and stirred for 2-3 h at 45±5°C, filtered and vacuum-dried.

[0095] Crude Compound ID was taken in MTBE (5 vol) at 25±5°C and stirred for about 20 minutes at 25±5°C. The reaction mass temperature was raised to 45±5°C, stirred for 3-4 h at 45±5°C and then cooled to 20±5°C. The reaction mass was stirred for about 20 minutes at 20±5°C, filtered, followed by bed wash with water (0. 5 vol) and vacuum-dried.

[0096] The crude material was dissolved in acetone (10 vol) at 25±5°C and stirred for about 2h at 25±5°C. The reaction mass was filtered through a celite bed and washed with acetone (2.5 vol). The filtrate was slowly diluted with water (15 vol) at 25±5°C. The reaction mass was stirred for 2-3 h at 25±5°C, filtered and bed washed with water (2 vol) & vacuum-dried to afford Compound ID as brown solid.

[0097] Step 5 : 1 -((4-((2-(5-(((tert-butoxycarbonv0(2-methoxy ethvOaminolmethvOpyri din-2 -yl )thieno[3.2-b]pyridin-7-yl )oxy)-3 -fluorophenyl icarbamoyl level opropane-1 -carboxylic acid (Compound IE)

Compound 1E

[0098] To a solution of Compound ID (1.0 eq.) in tetrahydrofuran (7 vol.), aqueous potassium carbonate (1.0 eq.) in water (8 vol.) was added. The solution was cooled to 5±5°C, and stirred for about 60 min. While stirring, separately triethylamine (2.0 eq.) was added to a solution of 1,1-cyclopropanedicarboxylic acid (2.0 eq.) in tetrahydrofuran (8 vol.), at 5±5°C, followed by thionyl chloride (2.0 eq.) and stirred for about 60 min. The acid chloride mass was slowly added to the Compound ID solution at 5±5°C. The temperature was raised to 25±5°C and stirred for 3.0 h. The reaction was monitored by HPLC analysis.

[0099] After reaction completion, the mass was diluted with ethyl acetate (5.8 vol.), water (5.1 vol.), 10% (w/w) aqueous hydrochloric acid solution (0.8 vol.) and 25% (w/w) aqueous sodium chloride solution (2 vol.). The aqueous layer was separated and extracted with ethyl acetate (2 x 5 vol.). The combined organic layers were washed with a 0.5M aqueous sodium bicarbonate solution (7.5 vol.). The organic layer was treated with Darco activated charcoal (0.5 w/w) and sodium sulfate (0.3 w/w) at 25±5°C for 1.0 h. The organic layer was filtered through celite and washed with tetrahydofuran (5.0 vol.). The filtrate was concentrated under vacuum below 50°C to about 3 vol and co-distilled with ethyl acetate (2 x 5 vol.) under vacuum below 50°C up to ~ 3.0 vol. The organic layer was cooled to 15±5°C, stirred for about 60 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). The material was dried under vacuum at 40±5°C until water content was less than 1% to afford Compound IE as brown solid.

[00100] Step 6: tert-butyl (Y6-(7-(2-fluoro-4-(T-(Y4-fluorophenvDcarbamovDcvclopropane-l-carboxamido)phenoxy)thieno[3.2-b]pyridin-2-v0pyri din-3 – (2-
methoxyethvDcarbamate (Compound IF)

[00101] Pyridine (1.1 eq.) was added to a suspension of Compound IE (1.0 eq.) in tetrahydrofuran (10 vol.) and cooled to 5±5°C. Thionyl chloride (2.0 eq.) was added and stirred for about 60 min. The resulting acid chloride formation was confirmed by HPLC analysis after quenching the sample in methanol. Separately, aqueous potassium carbonate (2.5 eq.) solution (7.0 vol. of water) was added to a solution of 4-fluoroaniline (3.5 eq.) in tetrahydrofuran (10 vol.), cooled to 5±5°C, and stirred for about 60 min. The temperature of the acid chloride mass at 5±5°C was raised to a temperature of about 25±5°C and stirred for 3 h. The reaction monitored by HPLC analysis.

[00102] After completion of the reaction, the solution was diluted with ethyl acetate (25 vol.), the organic layer was separated and washed with a 1M aqueous sodium hydroxide solution (7.5 vol.), a 1M aqueous hydrochloric acid solution (7.5 vol.), and a 25% (w/w) aqueous sodium chloride solution (7.5 vol.). The organic layer was dried and and filtered with sodium sulfate (1.0 w/w). The filtrate was concentrated ~ 3 vol under vacuum below 50°C and co-distilled with ethyl acetate (3 x 5 vol.) under vacuum below 50°C to ~ 3.0 vol. Ethyl acetate (5 vol.) and MTBE (10 vol.) were charged, heated up to 50±5°C and stirred for 30-60 min. The mixture was cooled to 15±5°C, stirred for about 30 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). MGB3 content was analyzed by HPLC analysis. The material was dried under vacuum at 40±5°C until the water content reached about 3.0% to afford Compound IF as brown solid.

[00103] Step 7 : N-(3-fluoro-4-((2-(5-(((2-methoxyethv0amino)methv0pyridin-2-yl )thieno[3.2-b]pyridin-7-yl )oxy)phenyl)-N-(4-fluorophenyl level opropane-1. 1 -dicarboxamide (Compound 1)

Compound 1

[0100] To a mixture of Compound IF in glacial acetic acid (3.5 vol.) concentrated hydrochloric acid (0.5 vol.) was added and stirred at 25±5°C for 1.0 h. The reaction was monitored by HPLC analysis.

[0101] After reaction completion, the mass was added to water (11 vol.) and stirred for 20±5°C for 30 min. The pH was adjusted to 3.0 ± 0.5 using 10% (w/w) aqueous sodium bicarbonate solution and stirred for 20±5°C for approximately 3.0 h.. The mass was filtered, washed with water (4 x 5.0 vol.) and the pH of filtrate was checked after every wash. The material was dried under vacuum at 50±5°C until water content was about 10%.

[0102] Crude Compound 1 was taken in ethyl acetate (30 vol.), heated to 70±10°C, stirred for 1.0 h., cooled to 25±5°C, filtered, and washed with ethyl acetate (2 vol.). The material was dries under vacuum at 45±5°C for 6.0 h.

[0103] Crude Compound 1 was taken in polish filtered tetrahydrofuran (30 vol.) and pre washed Amberlyst A-21 Ion exchange resin and stirred at 25±5°C until the solution became clear. After getting the clear solution, the resin was filtered and washed with polish filtered tetrahydrofuran (15 vol.). The filtrate was concentrated by -50% under vacuum below 50°C and co-distilled with polish filtered IPA (3 x 15.0 vol.) and concentrated up to -50% under vacuum below 50°C. Charged polish filtered IPA (15 vol.) was added and the solution concentrated under vacuum below 50°C to – 20 vol. The reaction mass was heated to 80±5°C, stirred for 60 min. and cooled to 25±5°C. The resultant reaction mass was stirred for about 20 hours at 25±5°C. The reaction mass was cooled to 0±5°C, stirred for 4-5 hours, filtered, and washed with polish filtered IPA (2 vol.). The material was dried under vacuum at 45±5°C, until the water content was about 2%, to obtain the desired product Compound 1. ¾-NMR (400 MHz, DMSO- d): 510.40 (s, 1H), 10.01 (s, 1H), 8.59 – 8.55 (m, 1H), 8.53 (d, J= 5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.70 – 7.60 (m, 2H), 7.56 – 7.43 (m, 2H), 7.20 – 7.11 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J= 5.6 Hz, 2H), 3.25 (s, 3H), 2.66 (t, J= 5.6 Hz, 2H), 1.48 (s, 4H)ppm. MS: M/e 630 (M+l)⁺.

EXAMPLE 2

Preparation of Crystalline Form D of N-(3-fluoro-4-((2-(5-(((2- methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cyclopropane-l, 1-dicarboxamide

EXAMPLE 2A: Preparation of Compound 1 Crystalline Form D

[0104] To a 50 L reactor, 7.15 Kg of Compound 1, 40 g of Form D as crystal seed and 21 L acetone (>99%) were added. The mixture was heated to reflux ( ~56 °C) for 1~2 h. The mixture was agitated with an internal temperature of 20±5 °C for at least 24 h. Then, the suspension was filtered and washed the filter cake with 7 L acetone. The wet cake was dried under vacuum at <45 °C, to obtain 5.33 kg of Compound 1 of desired Form D

[0105] X-Ray Powder Diffraction (XRPD)

The XRPD patterns were collected with a PAN alytical X’ Pert PRO MPD diffractometer using auincident beam of Cu radiation produced using au Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X -rays through the specimens and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si Ill peak is consistent with the NIST-certified position. A specimen of each sample was sandwiched between 3 -pm -thick films and analyzed in transmission geometly. A beam-stop, short autiscatter extension, and an autiscatter knife edge were used to minimize the background generated by air. Sober slits for the incident aud diffracted beauls were used to minimize broadening from axial divergence. The diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimens and Data Collector software v. 2.2b. Pattern Match v2.3.6 was used to create XRPD patterns.

[0106] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D), see Figure 1A. The XRPD pattern yielded is substantially the same as that shown in Figure 3C.

[0107] Differential Scanning Calorimetry (DSC)

[0108] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The TAWN sensitivity was 11.9. The samples were placed into aluminum DSC pans, covered with lids, and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lids were pierced prior to sample analyses. The method name on the thermograms is an abbreviation for the start and end temperature as well as the heating rate; e.g., -30-250-10 means “from ambient to 250°C, at 10°C/min.” The nitrogen flow rate was 50.0 mL/min. This instrument does not provide gas pressure value as required by USP because it is the same as atmospheric pressure.

[0109] A broad small endotherm with a peak maximum at approximately 57°C to 62°C (onset ~20°C to 22°C) followed by a sharp endotherm with a peak maximum at approximately 180°C (onset ~178°C) were observed. These events could be due to the loss of volatiles and a melt, respectively (see Figure IB).

[0110] In an alternative embodiment Form D was prepared as follows. Designated Material O was suspended in 600 pL of acetone. Initial dissolution was observed followed by re precipitation. The amount of suspended solids was not measured because the target of the experiment was to get a suspension with enough solids to slurry isolate and collect XRPD data. Based on the solubility of Form D in acetone a very rough estimate for the scale of the experiment is about 80-100mg. The suspension was stirred at ambient temperature for approximately 2 5 weeks after which the solids were isolated by centrifugation with filtration. XRPD data appeared to be consistent with Form D The sample was then dried in vacuum oven at ~40 °C for ~2 5 hours. The XRPD pattern of the final solids was consistent with Form D EXAMPLE 2B: Preparation of Compound 1 Form D

[0111] 427.0 mg of Compound 1 was dissolved in 5 mL of THF to obtain a clear brown solution. The resulting solution was filtered, and the filtrate evaporated under flow of nitrogen. A sticky solid was obtained, which was dried under vacuum in room temperature for ~5 min, still a sticky brown solid obtained. It was dissolved in 0.2 mL of EtOAc and sonicated to dissolve. The solution obtained was stirred at room temperature for 15 min and a solid precipitated. The resulting solid was added 0.4 mL of EtOAc and stirred in room temperature for 21 h 40 min to ontian a suspension. The solid was spparated from mother liquor by centrifugation, then the resulting solid was resuspended the in 0.6 mL of EtOAc and stirred in room temperature for 2 days. The solid was isolated by centrifugation, to obtain Compound 1 of desired Form D.

[0112] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D).

EXAMPLE 2C: Preparation of Compound 1 Form D

[0113] Single crystal X-ray diffraction data of Compound 1 was collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer, with Mo Ka radiation (l = 0.71073 A). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. The structure was solved by a dual-space algorithm using SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier maps. Framework hydrogen atoms were placed geometrically and constrained using the riding model to the parent atoms. Final structure refinement was done using the SHELXL program by minimizing the sum of squared deviations of F2 using a full-matrix technique.

Preparation of Compound 1 Form D ( a Single Crystal )

[0114] Compound 1 Form D was dissolved in a mixture of acetone/ ACN (1/2) with the concentration of Compound 1 at ~7 mg/mL. A block single crystal was obtained, which was a single crystal.

[0115] The XRPD pattern was used to characterize the single crystal of Compound 1 Form D obtained, see Figure 2A. The crystal structural data are summarized in Table IB. The refined single crystal structure were shown in Figure 2B. The single crystal structure of Compound 1 Form D is in the P-1 space group and the triclinic crystal system. The terminal long alkyl chain is found to have large ellipsoids, indicating high mobility with disordered atoms.

[0116] The theoretical XRPD calculated from the single crystal structure and experimental XRPD are essentially similar (Figure 2A). A few small peaks are absent or shift because of orientation preference, disorder and tested temperature (180 K for single crystal data and 293 K for experimental one).

[0117] Table IB. Crystal Data and Structure Refinement for Compound 1 Form D (a Single Crystal)

References

Identifiers

show IUPAC name
CAS Number	1123837-84-2
ChemSpider	52083477
UNII	CWG62Q1VTB
KEGG	D11140
Chemical and physical data
Formula	C₃₃H₂₉F₂N₅O₄S
Molar mass	629.68 g·mol⁻¹
3D model (JSmol)	Interactive image
hide SMILESCOCCNCc1ccc(nc1)c2cc3c(s2)c(ccn3)Oc4ccc(cc4F)NC(=O)C5(CC5)C(=O)Nc6ccc(cc6)F
hide InChIInChI=1S/C33H29F2N5O4S/c1-43-15-14-36-18-20-2-8-25(38-19-20)29-17-26-30(45-29)28(10-13-37-26)44-27-9-7-23(16-24(27)35)40-32(42)33(11-12-33)31(41)39-22-5-3-21(34)4-6-22/h2-10,13,16-17,19,36H,11-12,14-15,18H2,1H3,(H,39,41)(H,40,42)Key:WLAVZAAODLTUSW-UHFFFAOYSA-N

///////////// sitravatinib, phase 3, シトラバチニブ , MGCD516, MG-516, Sitravatinib (MGCD516), UNII-CWG62Q1VTB, CWG62Q1VTB, MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , Antineoplastic, MGCD 516

#sitravatinib, #phase 3, #シトラバチニブ , #MGCD516, #MG-516#Sitravatinib (MGCD516), #UNII-#CWG62Q1VTB, #CWG62Q1VTB, #MGCD-516, ситраватиниб , سيترافاتينيب , 司曲替尼 , #Antineoplastic, #MGCD516

COCCNCC1=CN=C(C=C1)C2=CC3=NC=CC(=C3S2)OC4=C(C=C(C=C4)NC(=O)C5(CC5)C(=O)NC6=CC=C(C=C6)F)F

RIDINILAZOLE

January 27, 2021 10:56 am / 2 Comments on RIDINILAZOLE

RIDINILAZOLE

SMT19969

Molecular FormulaC₂₄H₁₆N₆
Average mass388.424 Da
ридинилазол [Russian] [INN]ريدينيلازول [Arabic] [INN]利地利唑 [Chinese] [INN]
リジニラゾール;

10075
2,2′-Di(4-pyridinyl)-3H,3’H-5,5′-bibenzimidazole
308362-25-6[RN]6,6′-Bi-1H-benzimidazole, 2,2′-di-4-pyridinyl-

Summit Therapeutics (formerly Summit Corp ) is developing ridinilazole the lead compound from oral narrow-spectrum, GI-restricted antibiotics, which also include SMT-21829, for the treatment of Clostridium difficile infection and prevention of recurrent disease.

Ridinilazole (previously known as SMT19969) is an investigational small molecule antibiotic being evaluated for oral administration to treat Clostridioides difficile infection (CDI). In vitro, it is bactericidal against C. difficile and suppresses bacterial toxin production; the mechanism of action is thought to involve inhibition of cell division.^[1] It has properties which are desirable for the treatment of CDI, namely that it is a narrow-spectrum antibiotic which exhibits activity against C. difficile while having little impact on other normal intestinal flora and that it is only minimally absorbed systemically after oral administration.^[2] At the time ridinilazole was developed, there were only three antibiotics in use for treating CDI: vancomycin, fidaxomicin, and metronidazole.^[1]^[2] The recurrence rate of CDI is high, which has spurred research into other treatment options with the aim to reduce the rate of recurrence.^[3]^[4]

As of 2019, two phase II trials have been completed and two phase III trials comparing ridinilazole to vancomycin for CDI are expected to be completed in September 2021.^[2][5][6] Ridinilazole was designated as a Qualified Infectious Disease Product (QIDP) and was granted Fast Track status by the U.S. FDA.^[2] Fast Track status is reserved for drugs designed to treat diseases where there is currently a gap in the treatment, or a complete lack thereof.^[7] The QIDP designation adds five more years of exclusivity for ridinazole upon approval.^[8]

PATENT

WO-2021009514

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021009514&tab=PCTDESCRIPTION&_cid=P22-KKEXJ9-06647-1

Process for preparing ridinilazole useful for treating Clostridium difficile infection. Also claimed is the crystalline form of a compound.

The present invention relates to processes for the preparation of 2,2′-di(pyridin-4-yl)-1/-/,T/-/-5,5′-bibenzo[d]imidazole (which may also be known as 5,5’-bis[2-(4-pyridinyl)-1/-/-benzimidazole], 2,2′-bis(4-pyridyl)-3/-/,3’/-/-5,5′-bibenzimidazole or 2-pyridin-4-yl-6-(2-pyridin-4-yl-3/-/-benzimidazol-5-yl)-1/-/-benzimidazole), referenced herein by the INN name ridinilazole, and pharmaceutically acceptable derivatives, salts, hydrates, solvates, complexes, bioisosteres, metabolites or prodrugs thereof. The invention also relates to various crystalline forms of ridinilazole, to processes for their preparation and to related pharmaceutical preparations and uses thereof (including their medical use and their use in the efficient large-scale synthesis of ridinilazole).

WO2010/063996 describes various benzimidazoles, including ridinilazole, and their use as antibacterials (including in the treatment of CDAD).

WO 2011/151621 describes various benzimidazoles and their use as antibacterials

(including in the treatment of CDAD).

W02007056330, W02003105846 and W02002060879 disclose various 2-amino benzimidazoles as antibacterial agents.

W02007148093 discloses various 2-amino benzothiazoles as antibacterial agents.

W02006076009, W02004041209 and Bowser et at. (Bioorg. Med. Chem. Lett., 2007, 17, 5652-5655) disclose various substituted benzimidazole compounds useful as anti-infectives that decrease resistance, virulence, or growth of microbes. The compounds are said not to exhibit intrinsic antimicrobial activity in vitro.

US 5,824,698 discloses various dibenzimidazoles as broad-spectrum antibiotics, disclosing activity against both Gram-negative and Gram-positive bacteria, including Staphylococcus spp.and Enterococcus spp. However, this document does not disclose activity against anaerobic spore-forming bacteria and in particular does not disclose activity against any Clostridioides spp. (including C. difficile).

US 2007/0112048 A1 discloses various bi- and triarylimidazolidines and bi- and

triarylamidines as broad-spectrum antibiotics, disclosing activity against both Gram negative and Gram-positive bacteria, including Staphylococcus spp., Enterococcus spp. and Clostridioides spp. However, this document does not disclose compounds of formula (I) as described herein.

Chaudhuri et al. (2007) J.Org. Chem. 72, 1912-1923 describe various bis-2-(pyridyl)-1 H-benzimidazoles (including compounds of formula I as described herein) as DNA binding agents. This document is silent as to potential antibacterial activity.

Singh et al. (2000) Synthesis 10: 1380-1390 describe a condensation reaction for producing 2,2′-di(pyridin-4-yl)-1/-/,T/-/-5,5′-bibenzo[d]imidazole using 4-pyridine

carboxaldehyde, FeCI₃, 0₂, in DMF at 120°C.

Bhattacharya and Chaudhuri (2007) Chemistry – An Asian Journal 2: 648-655 describe a condensation reaction for producing 2,2′-di(pyridin-4-yl)-1/-/,T/-/-5,5′-bibenzo[d]imidazole using 4-pyridine carboxaldehyde and nitrobenzene at 120°C.

WO2019/068383 describes the synthesis of ridinilazole by metal-ion catalyzed coupling of 3,4,3’,4’-tetraaminobiphenyl with 4-pyridinecarboxaldehyde in the presence of oxygen, followed by the addition of a complexing agent.

PATENT

WO2010063996

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010063996&_cid=P22-KKEXNB-07493-1

claiming antibacterial compounds. Bicyclic heteroaromatic compounds, particularly bi-benzimidazole derivatives.

WO2007056330, WO2003105846 and WO2002060879 disclose various 2-amino benzimidazoles as antibacterial agents.

WO2007148093 discloses various 2-amino benzothiazoles as antibacterial agents.

WO2006076009, WO2004041209 and Bowser et al. (Bioorg. Med. Chem. Lett., 2007, 17, 5652-5655) disclose various substituted benzimidazole compounds useful as anti-infectives that decrease resistance, virulence, or growth of microbes. The compounds are said not to exhibit intrinsic antimicrobial activity in vitro.

US 2007/0112048 A1 discloses various bi- and triarylimidazolidines and bi- and triarylamidines as broad-spectrum antibiotics, disclosing activity against both Gram-negative and Gram-positive bacteria, including Staphylococcus spp., Enterococcus spp.

and Clostridium spp. However, this document does not disclose compounds of general formula (I) as described herein.

Chaudhuri et al. (J.Org. Chem., 2007, 72, 1912-1923) describe various bis-2-(pyridyl)-1 H-benzimidazoles (including compounds of formula I as described herein) as DNA binding agents. This document is silent as to potential antibacterial activity.

PATENT

Product PATENT, WO2010063996 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010063996&_cid=P22-KKEXS7-08574-1

protection in the EP until 2029 and expire in the US in December 2029.

PAPER

https://www.frontiersin.org/articles/10.3389/fmicb.2018.01206/full

PAPER

Synthesis (2000), (10), 1380-1390.

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/s-2000-7111

PAPERT

Chemistry – An Asian Journal (2007), 2(5), 648-655.

https://onlinelibrary.wiley.com/doi/abs/10.1002/asia.200700014

Studies of double‐stranded‐DNA binding have been performed with three isomeric bis(2‐(n‐pyridyl)‐1H‐benzimidazole)s (n=2, 3, 4). Like the well‐known Hoechst 33258, which is a bisbenzimidazole compound, these three isomers bind to the minor groove of duplex DNA. DNA binding by the three isomers was investigated in the presence of the divalent metal ions Mg²⁺, Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺. Ligand–DNA interactions were probed with fluorescence and circular dichroism spectroscopy. These studies revealed that the binding of the 2‐pyridyl derivative to DNA is dramatically reduced in the presence of Co²⁺, Ni²⁺, and Cu²⁺ ions and is abolished completely at a ligand/metal‐cation ratio of 1:1. Control experiments done with the isomeric 3‐ and 4‐pyridyl derivatives showed that their binding to DNA is unaffected by the aforementioned transition‐metal ions. The ability of 2‐(2‐pyridyl)benzimidazole to chelate metal ions and the conformational changes of the ligand associated with ion chelation probably led to such unusual binding results for the ortho isomer. The addition of ethylenediaminetetraacetic acid (EDTA) reversed the effects completely.

PAPER

Journal of Organic Chemistry (2007), 72(6), 1912-1923.

https://pubs.acs.org/doi/10.1021/jo0619433

Three symmetrical positional isomers of bis-2-(n-pyridyl)-1H-benzimidazoles (n = 2, 3, 4) were synthesized and DNA binding studies were performed with these isomeric derivatives. Like bisbenzimidazole compound Hoechst 33258, these molecules also demonstrate AT-specific DNA binding. The binding affinities of 3-pyridine (m-pyben) and 4-pyridine (p-pyben) derivatized bisbenzimidazoles to double-stranded DNA were significantly higher compared to 2–pyridine derivatized benzimidazole o-pyben. This has been established by combined experimental results of isothermal fluorescence titration, circular dichroism, and thermal denaturation of DNA. To rationalize the origin of their differential binding characteristics with double-stranded DNA, computational structural analyses of the uncomplexed ligands were performed using ab initio/Density Functional Theory. The molecular conformations of the symmetric head-to-head bisbenzimidazoles have been computed. The existence of intramolecular hydrogen bonding was established in o-pyben, which confers a conformational rigidity to the molecule about the bond connecting the pyridine and benzimidazole units. This might cause reduction in its binding affinity to double-stranded DNA compared to its para and meta counterparts. Additionally, the predicted stable conformations for p-, m-, and o-pyben at the B3LYP/6-31G* and RHF/6-31G* levels were further supported by experimental pK_a determination. The results provide important information on the molecular recognition process of such symmetric head to head bisbenzimidazoles toward duplex DNA.

Patent

US 8975416

PATENT

WO 2019068383

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019068383

Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. CDI remains a challenge to treat clinically, because of a limited number of antibiotics available and unacceptably high recurrence rates. Because of this, there has been significant demand for creating innovative therapeutics, which has resulted in the development of several novel antibiotics.

Ridinilazole (SMT19969) is the INN name of 5,5’bis[2-(4-pyridinyl)-lH-benzimidazole], which is a promising non-absorbable small molecule antibiotic intended for oral use in the treatment of CDI. It has been shown to exhibit a prolonged post-antibiotic effect and treatment with ridinilazole has resulted in decreased toxin production. A phase 1 trial demonstrated that oral ridinilazole is well tolerated and specifically targets Clostridia whilst sparing other faecal bacteria.

Ridinilazole has the following chemical structure:

Bhattacharya & Chaudhuri (Chem. Asian J., 2007, No. 2, 648-655) report performing double-stranded DNA binding with three benzimidazole derivatives, including ridinilazole. The compounds have been prepared by dissolving the reactants in nitrobenzene, heating at 120°C for 8- 1 Oh and purifying the products by column chromatography over silica gel. The compounds were obtained in 65-70% yield. Singh et al., (Synthesis, 2000, No. 10, 1380-1390) describe a catalytic redox cycling approach based on Fe(III) and molecular oxygen as co-oxidant for providing access to benzimidazole and

imidazopyridine derivatives, such as ridinilazole. The reaction is performed at high temperatures of 120°C and the product is isolated in 91% yield by using silica flash chromatography.

Both processes are not optimal, for example in terms of yield, ease of handling and scalability. Thus, there is a need in the art for an efficient and scalable preparation of ridinilazole, which overcomes the problems of the prior art processes.

Example 1 : Preparation of crude ridinilazole free base

A solution of 3,4,3′,4′-tetraaminobiphenyl (3.28 g, 15.3 mmol) and isonicotinaldehyde (3.21 g, 30.0 mmol) in DMF (40 mL) was stirred at 23 °C for one hour. Then anhydrous ferric chloride (146 mg, 0.90 mmol), water (0.10 mL, 5.4 mmol) and additional DMF (2 mL) were added and fresh air was bubbled into the solution during vigorous stirring for 5 hours at room temperature. Next, water (80 mL) and EDTA (0.29 g) were added resulting in a brownish suspension, which was stirred overnight. The product was isolated by filtration, washed with water, and dried in a desiccator in vacuo as a brown powder (5.56 g; 95%). The addition of EDTA had held iron in solution and the crude ridinilazole contained significantly lower amounts of iron than comparative example 1.

Example 12: Formation of essentially pure ridinilazole free base

To a suspension von ridinilazole tritosylate (1 10 mg, 0.12 mmol) in water (35 mL) featuring a pH value of about 4.5 stirring at 70 °C sodium bicarbonate (580 mg, 6.9 mmol) were added and caused a change of color from orange to slightly tan. The mixture, now at a pH of about 8.5, was cooled down to room temperature and the solids were separated by filtration, washed with water (1 ML) and dried in vacuo providing 40 mg (85%) essentially pure ridinilazole as a brownish powder.

Spectroscopic analysis:

¾ NMR (DMSO-de, 300 MHz): δ 7.55 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.88 (s, 2H), 8.13 (d, J = 5.8 Hz, 4H), 8.72 (d, J = 5.8 Hz, 4H) ppm.

¹³C NMR (DMSO-d₆, 75 MHz): δ 1 13.4 (2C), 1 16.4 (2C), 120.4 (4C), 121.8 (2C), 135.7 (2C), 138.7 (2C), 140.7 (2C), 141.4 (2C), 150.3 (4C), 151.1 (2C) ppm.

IR (neat): v 3033 (w), 1604 (s), 1429 (m), 1309 (m), 1217 (m), 1 1 15 (w), 998 (m), 964 (m), 824 (m), 791 (s), 690 (s), 502 (s) cm .

UV-Vis (MeOH): 257, 341 nm.

The sharp peaks in the ¾ NMR indicated that iron had been efficiently removed.

Comparative example 1 : Preparation of ridinilazole

A solution of 3,4,3′,4′-tetraaminobiphenyl (0.69 g, 3.2 mmol) and isonicotinaldehyde (0.64 g, 6.0 mmol) in DMF (20 mL) was stirred at 80°C for one hour. Then ferric chloride hexahydrate (49 mg, 0.18 mmol), water (0.10 mL, 5.4 mmol) and additional DMF (2 mL) were added and fresh air was bubbled into the solution during vigorous stirring for 10 hours at 120 °C. After cooling to room temperature water (50 mL) and the mixture was stirred for one hour. A black crude product was isolated by filtration and comprised ridinilazole and iron.

References

^ Jump up to:^a ^b Cho JC, Crotty MP, Pardo J (March 2019). “Clostridium difficile infection”. Annals of Gastroenterology. 32 (2): 134–140. doi:10.20524/aog.2018.0336. PMC 6394264. PMID 30837785.
^ Jump up to:^a ^b ^c ^d Carlson TJ, Endres BT, Bassères E, Gonzales-Luna AJ, Garey KW (April 2019). “Ridinilazole for the treatment of Clostridioides difficile infection”. Expert Opinion on Investigational Drugs. 28 (4): 303–310. doi:10.1080/13543784.2019.1582640. PMID 30767587.
^ Bassères E, Endres BT, Dotson KM, Alam MJ, Garey KW (January 2017). “Novel antibiotics in development to treat Clostridium difficile infection”. Current Opinion in Gastroenterology. 33 (1): 1–7. doi:10.1097/MOG.0000000000000332. PMID 28134686. These tables highlight the increased drug development directed towards CDI due to the rise in prevalence of infections and to attempt to reduce the number of recurrent infections.
^ Vickers RJ, Tillotson G, Goldstein EJ, Citron DM, Garey KW, Wilcox MH (August 2016). “Ridinilazole: a novel therapy for Clostridium difficile infection”. International Journal of Antimicrobial Agents. 48 (2): 137–43. doi:10.1016/j.ijantimicag.2016.04.026. PMID 27283730. there exists a significant unmet and increasing medical need for new therapies to treat CDI, specifically those that can reduce the rate of disease recurrence.
^ Clinical trial number NCT03595553 for “Ri-CoDIFy 1: Comparison of Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection” at ClinicalTrials.gov
^ Clinical trial number NCT03595566 for “Ri-CoDIFy 2: To Compare Ridinilazole Versus Vancomycin Treatment for Clostridium Difficile Infection” at ClinicalTrials.gov
^ “Fast Track”. U.S. Food and Drug Administration. 2018-11-03.
^ “”HHS spurs new antibiotic development for biodefense and common infections””. Public Health Emergency. U.S. Department of Health and Human Services. Retrieved 2020-12-04.

Clinical data

Other names	SMT19969
ATC code	None
Identifiers
IUPAC name [show]
CAS Number	308362-25-6
PubChem CID	16659285
ChemSpider	17592423
UNII	06DX01190R
KEGG	D11958
Chemical and physical data
Formula	C₂₄H₁₆N₆
Molar mass	388.42 g/mol
3D model (JSmol)	Interactive image
SMILES [hide]c6cc(c5nc4ccc(c3ccc2nc(c1ccncc1)[nH]c2c3)cc4[nH]5)ccn6

/////////RIDINILAZOLE, SMT19969, SMT 19969, ридинилазол , ريدينيلازول , 利地利唑 , リジニラゾール , Qualified Infectious Disease Product, QIDP, Fast Track , PHASE 3, Clostridioides difficile infection ,

Esketamine

January 23, 2021 2:29 am / Leave a comment

Esketamine

Molecular FormulaC₁₃H₁₆ClNO
Average mass237.725 Da

(+)-Ketamine(2S)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
(S)-Ketamine33643-46-8[RN]7884Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (2S)-Cyclohexanone, 2-(2-chlorophenyl)-2-(methylamino)-, (S)-
KetamineCAS Registry Number: 6740-88-1CAS Name: 2-(2-Chlorophenyl)-2-(methylamino)cyclohexanoneMolecular Formula: C13H16ClNOMolecular Weight: 237.73Percent Composition: C 65.68%, H 6.78%, Cl 14.91%, N 5.89%, O 6.73%Literature References: Prepn: C. L. Stevens, BE634208; idem,US3254124 (1963, 1966 both to Parke, Davis). Isoln of optical isomers: T. W. Hudyma et al.,DE2062620 (1971 to Bristol-Myers), C.A.75, 118119x (1971). Clinical pharmacology of racemate and enantiomers: P. F. White et al.,Anesthesiology52, 231 (1980). Toxicity: E. J. Goldenthal, Toxicol. Appl. Pharmacol.18, 185 (1971). Enantioselective HPLC determn in plasma: G. Geisslinger et al.,J. Chromatogr.568, 165 (1991). Comprehensive description: W. C. Sass, S. A. Fusari, Anal. Profiles Drug Subs.6, 297-322 (1977). Review of pharmacology and use in veterinary medicine: M. Wright, J. Am. Vet. Med. Assoc.180, 1462-1471 (1982). Review of pharmacology and clinical experience: D. L. Reich, G. Silvay, Can. J. Anaesth.36, 186-197 (1989); in pediatric procedures: S. M. Green, N. E. Johnson, Ann. Emerg. Med.19, 1033-1046 (1990).Properties: Crystals from pentane-ether, mp 92-93°. uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5). pKa 7.5. pH of 10% aq soln 3.5.Melting point: mp 92-93°pKa: pKa 7.5Absorption maximum: uv max (0.01N NaOH in 95% methanol): 301, 276, 268, 261 nm (A1%1cm 5.0, 7.0, 9.8, 10.5)
Derivative Type: HydrochlorideCAS Registry Number: 1867-66-9Manufacturers’ Codes: CI-581Trademarks: Ketalar (Pfizer); Ketanest (Pfizer); Ketaset (Fort Dodge); Ketavet (Gellini); Vetalar (Bioniche)Molecular Formula: C13H16ClNO.HClMolecular Weight: 274.19Percent Composition: C 56.95%, H 6.25%, Cl 25.86%, N 5.11%, O 5.84%Properties: White crystals, mp 262-263°. Soly in water: 20 g/100 ml. LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal).Melting point: mp 262-263°Toxicity data: LD50 in adult mice, rats (mg/kg): 224 ±4, 229 ±5 i.p. (Goldenthal)
NOTE: This is a controlled substance (depressant): 21 CFR, 1308.13.Therap-Cat: Anesthetic (intravenous).Therap-Cat-Vet: Anesthetic (intravenous).Keywords: Anesthetic (Intravenous).Esketamine hydrochloride, S enantiomer of ketamine, is in phase III clinical trials by Johnson & Johnson for the treatment of depression.Drug Name：Esketamine HydrochlorideResearchCode：JNJ-54135419MOA：Dopamine reuptake inhibitor; NMDA receptor antagonistIndication：DepressionStatus：Phase III (Active)Company：Johnson & Johnson (Originator)

Molecular Weight	274.19
Formula	C13H16ClNO•HCl
CAS No.	33643-46-8 (Esketamine); 33643-47-9 (Esketamine Hydrochloride);

Route 1

Reference：1. US6040479.

https://patents.google.com/patent/US6040479A/en

EXAMPLE 1

50 g (0.21 mol) R,S-ketamine are dissolved in 613 ml of acetone at the boiling point and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid. In order to obtain a clear solution, 40 ml of water are added thereto at the boiling point and subsequently the clear solution is filtered off while still hot. After the addition of seed crystals obtained in a small preliminary experiment, the whole is allowed to cool to ambient temperature while stirring. After standing overnight, the crystals formed are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.).

Yield (tartrate): 64.8 g

m.p.: 161° C.

[α]_D : +26.1° (c=2/H₂ O)

Thereafter, the crystallisate is recrystallised in a mixture of 1226 ml acetone and 90 ml water. After cooling to ambient temperature and subsequently stirring for 4 hours, the crystals are filtered off with suction and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C). There are obtained 38.8 g of tartrate (95.29% of theory).

m.p.: 175.3° C.

[α]_D : +68.9° (c=2/H₂ O)

The base is liberated by taking up 38.8 g of tartrate in 420 ml of aqueous sodium hydroxide solution and stirring with 540 ml of diethyl ether. The ethereal phase is first washed with water and subsequently with a saturated solution of sodium chloride. The organic phase is dried over anhydrous sodium sulphate. After filtering, the solution is evaporated to dryness on a rotary evaporator, a crystalline, colourless product remaining behind.

Yield (crude base): 21.5 g=86.0% of theory

m.p.: 118.9° C. (literature: 120-122° C.)

[α]_D : -55.8° (c=2/EtOH) (literature: [α]_D : -56.35° ).

In order possibly to achieve a further purification, the base can be recrystallised from cyclohexane. For this purpose, 10.75 g of the crude base are dissolved in 43 ml cyclohexane at the boiling point. While stirring, the clear solution is slowly cooled to about 10° C. and then stirred at this temperature for about 1 hour. The crystallisate which precipitates out is filtered off with suction and dried to constant weight.

Yield (base): 10.3 g=82.4% of theory

m.p.: 120° C. (literature: 120-122° C.)

[α]_D : -56.8° (c=2/EtOH) (literature: [α]_D : -56.35° )

EXAMPLE 2

125 ml of water are taken and subsequently 31.5 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine added thereto. While stirring, this mixture is warmed to 50-60° C. until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is first washed with water (1-6° C.) and subsequently washed twice with, in each case, 20 ml of acetone. Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 31.79 g of tartrate (78.23%) of theory).

EXAMPLE 3

150 ml of water are taken and subsequently mixed with 39.8 g (0.27 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine. While stirring, this mixture is warmed to 50-60° C. until a clear solution results.

After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is successively washed with 8 ml of water (1-6° C.) and thereafter twice with, in each case, 20 ml acetone.

Drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.) gives 32.58 g of tartrate (80.02% of theory).

EXAMPLE 4

150 ml of water and 50 ml isopropanol are taken. After the addition of 39.8 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine, the mixture is heated to reflux temperature while stirring until a solution results (possibly add water until all is dissolved).

Subsequently, while stirring, the solution is allowed to cool to ambient temperature and stirred overnight. The crystals are filtered off with suction and subsequently washed with a 1:2 mixture of 20 ml of water/isopropanol and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 24.45 g of tartrate (62.63% of theory).

EXAMPLE 5

50 g (0.21 mol) R,S-ketamine are dissolved at the boiling point in 300 ml acetone and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaric acid and 100 ml of water. The whole is allowed to cool while stirring and possibly seeded.

After standing overnight, the crystals formed are filtered off with suction, then washed twice with, in each case, 20 ml acetone and dried in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.). There are obtained 30.30 g of tartrate (74.57% of theory).

EXAMPLE 6

75 ml of water and 50 ml isopropanol are taken and subsequently 39.8 g (0.27 mol) L-(+)-tartaric acid added thereto. While stirring, the mixture is heated to reflux temperature until a clear solution results. After cooling to ambient temperature while stirring and subsequently stirring overnight, the crystals formed are filtered off with suction. Subsequently, the crystallisate is washed with a 1:2 mixture of 20 ml water/isopropanol. After drying in a circulating air drying cabinet (first at ambient temperature and then at 50-60° C.), there are obtained 34.84 g of tartrate (85.74% of theory).

EXAMPLE 7

20 g of the S-(+)-tartrate obtained in Example 4 are dissolved in 100 ml of water at 30-40° C. With about 7 ml of 50% sodium hydroxide solution, an S-(-)-ketamine base is precipitated out up to about pH 13. It is filtered off with suction and washed neutral with water to pH 7-8. Subsequently, it is dried for about 24 hours at 50° C. in a circulating air drying cabinet. There are obtained 11.93 g S-(-)-ketamine (97.79% of theory).

EXAMPLE 8

5 g of the S-(-)-ketamine obtained in Example 7 are dissolved in 50 ml isopropanol at about 50° C. and possibly filtered off with suction over kieselguhr. Subsequently, gaseous hydrogen chloride is passed in at 50-60° C. until a pH value of 0-1 is reached. The reaction mixture is allowed to cool to ambient temperature, filtered off with suction and washed with about 5 ml isopropanol. The moist product is dried overnight at about 50° C. in a circulating air drying cabinet. There are obtained 5.09 g S-(+)-ketamine hydrochloride (88.06% of theory).

Route 2

Reference：1. J. Am. Chem. Soc. 2015, 137, 3205-3208.

https://pubs.acs.org/doi/10.1021/jacs.5b00229

Here we report the direct asymmetric amination of α-substituted cyclic ketones catalyzed by a chiral phosphoric acid, yielding products with a N-containing quaternary stereocenter in high yields and excellent enantioselectivities. Kinetic resolution of the starting ketone was also found to occur on some of the substrates under milder conditions, providing enantioenriched α-branched ketones, another important building block in organic synthesis. The utility of this methodology was demonstrated in the short synthesis of (S)-ketamine, the more active enantiomer of this versatile pharmaceutical.

CLIP

Initial reagent: cyclopentyl Grignard Step 0: Producing cyclopentyl Grignard Reacting cyclopentyl bromide with magnesium in solvent (ether or THF) Best results: distill solvent from Grignard under vacuum and replace with hydrocarbon solvent (e.g. benzene) Step 1: processing to (o-chlorophenyl)-cyclopentyl ketone Adding o-chlorobenzonitrile to cyclopentyl Grignard in solvent, stirring for long period of time (typically three days) Hydrolyzing reaction with mixture containing crushed ice, ammonium chloride and some ammonium hydroxide Extraction with organic solvent gives (o-chlorophenyl)-cyclopentyl ketone

Step 2: processing to alpha-bromo (o-chlorophenyl)-cyclopentyl ketone ketone processed with bromine in carbon tetrachloride at low temperature (typical T = 0°C), addition of bromine dropwise forming orange suspension Suspension washed in dilute aquerous solution of sodium bisufide and evaporated giving 1-bromocyclopentyl-(o-chlorophenyl)-ketone Note: bromoketone is unstable, immeadiate usage. Bromination carried out with NBromosuccinimide result higher yield (roughly 77%) Step 3: processing to 1-hydroxycyclopentyl-(o-chlorophenyl)-ketone-N-methylimine Dissolving bromoketone in liquid methylamine freebase (or benzene as possible solvent) After time lapse (1h): excess methylamine evaporated, residue dissolved in pentane and filtered evaporation of solvent yields 1-hydroxy-cyclopentyl-(o-chlorophenyl)-ketone N-methylimine Note: longer time span (4-5d) for evaporation of methylaminemay increase yield Step 4: processing to 2-Methylamino-2-(o-chlorophenyl)-cyclohexanone (Ketamine) Method: Thermal rearragement (qualitative yield after 30min in 180°C) N-methylimine dissolved in 15ml decalin, refluxed for 2.5h Evaporation of solvent under reduced temperature followed by extraction of residue with dilute hydrochloric acid Treatment with decolorizing charcoal (solution: acidic => basic) Recrystallization from pentane-ether Note – alternative to use of decalin: pressure bomb

racemic compound, in pharmaceutical preparation racemic more active enantiomere esketamine (S-Ketamine) available as Ketanest S, but Arketamine (R-Ketamine) never marketed for clinical use, Optical rotation: varies between salt and free base form free base form: (S)-Ketamine dextrorotation  (S)-(+)-ketamine hydrochloridesalt: levorotation(S)-(-)-ketamine  Reason found in molecular level: different orientation of substituents: freebase: o-chlorophenyl equatorial, methylamino axia

Sources: http://creationwiki.org/Ketamine#Synthesis http://www.lycaeum.org/rhodium/chemistry/pcp/ketamine.html https://pubchem.ncbi.nlm.nih.gov/compound/ketamine https://pubchem.ncbi.nlm.nih.gov/compound/ketamine#section=Drug-Warning http://www.rsc.org/chemistryworld/2014/02/ketamine-special-k-drugs-podcast http://drugabuse.com/library/the-effects-of-ketamine-use/ http://www.drugfreeworld.org/drugfacts/prescription/ketamine.html http://onlinelibrary.wiley.com/doi/10.1002/1615-9314(20021101)25:15/17%3C1155::AID-JSSC1155%3E3.0.CO;2-M/pdf

CLIP

Process Research and Impurity Control Strategy of Esketamine Organic Process Research & Development ( IF 3.023
) Pub Date: 2020-03-18 , DOI: 10.1021/acs.oprd.9b00553
Shenghua Gao; Xuezhi Gao; Zhezhou Yang; Fuli Zhang
An improved synthesis of ( S )-ketamine (esketamine) has been developed, which was cost-effective, and the undesired isomer could be recovered by racemization. Critical process parameters of each step were identified as well as the process-related impurities. The formation mechanisms and control strategies of most impurities were first discussed. Moreover, the ( S )-ketamine tartrate is a dihydrate, which was disclosed for the first time. The practicable racemization catalyzed by aluminum chloride was carried out in quantitative yield with 99% purity . The ICH-grade quality ( S)-ketamine hydrochloride was obtained in 51.1% overall yield (14.0% without racemization) by chiral resolution with three times recycling of the mother liquors. The robust process of esketamine could be industrially scalable.

Process Research and ketamine impurity control strategy

has been developed an improved ( S ) – ketamine (esketamine) synthesis, the high cost-effective way, the undesired isomer may be recycled by racemization. Determine the key process parameters and process-related impurities for each step. First, the formation mechanism and control strategy of most impurities are discussed. In addition, ( S )-ketamine tartrate is a dihydrate, which is the first time it has been published. The feasible racemization catalyzed by aluminum chloride proceeds in a quantitative yield with a purity of 99%. ICH grade quality ( S) 5-ketamine hydrochloride can be obtained through chiral resolution and three times the mother liquor recovery rate. The total yield is 51.1% (14.0% without racemization). The robust process of ketamine can be used in Industrial promotion.

CLIP

CLIP

https://link.springer.com/article/10.1007/s13738-018-1404-1#citeas

Taghizadeh, M.J., Gohari, S.J.A., Javidan, A. et al. A novel strategy for the asymmetric synthesis of (S)-ketamine using (S)-tert-butanesulfinamide and 1,2-cyclohexanedione. J IRAN CHEM SOC 15, 2175–2181 (2018). https://doi.org/10.1007/s13738-018-1404-1

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DOIhttps://doi.org/10.1007/s13738-018-1404-1

Abstract

We present a novel asymmetric synthesis route for synthesis of (S)-ketamine using a chiral reagent according to the strategy (Scheme 1), with good enantioselectivity (85% ee) and yield. In this procedure, the (S)-tert-butanesulfinamide (TBSA) acts as a chiral auxiliary reagent to generate (S)-ketamine. A series of new intermediates were synthesized and identified for the first time in this work (2–4). The monoketal intermediate (1) easily obtained after partial conversion of one ketone functional group of 1,2-cyclohexanedione into a ketal using ethylene glycol. The sulfinylimine (2) was obtained by condensation of (S)-tert-butanesulfinamide (TBSA) with (1), 4-dioxaspiro[4.5]decan-6-one in 90% yield. The (S)-N–tert-butanesulfinyl ketamine (3) was prepared on further reaction of sulfinylimine (2) with appropriate Grignard reagent (ArMgBr) in which generated chiral center in 85% yield and with 85% diastereoselectivity. Methylation of amine afforded the product (4). Finally, the sulfinyl- and ketal-protecting groups were removed from the compound (4) by brief treatment with stoichiometric quantities of HCl in a protic solvent gave the (S)-ketamine in near quantitative yield.

Esketamine, sold under the brand name Spravato^[4] among others,^[6]^[7] is a medication used as a general anesthetic and for treatment-resistant depression.^[4]^[1] Esketamine is used as a nasal spray or by injection into a vein.^[4]^[1]

Esketamine acts primarily as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist.^[1]^[8] It also acts to some extent as a dopamine reuptake inhibitor but, unlike ketamine, does not interact with the sigma receptors.^[1] The compound is the S(+) enantiomer of ketamine, which is an anesthetic and dissociative similarly.^[1] It is unknown whether its antidepressant action is superior, inferior or equal to racemic ketamine and its opposite enantiomer, arketamine, which are both being investigated for the treatment of depression.

Esketamine was introduced for medical use in 1997.^[1] In 2019, it was approved for use with other antidepressants, for the treatment of depression in adults in the United States.^[9]

In August 2020, it was approved by the U.S. Food and Drug Administration (FDA) with the added indication for the short-term treatment of suicidal thoughts.^[10]

Medical uses

Anesthesia

Esketamine is a general anesthetic and is used for similar indications as ketamine.^[1] Such uses include induction of anesthesia in high-risk patients such as those with hemorrhagic shock, anaphylactic shock, septic shock, severe bronchospasm, severe hepatic insufficiency, cardiac tamponade, and constrictive pericarditis; anesthesia in caesarian section; use of multiple anesthetics in burns; and as a supplement to regional anesthesia with incomplete nerve blocks.^[1]

Depression

Similarly to ketamine, esketamine appears to be a rapid-acting antidepressant.^[8]^[11] It received a breakthrough designation from the FDA for treatment-resistant depression (TRD) in 2013 and major depressive disorder (MDD) with accompanying suicidal ideation in 2016.^[12]^[11] The medication was studied for use in combination with an antidepressant in people with TRD who had been unresponsive to treatment;^[12]^[8]^[11] six phase III clinical trials for this indication were conducted in 2017.^[12]^[8]^[11] It is available as a nasal spray.^[12]^[8]^[11]

In February 2019, an outside panel of experts recommended that the FDA approve the nasal spray version of esketamine,^[13] provided that it be given in a clinical setting, with people remaining on site for at least two hours after. The reasoning for this requirement is that trial participants temporarily experienced sedation, visual disturbances, trouble speaking, confusion, numbness, and feelings of dizziness during immediately after.^[14]

In January 2020, esketamine was rejected by the National Health Service of Great Britain. NHS questioned the benefits and claimed that it was too expensive. People who have been already using the medication were allowed to complete treatment if their doctors consider this necessary.^[15]

Side effects

Most common side effects when used in those with treatment resistant depression include dissociation, dizziness, nausea, sleepiness, anxiety, and increased blood pressure.^[16]

Pharmacology

Esketamine is approximately twice as potent as an anesthetic as racemic ketamine.^[17] It is eliminated from the human body more quickly than arketamine (R(–)-ketamine) or racemic ketamine, although arketamine slows its elimination.^[18]

A number of studies have suggested that esketamine has a more medically useful pharmacological action than arketamine or racemic ketamine^{[citation needed]} but, in mice, that the rapid antidepressant effect of arketamine was greater and lasted longer than that of esketamine.^[19] The usefulness of arketamine over eskatamine has been supported by other researchers.^[20]^[21]^[22]

Esketamine inhibits dopamine transporters eight times more than arketamine.^[23] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.^[24]^[25] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.^[17]^[26] This is however in contradiction with R-ketamine being devoid of psychotomimetic side effects.^[27]

Unlike arketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while arketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while arketamine is reportedly more relaxing.^[26] However, another study found no difference between racemic and (S)-ketamine on the patient’s level of vigilance.^[24] Interpretation of this finding is complicated by the fact that racemic ketamine is 50% (S)-ketamine.

History

Esketamine was introduced for medical use as an anesthetic in Germany in 1997, and was subsequently marketed in other countries.^[1]^[28] In addition to its anesthetic effects, the medication showed properties of being a rapid-acting antidepressant, and was subsequently investigated for use as such.^[8]^[12] In November 2017, it completed phase III clinical trials for treatment-resistant depression in the United States.^[8]^[12] Johnson & Johnson filed a Food and Drug Administration (FDA) New Drug Application (NDA) for approval on September 4, 2018;^[29] the application was endorsed by an FDA advisory panel on February 12, 2019, and on March 5, 2019, the FDA approved esketamine, in conjunction with an oral antidepressant, for the treatment of depression in adults.^[9]

In the 1980s and ’90s, closely associated ketamine was used as a club drug known as “Special K” for its trip-inducing side effects.^[30]^[31]

Society and culture

Names

Esketamine is the generic name of the drug and its INN and BAN, while esketamine hydrochloride is its BANM.^[28] It is also known as S(+)-ketamine, (S)-ketamine, or (–)-ketamine, as well as by its developmental code name JNJ-54135419.^[28]^[12]

Esketamine is marketed under the brand name Spravato for use as an antidepressant and the brand names Ketanest, Ketanest S, Ketanest-S, Keta-S for use as an anesthetic (veterinary), among others.^[28]

Availability

Esketamine is marketed as an antidepressant in the United States;^[9] and as an anesthetic in the European Union.^[28]

Legal status

Esketamine is a Schedule III controlled substance in the United States.^[4]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie. 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
^ “Spravato 28 mg nasal spray, solution – Summary of Product Characteristics (SmPC)”. (emc). Retrieved 24 November 2020.
^ “Vesierra 25 mg/ml solution for injection/infusion – Summary of Product Characteristics (SmPC)”. (emc). 21 February 2020. Retrieved 24 November2020.
^ Jump up to:^a ^b ^c ^d ^e “Spravato- esketamine hydrochloride solution”. DailyMed. 6 August 2020. Retrieved 26 September 2020.
^ “Spravato EPAR”. European Medicines Agency (EMA). 16 October 2019. Retrieved 24 November 2020.
^ “Text search results for esketamine: Martindale: The Complete Drug Reference”. MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August 2017.^{[dead link]}
^ Brayfield A, ed. (9 January 2017). “Ketamine Hydrochloride”. MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 20 August2017.^{[dead link]}
^ Jump up to:^a ^b ^c ^d ^e ^f ^g Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
^ Jump up to:^a ^b ^c “FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic”. U.S. Food and Drug Administration (FDA) (Press release). Retrieved 2019-03-06.
^ “FDA Approves A Nasal Spray To Treat Patients Who Are Suicidal”. NPR. 4 August 2020. Retrieved 27 September 2020.
^ Jump up to:^a ^b ^c ^d ^e Lener MS, Kadriu B, Zarate CA (March 2017). “Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression”. Drugs. 77 (4): 381–401. doi:10.1007/s40265-017-0702-8. PMC 5342919. PMID 28194724.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Esketamine – Johnson & Johnson – AdisInsight”. Retrieved 7 November 2017.
^ Koons C, Edney A (February 12, 2019). “First Big Depression Advance Since Prozac Nears FDA Approval”. Bloomberg News. Retrieved February 12, 2019.
^ Psychopharmacologic Drugs Advisory Committee (PDAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee (February 12, 2019). “FDA Briefing Document” (PDF). Food and Drug Administration. Retrieved February 12, 2019. Meeting, February 12, 2019. Agenda Topic: The committees will discuss the efficacy, safety, and risk-benefit profile of New Drug Application (NDA) 211243, esketamine 28 mg single-use nasal spray device, submitted by Janssen Pharmaceutica, for the treatment of treatment-resistant depression.
^ “Anti-depressant spray not recommended on NHS”. BBC News. 28 January 2020.
^ “Esketamine nasal spray” (PDF). U.S. Food and Drug Administration (FDA). Retrieved 21 October 2019.
^ Jump up to:^a ^b Himmelseher S, Pfenninger E (December 1998). “[The clinical use of S-(+)-ketamine–a determination of its place]”. Anasthesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie (in German). 33 (12): 764–70. doi:10.1055/s-2007-994851. PMID 9893910.
^ Ihmsen H, Geisslinger G, Schüttler J (November 2001). “Stereoselective pharmacokinetics of ketamine: R(–)-ketamine inhibits the elimination of S(+)-ketamine”. Clinical Pharmacology and Therapeutics. 70 (5): 431–8. doi:10.1067/mcp.2001.119722. PMID 11719729.
^ Zhang JC, Li SX, Hashimoto K (January 2014). “R (-)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine”. Pharmacology, Biochemistry, and Behavior. 116: 137–41. doi:10.1016/j.pbb.2013.11.033. PMID 24316345. S2CID 140205448.
^ Muller J, Pentyala S, Dilger J, Pentyala S (June 2016). “Ketamine enantiomers in the rapid and sustained antidepressant effects”. Therapeutic Advances in Psychopharmacology. 6 (3): 185–92. doi:10.1177/2045125316631267. PMC 4910398. PMID 27354907.
^ Hashimoto K (November 2016). “Ketamine’s antidepressant action: beyond NMDA receptor inhibition”. Expert Opinion on Therapeutic Targets. 20 (11): 1389–1392. doi:10.1080/14728222.2016.1238899. PMID 27646666. S2CID 1244143.
^ Yang B, Zhang JC, Han M, Yao W, Yang C, Ren Q, Ma M, Chen QX, Hashimoto K (October 2016). “Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression”. Psychopharmacology. 233 (19–20): 3647–57. doi:10.1007/s00213-016-4399-2. PMC 5021744. PMID 27488193.
^ Nishimura M, Sato K (October 1999). “Ketamine stereoselectively inhibits rat dopamine transporter”. Neuroscience Letters. 274 (2): 131–4. doi:10.1016/s0304-3940(99)00688-6. PMID 10553955. S2CID 10307361.
^ Jump up to:^a ^b Doenicke A, Kugler J, Mayer M, Angster R, Hoffmann P (October 1992). “[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings]”. Der Anaesthesist (in German). 41 (10): 610–8. PMID 1443509.
^ Pfenninger E, Baier C, Claus S, Hege G (November 1994). “[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses]”. Der Anaesthesist (in German). 43 Suppl 2: S68-75. PMID 7840417.
^ Jump up to:^a ^b Vollenweider FX, Leenders KL, Oye I, Hell D, Angst J (February 1997). “Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)”. European Neuropsychopharmacology. 7 (1): 25–38. doi:10.1016/s0924-977x(96)00042-9. PMID 9088882. S2CID 26861697.
^ Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, Dong C, Hashimoto K (September 2015). “R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects”. Translational Psychiatry. 5 (9): e632. doi:10.1038/tp.2015.136. PMC 5068814. PMID 26327690.
^ Jump up to:^a ^b ^c ^d ^e “Esketamine”. Drugs.com.
^ “Janssen Submits Esketamine Nasal Spray New Drug Application to U.S. FDA for Treatment-Resistant Depression”. Janssen Pharmaceuticals, Inc.
^ Marsa, Linda (January 2020). “A Paradigm Shift for Depression Treatment”. Discover. Kalmbach Media.
^ Hoffer, Lee (7 March 2019). “The FDA Approved a Ketamine-Like Nasal Spray for Hard-to-Treat Depression”. Vice. Retrieved 11 February 2020.

External links

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

Clinical data


Trade names	Spravato, Ketanest, Vesierra, others
Other names	Esketamine hydrochloride; (S)-Ketamine; S(+)-Ketamine; JNJ-54135419
AHFS/Drugs.com	Monograph
MedlinePlus	a619017
License data	US DailyMed: EsketamineUS FDA: Esketamine
Addiction liability	Low–moderate^{[citation needed]}
Routes of administration	Intranasal, Intravenous infusion^[1]
Drug class	NMDA receptor antagonists; Antidepressants; General anesthetics; Dissociative hallucinogens; Analgesics
ATC code	N01AX14 (WHO) N06AX27 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug)UK: POM (Prescription only) ^[2]^[3]US: Schedule III ^[4]EU: Rx-only ^[5]In general: ℞ (Prescription only)
Identifiers
IUPAC name [show]
CAS Number	33643-46-8as HCl: 33795-24-3
PubChem CID	182137
IUPHAR/BPS	9152
DrugBank	DB01221
ChemSpider	158414
UNII	50LFG02TXDas HCl: 5F91OR6H84
KEGG	D07283as HCl: D10627
ChEBI	CHEBI:6121
ChEMBL	ChEMBL742
CompTox Dashboard (EPA)	DTXSID6047810
ECHA InfoCard	100.242.065
Chemical and physical data
Formula	C₁₃H₁₆ClNO
Molar mass	237.73 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide]CN[C@](C1=C(Cl)C=CC=C1)(CCCC2)C2=O
InChI [hide]InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1Key:YQEZLKZALYSWHR-ZDUSSCGKSA-N

/////////////Esketamine, JNJ 54135419, phase 3

ROLUPERIDONE

January 7, 2021 7:43 am / Leave a comment

Molecular FormulaC₂₂H₂₃FN₂O₂
Average mass366.429 Da

Roluperidone

CAS 359625-79-9

1937215-88-7 hcl

ролуперидон [Russian] [INN]

رولوبيريدون [Arabic] [INN]

罗鲁哌酮 [Chinese] [INN]

1H-Isoindol-1-one, 2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]-4-piperidinyl]methyl]-2,3-dihydro-2-({1-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl}methyl)-1-isoindolinone

2-[[1- [2–fluorophenyl) -2-oxotyl] piperidine –4-yl] methyl] isoindrin-hydrochloride

CYR-101

UNII-4P31I0M3BF

MIN-101

SYN

Roluperidone (former developmental code names MIN-101, CYR-101, MT-210) is a 5-HT_2A and σ₂ receptor antagonist that is under development by Minerva Neurosciences for the treatment of schizophrenia.^[1]^[2]^[3]^[4] One of its metabolites also has some affinity for the H₁ receptor.^[2] As of May 2018, the drug is in phase III clinical trials.^[5]

Minerva Neurosciences (following the merger of Cyrenaic and Sonkei Pharmaceuticals ), under license from Mitsubishi Tanabe Pharma , is developing roluperidone (MIN-101, CYR-101, MT-210), a dual 5-HT2A /sigma 2 antagonist, as a modified-release formulation, for the potential oral treatment of schizophrenia. In December 2017, a phase III trial was initiated in patients with negative symptoms of schizophrenia. By March 2020, Minerva had filed an IND for apathy in dementia.

Schizophrenia is a complex, challenging, and heterogeneous psychiatric condition, affecting up to 0.7% of the world population according to the World Health Organization (WHO, 2006). Patients suffering with schizophrenia present with a range of symptoms, including: positive symptoms, such as delusions, hallucinations, thought disorders, and agitation; negative symptoms, such as mood flatness and lack of pleasure in daily life; cognitive symptoms, such as the decreased ability to understand information and make decisions, difficulty focusing, and decreased working memory function; and sleep disorders.

The etiology of schizophrenia is not fully understood. A major explanatory hypothesis for the pathophysiology of schizophrenia is the Dopamine (DA) hypothesis, which proposes that hyperactivity of DA transmission is responsible for expressed symptoms of the disorder. This hypothesis is based on the observation that drugs effective in treating schizophrenia share the common feature of blocking DA D2 receptors. However, these so-called typical antipsychotics are associated with a very high incidence of extrapyramidal symptoms (EPS). Furthermore, negative symptoms and cognitive impairment are considered relatively unresponsive to typical antipsychotics.

Most currently approved therapies for schizophrenia show efficacy primarily in the management of positive symptoms. An estimated 4.2 million people suffered from schizophrenia in 2012 in the United States and the five major European Union markets. Of those, an estimated 48% experienced predominantly negative symptoms and 80% suffered from cognitive impairment. In addition, about 50% of patients with schizophrenia experience sleep disorders, which can further exacerbate both positive and negative symptoms.

The introduction of the so-called atypical antipsychotics in the last decade represented a significant advance in the treatment of schizophrenia. Although these atypical antipsychotics differ widely in chemical structure and receptor-binding profiles, they share a characteristic of potent antagonism of the Serotonin (5-hydroxytryptamine) type 2 receptor (5-HT2A). A high 5-HT2A:D2 affinity ratio is thought to substantially reduce the liability for inducing EPS, compared with typical antipsychotics.

However, many patients are still treatment-noncompliant despite the advantage of atypical antipsychotics of tolerability. Although the risk of EPS is clearly lower with the atypical antipsychotics, the high doses required with some atypical antipsychotics are likely to result in an increased incidence of EPS and require concomitant medications such as antiparkinson drugs.

In addition to EPS, antipsychotic medications cause a broad spectrum of side effects including sedation, anticholinergic effects, prolactin elevation, orthostatic hypotension, weight gain, altered glucose metabolism, and QTc prolongation. These side effects can affect patients’ compliance with their treatment regimen. It should be noted that noncompliance with treatment regimen is a primary reason for relapse of the disease.

Although atypical antipsychotics offer advantages over typical antipsychotics in terms of symptom alleviation and side effect profile, these differences are generally modest. A certain population of patients still remains refractory to all currently available antipsychotics. Newer agents to address these issues continue to be sought.

Product Ingredients

INGREDIENT	UNII	CAS	INCHI KEY
Roluperidone hydrochloride	WFL7TF8DTP	1937215-88-7	NZKANSJXJCILHS-UHFFFAOYSA-N

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2001064670

Example 1: 2-[[1- [2–fluorophenyl) -2-oxotyl] piperidine –4-yl] methyl] isoindrin-hydrochloride (Compound 1 in Table 1)

a) tert-Butyl 4-aminomethylpiperidine-carpoxylate hydrochloride’salt

4-Aminomethylpiperidin 5. 71g as a starting material

Tert-Butyl 4-aminomethylbiperidine-power reportage was synthesized according to the method described in Synthetic Commun., 22 (16), 2357-2360 (1992). This compound was dissolved in 80 ml of ethyl acetate, 4N ethyl monoacetate hydrochloride was added, and the mixture was stirred. Precipitated solid

Was collected to obtain 10.27 g (yield 82%) of the indicated compound. At melting point 236-240.

Ή-NMR (DMS0-d ₆ ): 8.00 (3H, s), 3. 92 (2H, br d, J = 12.6), 2.68 H, m), 1.77- 1. 65 (3H, m), 1.39 (9H, s), 1.02 (2H, m) b) 2-Bromomethylbenzoic acid etyl ester

2-Methylbenzoic acid etyl ester (2.00 g, 11.9 mmol) is dissolved in carbon tetrachloride (60 ml), and N-promosucciimide (2.56 g, 14.4 mmo 1) and a catalytic amount of benzoyl peroxide are added to the solution. In addition, heat reflux. After 1 hour, the reaction mixture was cooled to room temperature, hexan (40 m was added, the insoluble material was filtered off, and the filtrate was distilled off under reduced pressure to obtain 3.16 g of the indicated compound as a yellow oil. It was used for the next reaction without purification as it was.

c) tert-Butyl 4- (1-oxoisoindrin-2 -ylmethyl) piperidine-1 -carpoxylate

Add 3.15 g of the compound obtained in Example lb and the compound (3.00 g, 12. Ommol) obtained in Example la to dimethylformamide (30πΠ), and stir at room temperature with trietylamine (3.5 ml, 25 mmol). ) Is added and stirred at the same temperature for 17 hours. Water is added to the reaction mixture, and the mixture is extracted with a mixed solvent of etyl hexane vinegar. The organic layer is washed with 10% aqueous quenic acid solution, water, sodium bicarbonate solution, and saturated brine, and dried with magnesium sulfate. The insoluble material was filtered, the filtrate was distilled off under reduced pressure, and the obtained oil was purified by silicon gel column chromatography (etyl-hexan acetate). I got it as a thing.

Ή-NMR (CDC1 ₃ ): 7.85 (1H, d, J = 7.5), 7.4-7.6 (3Η, m),

4.41 (2H, s), 4.0-4.2 (2H, m), 3.4-3.6 (2H, m), 2.6-2.8 (2H, m), 1.8-2.0 (1H, m), 1.5 -1.7 (4H, m), to 45 (9H, s)

d) 2- (Piperidine -4 -Ilmethyl) Isondrin -1 -On Hydrochloride

The compound (1.6 lg, 4.87 mmol) obtained in Example 1c is dissolved in methylene chloride (5 ml) and ethanol (lm mixed solvent, and at room temperature, 4 standard ethyl acetate solvent (5 ml, 20 mmol) is added. Stir at warm temperature for 1 hour and filter the precipitated solid. The obtained solid was washed with ethanol acetate and then dried under reduced pressure to give the indicated compound 7260 ^ (yield 56%) as a colorless solid. ..

Ή-NMR (DMS0-d ₆ ): 8. 83 (1H, brs), 8. 53 (1H, brs), 7. 4-7. 7 (4 Η, m), 4. 50 (2H, s), 3. 44 (2H, d, J = 7.2), 3. 2-3. 3 (2H, i), 2. 7-2.9 (2H, m), 1. 9-2.1 (1H) , m), 1. 6-1. 8 (2H, m), 1. 3-1. 5 (2H, m)

e) 2- [Π_ [2- (4-Fluo-mouth phenyl) -2-oxotil] Piperidin –4-yl] Methyl] Isoindrin-卜 on

Add the compounds obtained in Example Id (518 mg, 1. 94 mmo and 2-cloucet -4, -fluoroacetophenone (358 mg, 2.07 mmol) to dimethylform amamide (12 ml) with stirring at room temperature. Add trietylamine (575 1, 4. 13 mmol). After stirring at the same temperature for 4 hours, add water to the reaction solution and extract with ethyl acetate. The organic layer is washed with water and saturated saline and sodium sulfate. Dry with thorium. Filter the insoluble material and concentrate the filtrate under reduced pressure to obtain 0.70 g of orange oil. Add hexane to the obtained oil to solidify. Filter this. By drying under reduced pressure, 551 mg (yield 77%) of the notation compound was obtained as a pale yellow solid.

^! H-NMR (CDC1 ₃ ): 8.0-8 . 1 (2H, m), 7. 85 (1H, d = 7.2), 7.4-7. 55 (3 Η, m), 7.1 2 ( 2H, t), 4. 41 (2H, s), 3. 73 (2H, s), 3.51 (2H, d, J = 7.5), 2. 9-3. 0 (2H, m) , 2. 1-2. 2 (2H, m), 1. 4-19.9 (5H, m)

f) 2- [Π- [2- (4 -Fluolophenyl) -2 -Oxoetyl] Piperidin –4-yl] Methyl] Isoindoline-Piol hydrochloride

The compound (550 mg, 1.5 Ommo 1) obtained in Example le was used as an etano.

Dissolve in (2 ml) and add 4 specified ethyl hydrochloride solvent (2 ml, 8 imol) at room temperature and stir at the same temperature for 15 minutes. Ethyl acetate (10 ml) is added to the reaction solution, and the precipitated solid is filtered. The obtained solid is washed with ethyl acetate and then dried under reduced pressure to obtain 364 mg of white powder. This was recrystallized from ethanol monoacetate to give 246 mg (yield 41%) of the notation compound as a colorless solid. At melting point 182-188.

Ή-NMR (DMS0-d ₆ ): 9.93 (1H, brs), 8.0-8. 2 (2H, m), 7.4-7.7 (6 Η, m), 4. 9-5.1 (2H, m), 4.53 (2H, s), 2.9-3.6 (6H, m), 1.6-2.2 (5H, m)

PATENT

https://patents.google.com/patent/US7166617B2/en

Example 12-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one hydrochloride (Compound 1 in Table 1)a) tert-Butyl 4-aminomethylpiperidine-1-carboxylate hydrochloride

By using 4-aminomethylpiperidine 5.71 g as a starting material, tert-butyl 4-aminomethylpiperidine-1-carboxylate was prepared according to the method described in Synthetic Commun., 22(16), 2357–2360 (1992). The resulting compound was dissolved in 80 ml of ethyl acetate, and the solution was added with 4N hydrogen chloride-ethyl acetate and stirred. The precipitated solids were collected by filtration to obtain the title compound (10.27 g, yield: 82%).

Melting point: 236–240° C. ¹H-NMR(DMSO-d₆): 8.00(3H,s), 3.92(2H, br d, J=12.6), 2.68(4H, m), 1.77–1.65(3H, m), 1.39(9H, s), 1.02(2H, m)

b) 2-Bromomethylbenzoic acid ethyl ester

2-Methylbenzoic acid ethyl ester (2.00 g, 11.9 mmol) was dissolved in carbon tetrachloride (60 ml), and the solution was added with N-bromosuccinimide (2.56 g, 14.4 mmol) and a catalytic amount of benzoylperoxide and then heated under reflux. After one hour, the reaction mixture was cooled to room temperature and added with hexane (40 ml) to remove insoluble solids by filtration. The filtrate was evaporated under reduced pressure to obtain the title compound 3.16 g as yellow oil. the product was used in the next reaction without purification.

c) tert-Butyl 4-(1-oxoisoindolin-2-yl-methyl)piperidine-1-carboxylate

The compound obtained in Example 1b (3.15 g), and the compound obtained in Example 1a (3.00 g, 12.0 mmol) were added in dimethylformamide (30 ml). The mixture was added with triethylamine (3.5 ml, 25 mmol) with stirring at room temperature, and then stirring was continued for 17 hours at the same temperature. Water was added to the reaction mixture and extracted with a mixed solvent of ethyl acetate-hexane. The organic layer was washed with 10% aqueous citric acid solution, water, aqueous sodium bicarbonate solution, and then with saturated brine and the dried over magnesium sulfate. Insoluble solids were removed by filtration, and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as yellow oil (yield: 41%)

¹H-NMR(CDCl₃): 7.85(1H,d,J=7.5), 7.4–7.6(3H,m), 4.41(2H,s), 4.0–4.2(2H,m), 3.4–3.6(2H,m), 2.6–2.8(2H,m), 1.8–2.0(1H,m), 1.5–1.7(4H,m), 1.45(9H,s)

d) 2-(Piperidin-4-yl-methyl)isoindolin-1-one hydrochloride

The compound obtained in Example 1c (1.61 g, 4.87 mmol) was dissolved in a mixed solvent of methylene chloride (5 ml) and ethanol (1 ml) and the solution was added with 4N hydrochloric acid in ethyl acetate (5 ml, 20 mmol) at room temperature. The mixture was stirred at the same temperature for 1 hour, and the precipitated solids were collected by filtration. The resulting solids were washed with ethyl acetate and then dried under reduced pressure to obtain the title compound as colorless solid (726 mg, yield: 56%).

¹H-NMR(DMSO-d₆): 8.83(1H,brs), 8.53(1H,brs), 7.4–7.7(4H,m), 4.50(2H,s), 3.44(2H,d,J=7.2), 3.2–3.3(2H,m), 2.7–2.9(2H,m), 1.9–2.1(1H,m), 1.6–1.8(2H,m), 1.3–1.5(2H,m)

e) 2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one

The compound obtained in Example 1d (518 mg, 1.94 mmol) and 2-chloro-4′-fluoroacetophenone (358 mg, 2.07 mmol) was added to dimethylformamide (12 ml), and the solution was added with triethylamine (575 μl, 4.13 mmol) with stirring at room temperature. Stirring was continued at the same temperature for 4 hours, and then the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, and then dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure to obtain orange oil (0.70 g). The resulting oil was solidified by adding hexane, and the solids were collected by filtration and dried under reduced pressure to obtain the title compound as pale yellow solid (551 mg, yield: 77%).

¹H-NMR(CDCl₃): 8.0–8.1(2H,m), 7.85(1H,d=7.2), 7.4–7.55(3H,m), 7.12(2H,t), 4.41(2H,s), 3.73(2H,s), 3.51(2H,d,J=7.5), 2.9–3.0(2H,m), 2.1–2.2(2H,m), 1.4–1.9(5H,m)

f) 2-[[1-[2-(4-Fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]isoindolin-1-one hydrochloride

The compound obtained in Example 1e (550 mg, 1.50 mmol) was dissolved in ethanol (2 ml), and the solution was added with 4N hydrochloric acid in ethyl acetate (2 ml, 8 mmol) at room temperature, and stirring was continued at the same temperature for 15 minutes. The reaction mixture was added with ethyl acetate (10 ml) and the precipitated solids were collected by filtration. The resulting solids were washed with ethyl acetate and then dried under reduced pressure to obtain white powder (364 mg). The product was recrystallized from ethanol-ethyl acetate to obtain the title compound as colorless solid (246 mg, yield: 41%)

Melting point: 182–188° C. ¹H-NMR(DMSO-d₆): 9.93(1H,brs), 8.0–8.2(2H,m), 7.4–7.7(6H,m), 4.9–5.1(2H,m), 4.53(2H,s), 2.9–3.6(6H,m), 1.6–2.2(5H, m)

PATENT

https://patents.google.com/patent/US9458130B2/en?oq=9%2c458%2c130+US

PATENT

WO-2020264486

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020264486&tab=PCTDESCRIPTION&_cid=P20-KJMHAP-74107-1

Novel crystalline form of roluperidone HCL (designated as form 4) as 5-HT 2a receptor antagonist useful for treating schizophrenia.

Roluperidone has the chemical name 2-({ l-[2-(4-Fluorophenyl)-2-oxoethyl]-4-piperidinyl}methyl)-l-isoindolinone. Roluperidone has the following chemical structure:

[0003] Roluperidone is reported to be a drug candidate with equipotent affinities for 5-hydroxytryptamine-2A (5-HT2A) and sigma2 and, at lower affinity levels, al -adrenergic receptors. A pivotal Phase 3 clinical trial is ongoing with roluperidone as a monotherapy for negative symptoms in patients diagnosed with schizophrenia.

[0004] Roluperidone is known from U.S. Patent No. 7,166,617.

[0005] Solid state form of 2-((l-(2-(4-Fluorophenyl)-2-oxoethyl)piperidin-4-yl)methyl)isoindolin-l-o-ne monohydrochloride dihydrate is known from U.S. Patent No.9,458,130.

Examples

[00113] Roluperidone can be prepared according to the procedure described in U.S. Patent No. 7,166,617.

Example 1: Preparation of Roluperidone HC1

[00114] 2.02 grams of Roluperidone was dissolved in acetone (80 mL). 2.76 mL of HC1 (2M) was added to the solution. The obtained suspension was stirred for 21 hours at 10°C and then filtered over black ribbon filter paper under vacuum. Obtained solid was analyzed by PXRD.

References

^ Mestre TA, Zurowski M, Fox SH (April 2013). “5-Hydroxytryptamine 2A receptor antagonists as potential treatment for psychiatric disorders”. Expert Opinion on Investigational Drugs. 22 (4): 411–21. doi:10.1517/13543784.2013.769957. PMID 23409724.
^ Jump up to:^a ^b Ebdrup BH, Rasmussen H, Arnt J, Glenthøj B (September 2011). “Serotonin 2A receptor antagonists for treatment of schizophrenia”. Expert Opinion on Investigational Drugs. 20 (9): 1211–23. doi:10.1517/13543784.2011.601738. PMID 21740279.
^ Köster LS, Carbon M, Correll CU (December 2014). “Emerging drugs for schizophrenia: an update”. Expert Opinion on Emerging Drugs. 19 (4): 511–31. doi:10.1517/14728214.2014.958148. PMID 25234340.
^ “Drug Development in Schizophrenia: Summary and Table”. Pharmaceutical Medicine. 28 (5): 265–271. 2014. doi:10.1007/s40290-014-0070-6. ISSN 1178-2595.
^ “Roluperidone – Minerva Neurosciences”. Adis Insight. Springer Nature Switzerland AG.

Clinical data

Other names	MIN-101; CYR-101; MT-210
Routes of administration	By mouth
Identifiers
IUPAC name [show]
CAS Number	359625-79-9
PubChemCID	9799284
DrugBank	DB13080
ChemSpider	7975049
UNII	4P31I0M3BF
KEGG	D11258
CompTox Dashboard (EPA)	DTXSID10189512
Chemical and physical data
Formula	C₂₂H₂₃F₂N₂O₂
Molar mass	385.435 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [show]
InChI [show]

/////////////////Roluperidone, PHASE 3, ролуперидон , رولوبيريدون , 罗鲁哌酮 , CYR 101, UNII-4P31I0M3BF , MIN 101,

C1CN(CCC1CN2CC3=CC=CC=C3C2=O)CC(=O)C4=CC=C(C=C4)F

Odevixibat

September 14, 2020 2:51 am / Leave a comment

Odevixibat

A-4250, AR-H 064974

CAS 501692-44-0

BUTANOIC ACID, 2-(((2R)-2-((2-((3,3-DIBUTYL-2,3,4,5-TETRAHYDRO-7-(METHYLTHIO)-1,1-DIOXIDO-5-PHENYL-1,2,5-BENZOTHIADIAZEPIN-8-YL)OXY)ACETYL)AMINO)-2-(4-HYDROXYPHENYL)ACETYL)AMINO)-, (2S)-

(2S)-2-[[(2R)-2-[[2-[(3,3-dibutyl-7-methylsulfanyl-1,1-dioxo-5-phenyl-2,4-dihydro-1λ⁶,2,5-benzothiadiazepin-8-yl)oxy]acetyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]butanoic acid

Molecular Formula	C37H48N4O8S2
Molecular Weight	740.929

- Bylvay
- New Drug Application (NDA): 215498
  Company: ALBIREO PHARMA INC

AZD8294 WHO 10706 AR-H064974 HY-109120 CS-0078340 D11716 US9694018, 5Originator Albireo AB
Developer Albireo AB; Albireo Pharma
ClassAcetamides; Butyric acids; Hepatoprotectants; Small molecules; Sulfones; Thiazepines
Mechanism of Action Sodium-bile acid cotransporter inhibitors

Orphan Drug Status Yes – Primary biliary cirrhosis; Biliary atresia; Intrahepatic cholestasis; Alagille syndrome
New Molecular Entity Yes

Phase III Biliary atresia; Intrahepatic cholestasis
Phase II Alagille syndrome; Cholestasis; Primary biliary cirrhosis
No development reported Non-alcoholic steatohepatitis

22 Jul 2020 Albireo initiates an expanded-access programme for Intrahepatic cholestasis in USA, Canada, Australia and Europe
14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Belgium (PO) after July 2020 (EudraCT2019-003807-37)
14 Jul 2020 Phase-III clinical trials in Biliary atresia (In infants, In neonates) in Germany, France, United Kingdom, Hungary (PO) (EudraCT2019-003807-37)

UPDATE Bylvay, FDA APPROVED2021/7/20 AND EMA 2021/7/16

Odevixibat, sold under the trade name Bylvay, is a medication for the treatment of progressive familial intrahepatic cholestasis (PFIC).^[1]

The most common side effects include diarrhea, abdominal pain, hemorrhagic diarrhea, soft feces, and hepatomegaly (enlarged liver).^[1]

Odevixibat is a reversible, potent, selective inhibitor of the ileal bile acid transporter (IBAT).^[1]^[2]

In May 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended granting a marketing authorization in the European Union for odevixibat for the treatment of PFIC in people aged six months or older.^[1]^[3]

A-4250 (odevixibat) is a selective inhibitor of the ileal bile acid transporter (IBAT) that acts locally in the gut. Ileum absorbs glyco-and taurine-conjugated forms of the bile salts. IBAT is the first step in absorption at the brush-border membrane. A-4250 works by decreasing the re-absorption of bile acids from the small intestine to the liver, whichreduces the toxic levels of bile acids during the progression of the disease. It exhibits therapeutic intervention by checking the transport of bile acids. Studies show that A-4250 has the potential to decrease the damage in the liver cells and the development of fibrosis/cirrhosis of the liver known to occur in progressive familial intrahepatic cholestasis. A-4250 is a designated orphan drug in the USA for October 2012. A-4250 is a designated orphan drug in the EU for October 2016. A-4250 was awarded PRIME status for PFIC by EMA in October 2016. A-4250 is in phase II clinical trials by Albireo for the treatment of primary biliary cirrhosis (PBC) and cholestatic pruritus. In an open label Phase 2 study in children with cholestatic liver disease and pruritus, odevixibat showed reductions in serum bile acids and pruritus in most patients and exhibited a favorable overall tolerability profile.

Odevixibat is a highly potent, non-systemic ileal bile acid transport inhibitor (IBATi) that has has minimal systemic exposure and acts locally in the small intestine. Albireo is developing odevixibat to treat rare pediatric cholestatic liver diseases, including progressive familial intrahepatic cholestasis, biliary atresia and Alagille syndrome.

With normal function, approximately 95 percent of bile acids released from the liver into the bile ducts to aid in liver function are recirculated to the liver via the IBAT in a process called enterohepatic circulation. In people with cholestatic liver diseases, the bile flow is interrupted, resulting in elevated levels of toxic bile acids accumulating in the liver and serum. Accordingly, a product capable of inhibiting the IBAT could lead to a reduction in bile acids returning to the liver and may represent a promising approach for treating cholestatic liver diseases.

The randomized, double-blind, placebo-controlled, global multicenter PEDFIC 1 Phase 3 clinical trial of odevixibat in 62 patients, ages 6 months to 15.9 years, with PFIC type 1 or type 2 met its two primary endpoints demonstrating that odevixibat reduced serum bile acids (sBAs) (p=0.003) and improved pruritus (p=0.004), and was well tolerated with a low single digit diarrhea rate. These topline data substantiate the potential for odevixibat to be first drug for PFIC patients. The Company intends to complete regulatory filings in the EU and U.S. no later than early 2021, in anticipation of regulatory approval, issuance of a rare pediatric disease priority review voucher and launch in the second half of 2021.

Odevixibat is being evaluated in the ongoing PEDFIC 2 open-label trial (NCT03659916) designed to assess long-term safety and durability of response in a cohort of patients rolled over from PEDFIC 1 and a second cohort of PFIC patients who are not eligible for PEDFIC 1.

Odevixibat is also currently being evaluated in a second Phase 3 clinical trial, BOLD (NCT04336722), in patients with biliary atresia. BOLD, the largest prospective intervention trial ever conducted in biliary atresia, is a double-blind, randomized, placebo-controlled trial which will enroll approximately 200 patients at up to 75 sites globally to evaluate the efficacy and safety of odevixibat in children with biliary atresia who have undergone a Kasai procedure before age three months. The company also anticipates initiating a pivotal trial of odevixibat for Alagille syndrome by the end of 2020.

For more information about the PEDFIC 2 or BOLD studies, please visit ClinicalTrials.gov or contact medinfo@albireopharma.com.

The odevixibat PFIC program, or elements of it, have received fast track, rare pediatric disease and orphan drug designations in the United States. In addition, the FDA has granted orphan drug designation to odevixibat for the treatment of Alagille syndrome, biliary atresia and primary biliary cholangitis. The EMA has granted odevixibat orphan designation, as well as access to the PRIority MEdicines (PRIME) scheme for the treatment of PFIC. Its Paediatric Committee has agreed to Albireo’s odevixibat Pediatric Investigation Plan for PFIC. EMA has also granted orphan designation to odevixibat for the treatment of biliary atresia, Alagille syndrome and primary biliary cholangitis.

PATENT

https://patents.google.com/patent/US9694018B1/en

Example 5

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine, Mw. 740.94.

This compound is prepared as described in Example 29 of WO3022286.

PATENT

https://patents.google.com/patent/WO2003022286A1/sv

Example 29

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-((R)-α-[N-((S)- 1-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine

A solution of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (Example 18; 0.075 g, 0.114 mmol), butanoic acid, 2-amino-, 1,1-dimethylethyl ester, hydrochloride, (2S)-(0.031 g, 0.160 mmol) and Ν-methylmorpholine (0.050 ml, 0.457 mmol) in DMF (4 ml) was stirred at RT for 10 min, after which TBTU (0.048 g, 0.149 mmol) was added. After 1h, the conversion to the ester was complete. M/z: 797.4. The solution was diluted with toluene and then concentrated. The residue was dissolved in a mixture of DCM (5 ml) and TFA (2 ml) and the mixture was stirred for 7h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-60% MeCΝ in 0.1M ammonium acetate buffer as eluent. The title compound was obtained in 0.056 g (66 %) as a white solid. ΝMR (400 MHz, DMSO-d₆): 0.70 (3H, t), 0.70-0.80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.80 (2H, brs), 4.00-4.15 (1H, m), 4.65 (1H, d(AB)), 4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.65-7.40 (11H, m), 8.35 (1H, d), 8.50 (1H, d) 9.40 (1H, brs).

PATENT

https://patents.google.com/patent/US20140323412A1/en

PATENT

https://patents.google.com/patent/WO2013063526A1/e

PATENT

https://patents.google.com/patent/WO2019245448A1/en

The compound l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(A/-{(R)-a-[A/-((S)-l-carboxypropyl) carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-l,2,5-benzothiadiazepine (odevixibat; also known as A4250) is disclosed in WO 03/022286. The structure of odevixibat is shown below.

As an inhibitor of the ileal bile acid transporter (IBAT) mechanism, odevixibat inhibits the natural reabsorption of bile acids from the ileum into the hepatic portal circulation. Bile acids that are not reabsorbed from the ileum are instead excreted into the faeces. The overall removal of bile acids from the enterohepatic circulation leads to a decrease in the level of bile acids in serum and the liver. Odevixibat, or a pharmaceutically acceptable salt thereof, is therefore useful in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases, and especially liver diseases that are associated with elevated bile acid levels.

According to the experimental section of WO 03/022286, the last step in the preparation of odevixibat involves the hydrolysis of a tert-butyl ester under acidic conditions. The crude compound was obtained by evaporation of the solvent under reduced pressure followed by purification of the residue by preparative HPLC (Example 29). No crystalline material was identified.

Amorphous materials may contain high levels of residual solvents, which is highly undesirable for materials that should be used as pharmaceuticals. Also, because of their lower chemical and physical stability, as compared with crystalline material, amorphous materials may display faster

decomposition and may spontaneously form crystals with a variable degree of crystallinity. This may result in unreproducible solubility rates and difficulties in storing and handling the material. In pharmaceutical preparations, the active pharmaceutical ingredient (API) is for that reason preferably used in a highly crystalline state. Thus, there is a need for crystal modifications of odevixibat having improved properties with respect to stability, bulk handling and solubility. In particular, it is an object of the present invention to provide a stable crystal modification of odevixibat that does not contain high levels of residual solvents, that has improved chemical stability and can be obtained in high levels of crystallinity.

Example 1

Preparation of crystal modification 1

Absolute alcohol (100.42 kg) and crude odevixibat (18.16 kg) were charged to a 250-L GLR with stirring under nitrogen atmosphere. Purified water (12.71 kg) was added and the reaction mass was stirred under nitrogen atmosphere at 25 ± 5 °C for 15 minutes. Stirring was continued at 25 ± 5 °C for 3 to 60 minutes, until a clear solution had formed. The solution was filtered through a 5.0 m SS cartridge filter, followed by a 0.2 m PP cartridge filter and then transferred to a clean reactor.

Purified water (63.56 kg) was added slowly over a period of 2 to 3 hours at 25 ± 5 °C, and the solution was seeded with crystal modification 1 of odevixibat. The solution was stirred at 25 ± 5 °C for 12 hours. During this time, the solution turned turbid. The precipitated solids were filtered through centrifuge and the material was spin dried for 30 minutes. The material was thereafter vacuum dried in a Nutsche filter for 12 hours. The material was then dried in a vacuum tray drier at 25 ± 5 °C under vacuum (550 mm Hg) for 10 hours and then at 30 ± 5 °C under vacuum (550 mm Hg) for 16 hours. The material was isolated as an off-white crystalline solid. The isolated crystalline material was milled and stored in LDPE bags.

An overhydrated sample was analyzed with XRPD and the diffractogram is shown in Figure 2.

Another sample was dried at 50 °C in vacuum and thereafter analysed with XRPD. The diffractogram of the dried sample is shown in Figure 1.

The diffractograms for the drying of the sample are shown in Figures 3 and 4 for 2Q ranges 5 – 13 ° and 18 – 25 °, respectively (overhydrated sample at the bottom and dry sample at the top).

References

^ Jump up to:^a ^b ^c ^d “First treatment for rare liver disease”. European Medicines Agency (EMA) (Press release). 21 May 2021. Retrieved 21 May 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ “Odevixibat”. Albireo Pharma. Retrieved 21 May 2021.
^ “Bylvay: Pending EC decision”. European Medicines Agency (EMA). 19 May 2021. Retrieved 21 May 2021.

External links

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

ClinicalTrials.gov

CTID	Title	Phase	Status	Date
NCT04336722	Efficacy and Safety of Odevixibat in Children With Biliary Atresia Who Have Undergone a Kasai HPE (BOLD)	Phase 3	Recruiting	2020-09-02
NCT04483531	Odevixibat for the Treatment of Progressive Familial Intrahepatic Cholestasis		Available	2020-08-25
NCT03566238	This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC 1 or 2	Phase 3	Active, not recruiting	2020-03-05
NCT03659916	Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC	Phase 3	Recruiting	2020-01-21
NCT03608319	Study of A4250 in Healthy Volunteers Under Fasting, Fed and Sprinkled Conditions	Phase 1	Completed	2018-09-19

CTID	Title	Phase	Status	Date
NCT02630875	A4250, an IBAT Inhibitor in Pediatric Cholestasis	Phase 2	Completed	2018-03-29
NCT02360852	IBAT Inhibitor A4250 for Cholestatic Pruritus	Phase 2	Terminated	2017-02-23
NCT02963077	A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384	Phase 1	Completed	2016-11-16

EU Clinical Trials Register

EudraCT	Title	Phase	Status	Date
2019-003807-37	A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Odevixibat (A4250) in Children with Biliary Atresia Who Have Undergone a Kasai Hepatoportoenterostomy (BOLD)	Phase 3	Ongoing	2020-07-29
2015-001157-32	An Exploratory Phase II Study to demonstrate the Safety and Efficacy of A4250	Phase 2	Completed	2015-05-13
2014-004070-42	An Exploratory, Phase IIa Cross-Over Study to Demonstrate the Efficacy	Phase 2	Ongoing	2014-12-09
2017-002325-38	An Open-label Extension Study to Evaluate Long-term Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 2)	Phase 3	Ongoing
2017-002338-21	A Double-Blind, Randomized, Placebo-Controlled, Phase 3 Study to Demonstrate Efficacy and Safety of A4250 in Children with Progressive Familial Intrahepatic Cholestasis Types 1 and 2 (PEDFIC 1)	Phase 3	Ongoing, Completed

Odevixibat
Clinical data

Trade names	Bylvay
Routes of administration	By mouth
ATC code	None
Identifiers
show IUPAC name
CAS Number	501692-44-0
PubChem CID	10153627
IUPHAR/BPS	11194
DrugBank	DB16261
ChemSpider	8329135
UNII	2W150K0UUC
KEGG	D11716
ChEMBL	ChEMBL4297588
Chemical and physical data
Formula	C₃₇H₄₈N₄O₈S₂
Molar mass	740.93 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

////////////odevixibat, Orphan Drug Status, phase 3, Albireo, A-4250, A 4250, AR-H 064974

CCCCC1(CN(C2=CC(=C(C=C2S(=O)(=O)N1)OCC(=O)NC(C3=CC=C(C=C3)O)C(=O)NC(CC)C(=O)O)SC)C4=CC=CC=C4)CCCC

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CILOFEXOR

September 5, 2020 4:53 am / Leave a comment

Cilofexor Chemical Structure

CILOFEXOR

C₂₈H₂₂Cl₃N₃O₅ ,

586.8 g/mol

1418274-28-8

GS-9674, Cilofexor (GS(c)\9674)

UNII-YUN2306954

YUN2306954

2-[3-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-oxazol-4-yl]methoxy]phenyl]-3-hydroxyazetidin-1-yl]pyridine-4-carboxylic acid

Cilofexor is under investigation in clinical trial NCT02943447 (Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis).

Cilofexor (GS-9674) is a potent, selective and orally active nonsteroidal FXR agonist with an EC₅₀ of 43 nM. Cilofexor has anti-inflammatory and antifibrotic effects. Cilofexor has the potential for primary sclerosing cholangitis (PSC) and nonalcoholic steatohepatitis (NASH) research.

Gilead , following a drug acquisition from Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022.

PATENT

Product case WO2013007387 , expiry EU in 2032 and in the US in 2034.

https://patents.google.com/patent/WO2013007387A1/en

Figure imgf000039_0001

PATENT

WO2020150136 claiming 2,6-dichloro-4-fluorophenyl compounds.

PATENT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020172075&tab=PCTDESCRIPTION&_cid=P20-KEP1ZU-65392-1

WO-2020172075

Novel crystalline forms of cilofexor as FXR agonists useful for treating nonalcoholic steatohepatitis. Gilead , following a drug acquisition from Phenex , is developing cilofexor tromethamine (formerly GS-9674), the lead from a program of farnesoid X receptor (FXR; bile acid receptor) agonists, for the potential oral treatment of non-alcoholic steatohepatitis (NASH), primary biliary cholangitis/cirrhosis (PBC) and primary sclerosing cholangitis. In March 2019, a phase III trial was initiated for PSC; at that time, the trial was expected to complete in August 2022. Family members of the cilofexor product case WO2013007387 , expire in the EU in 2032 and in the US in 2034.

solid forms of compounds that bind to the NR1H4 receptor (FXR) and act as agonists or modulators of FXR. The disclosure further relates to the use of the solid forms of such compounds for the treatment and/or prophylaxis of diseases and/or conditions through binding of said nuclear receptor by said compounds.

[0004] Compounds that bind to the NR1H4 receptor (FXR) can act as agonists or modulators of FXR. FXR agonists are useful for the treatment and/or prophylaxis of diseases and conditions through binding of the NR1H4 receptor. One such FXR agonist is the compound of Formula I:

[0005] Although numerous FXR agonists are known, what is desired in the art are physically stable forms of the compound of Formula I, or pharmaceutically acceptable salt thereof, with desired properties such as good physical and chemical stability, good aqueous solubility and good bioavailability. For example, pharmaceutical compositions are desired that address

challenges of stability, variable pharmacodynamics responses, drug-drug interactions, pH effect, food effects, and oral bioavailability.

[0006] Accordingly, there is a need for stable forms of the compound of Formula I with suitable chemical and physical stability for the formulation, therapeutic use, manufacturing, and storage of the compound.

[0007] Moreover, it is desirable to develop a solid form of Formula I that may be useful in the synthesis of Formula I. A solid form, such as a crystalline form of a compound of Formula I may be an intermediate to the synthesis of Formula F A solid form may have properties such as bioavailability, stability, purity, and/or manufacturability at certain conditions that may be suitable for medical or pharmaceutical uses.

Description

IC₅₀ & Target

EC50: 43 nM (FXR)^[1]

In Vivo

Cilofexor (GS-9674; 30 mg/kg; oral gavage; once daily; for 10 weeks; male Wistar rats) treatment significantly increases Fgf15 expression in the ileum and decreased Cyp7a1 in the liver in nonalcoholic steatohepatitis (NASH) rats. Liver fibrosis and hepatic collagen expression are significantly reduced. Cilofexor also significantly reduces hepatic stellate cell (HSC) activation and significantly decreases portal pressure, without affecting systemic hemodynamics^[3].

Animal Model:	Male Wistar rats received a choline-deficient high fat diet (CDHFD)^[3]
Dosage:	30 mg/kg
Administration:	Oral gavage; once daily; for 10 weeks
Result:	Significantly increased Fgf15 expression in the ileum and decreased Cyp7a1 in the liver. Liver fibrosis and hepatic collagen expression were significantly reduced.

Clinical Trial

NCT Number	Sponsor	Condition	Start Date	Phase
NCT02943460	Gilead Sciences	Primary Sclerosing Cholangitis	November 29, 2016	Phase 2
NCT02808312	Gilead Sciences	Nonalcoholic Steatohepatitis (NASH)	July 13, 2016	Phase 1
NCT02781584	Gilead Sciences	Nonalcoholic Steatohepatitis (NASH)\|Nonalcoholic Fatty Liver Disease (NAFLD)	July 13, 2016	Phase 2
NCT02943447	Gilead Sciences	Primary Biliary Cholangitis	December 1, 2016	Phase 2
NCT03987074	Gilead Sciences\|Novo Nordisk A+S	Nonalcoholic Steatohepatitis	July 29, 2019	Phase 2
NCT03890120	Gilead Sciences	Primary Sclerosing Cholangitis	March 27, 2019	Phase 3
NCT02854605	Gilead Sciences	Nonalcoholic Steatohepatitis (NASH)	October 26, 2016	Phase 2
NCT03449446	Gilead Sciences	Nonalcoholic Steatohepatitis	March 21, 2018	Phase 2
NCT02654002	Gilead Sciences	Nonalcoholic Steatohepatitis (NASH)	January 2016	Phase 1

Patent ID	Title	Submitted Date
US2019142814	Novel FXR (NR1H4) binding and activity modulating compounds	2019-01-15
US2019055273	ACYCLIC ANTIVIRALS	2017-03-09
US10220027	FXR (NR1H4) binding and activity modulating compounds	2017-10-13
US10071108	Methods and pharmaceutical compositions for the treatment of hepatitis b virus infection	2018-02-19
US2018000768	INTESTINAL FXR AGONISM ENHANCES GLP-1 SIGNALING TO RESTORE PANCREATIC BETA CELL FUNCTIONS	2017-09-06

Patent ID	Title	Submitted Date	Granted Date
US9820979	NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS	2016-12-05
US9539244	NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS	2015-08-12	2015-12-03
US9895380	METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTION	2014-09-10	2016-08-04
US2017355693	FXR (NR1H4) MODULATING COMPOUNDS	2017-06-12
US2016376279	FXR AGONISTS AND METHODS FOR MAKING AND USING	2016-09-12

Patent ID	Title	Submitted Date	Granted Date
US9139539	NOVEL FXR (NR1H4) BINDING AND ACTIVITY MODULATING COMPOUNDS	2012-07-12	2014-08-07
US2018133203	METHODS OF TREATING LIVER DISEASE	2017-10-27

ClinicalTrials.gov

CTID	Title	Phase	Status	Date
NCT03890120	Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Adults With Primary Sclerosing Cholangitis	Phase 3	Recruiting	2020-08-31
NCT02781584	Safety, Tolerability, and Efficacy of Selonsertib, Firsocostat, and Cilofexor in Adults With Nonalcoholic Steatohepatitis (NASH)	Phase 2	Recruiting	2020-08-13
NCT03987074	Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Adults With Nonalcoholic Steatohepatitis (NASH)	Phase 2	Completed	2020-07-29
NCT02943460	Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Sclerosing Cholangitis Without Cirrhosis	Phase 2	Completed	2020-06-09
NCT02943447	Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Biliary Cholangitis Without Cirrhosis	Phase 2	Completed	2020-02-11

ClinicalTrials.gov

CTID	Title	Phase	Status	Date
NCT03449446	Safety and Efficacy of Selonsertib, Firsocostat, Cilofexor, and Combinations in Participants With Bridging Fibrosis or Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH)	Phase 2	Completed	2019-12-24
NCT02854605	Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Participants With Nonalcoholic Steatohepatitis (NASH)	Phase 2	Completed	2019-01-29
NCT02808312	Pharmacokinetics and Pharmacodynamics of GS-9674 in Adults With Normal and Impaired Hepatic Function	Phase 1	Completed	2018-10-30
NCT02654002	Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674, and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics	Phase 1	Completed	2016-07-27

EU Clinical Trials Register

EudraCT	Title	Phase	Status	Date
2019-000204-14	A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects with Primary Sclerosing Cholangitis	Phase 3	Restarted, Ongoing	2019-09-11
2016-002496-10	A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH)	Phase 2	Completed	2017-02-21
2016-002443-42	A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Biliary Cholangitis Without Cirrhosis	Phase 2	Completed	2017-01-09
2016-002442-23	A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Primary Sclerosing Cholangitis Without Cirrhosis	Phase 2	Completed	2017-01-09

///////////CILOFEXOR, Cilofexor (GS(c)\9674), GS-9674, phase 3

C1CC1C2=C(C(=NO2)C3=C(C=CC=C3Cl)Cl)COC4=CC(=C(C=C4)C5(CN(C5)C6=NC=CC(=C6)C(=O)O)O)Cl

Desidustat

July 9, 2020 4:52 am / Leave a comment

Ranjit Desai

Inventor of Oxemia (Desidustat), a breakthrough PHD inhibitor approved for Chronic Kidney Diseases (CKD) / Accomplished pharma executive / 4 INDs in 4 years, ZYDUS LIFESCIENCES

DESIDUSTAT

Formal Name

N-[[1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl]carbonyl]-glycine

CAS Number 1616690-16-4

Molecular Formula C₁₆H₁₆N₂O₆

Formula Weight 332.3

FormulationA crystalline solid

λ_max233, 291, 335

2-(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetic acid

desidustat

Glycine, N-((1-(cyclopropylmethoxy)-1,2-dihydro-4-hydroxy-2-oxo-3-quinolinyl)carbonyl)-

N-(1-(Cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine

ZYAN1 compound

(1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Desidustat | C16H16N2O6 - PubChem

Oxemia (Desidustat) has received approval from the Drug Controller General of India. This was an incredible team effort by Zydans across the organization and I am so proud of what we have accomplished. Oxemia is a breakthrough treatment for Anemia associated with Chronic Kidney Disease in Patients either on Dialysis or Not on Dialysis, and will help improve quality of life for CKD patients. Team #zydus , on to our next effort!

Desidustat (INN, also known as ZYAN1) is a drug for the treatment of anemia of chronic kidney disease. This drug with the brand name Oxemia is discovered and developed by Zydus Life Sciences.^[1] The subject expert committee of CDSCO has recommended the grant of permission for manufacturing and marketing of Desidustat 25 mg and 50 mg tablets in India,based on some conditions related to package insert, phase 4 protocols, prescription details, and GCP.^[2] Clinical trials on desidustat have been done in India and Australia.^[3] In a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study, a mean hemoglobin increase of 1.57, 2.22, and 2.92 g/dL in desidustat 100, 150, and 200 mg arms, respectively, was observed.^[4] The Phase 3 clinical trials were conducted at additional lower doses as of 2019.^[5] Desidustat is developed for the treatment of anemia as an oral tablet, where currently injections of erythropoietin and its analogues are drugs of choice. Desidustat is a HIF prolyl-hydroxylase inhibitor. In preclinical studies, effects of desidustat was assessed in normal and nephrectomized rats, and in chemotherapy-induced anemia. Desidustat demonstrated hematinic potential by combined effects on endogenous erythropoietin release and efficient iron utilization.^[6]^[7] Desidustat can also be useful in treatment of anemia of inflammation since it causes efficient erythropoiesis and hepcidin downregulation.^[8] In January 2020, Zydus entered into licensing agreement with China Medical System (CMS) Holdings for development and commercialization of desidustat in Greater China. Under the license agreement, CMS will pay Zydus an initial upfront payment, regulatory milestones, sales milestones and royalties on net sales of the product. CMS will be responsible for development, registration and commercialization of desidustat in Greater China.^[9] It has been observed that desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines like IL-6 and oxidative stress ^[10] A clinical trial to evaluate the efficacy and safety of desidustat tablet for the management of Covid-19 patients is ongoing in Mexico, wherein desidustat has shown to prevent acute respiratory distress syndrome (ARDS) by inhibiting IL-6.^[11] Zydus has also received approval from the US FDA to initiate clinical trials of desidustat in chemotherapy Induced anemia (CIA).^[12]. Desidustat has met the primary endpoints in the phase 3 clinical trials and Zydus had filed the New Drug Application (NDA) to DCGI in November, 2021.^[13]\

CLIP

https://www.businesstoday.in/industry/pharma/story/zydus-receives-dcgi-approval-for-new-drug-oxemia-what-you-need-to-know-324966-2022-03-07

Zydus receives DCGI approval for new drug Oxemia; what you need to know

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, Zydus said in a statement.

Gujarat-based pharma company Zydus Lifesciences on Monday received the Drugs Controller General of India (DCGI) approval for its new drug application for a first-of-its-kind oral treatment for anemia associated with Chronic Kidney Disease (CKD) – Oxemia (Desidustat).

The new drug is an oral, small molecule hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor, the drug firm said in a statement.

Desidustat showed good safety profile, improved iron mobilization and LDL-C reduction in CKD patients in DREAM-D and DREAM-ND Phase III clinical trials, conducted in approximately 1,200 subjects. Desidustat provides CKD patients with an oral convenient therapeutic option for the treatment of anemia. The pharma major did not, however, declare the cost per dose if the drug is available in the market.

“After more than a decade of research and development into the science of HIF-PH inhibitors, results have demonstrated that Oxemia addresses this unmet need and additionally reduces hepcidin, inflammation and enables better iron mobilization. This advancement offers ease of convenience for the patient and will also reduce the disease burden by providing treatment at an affordable cost, thereby improving the quality of life for patients suffering from Chronic Kidney Disease,” Chairman of Zydus Lifesciences Pankaj Patel said.

Chronic Kidney Disease (CKD) is a progressive medical condition characterised by a gradual loss of kidney function and is accompanied by comorbidities like anemia, cardiovascular diseases (hypertension, heart failure and stroke), diabetes mellitus, eventually leading to kidney failure.

PATENT

US277539705

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=C922CC7937C0B6D7F987FE395E8B6F34.wapp2nB?docId=US277539705&_cid=P21-KCEB8C-83913-1

Patent applications WO 2004041818, US 20040167123, US 2004162285, US 20040097492 and US 20040087577 describes the utility of N-arylated hydroxylamines of formula (IV), which are intermediates useful for the synthesis of certain quinolone derivatives (VI) as inhibitors of hepatitis C (HCV) polymerase useful for the treatment of HCV infection. In these references, the compound of formula (IV) was prepared using Scheme 1 which involves partial reduction of nitro group and subsequent O-alkylation using sodium hydride as a base.

(MOL) (CDX)

The patent application WO 2014102818 describes the use of certain quinolone based compound of formula (I) as prolyl hydroxylase inhibitors for the treatment of anemia. Compound of formula (I) was prepared according to scheme 2 which involved partial reduction of nitro group and subsequent O-alkylation using cesium carbonate as a base.

(MOL) (CDX)

The drawback of process disclosed in WO 2014102818 (Scheme 2) is that it teaches usage of many hazardous reagents and process requires column chromatographic purification using highly flammable solvent at one of the stage and purification at multi steps during synthesis, which is not feasible for bulk production.

Scheme 3:

(MOL) (CDX)

Scheme 4.

(MOL) (CDX)

The process for the preparation of compound of formula (I-a) comprises the following steps:

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, Ethanol (1.25 L) charged at room temperature. 2-iodobenzoic acid (250 g, 1.00 mol) was added in one lot at room temperature. Sulphuric acid (197.7 g, 2.01 mol) was added carefully in to reaction mixture at 20 to 35° C. The reaction mixture was heated to 80 to 85° C. Reaction mixture was stirred for 20 hours at 80 to 85° C. After completion of reaction distilled out ethanol at below 60° C. The reaction mixture was cooled down to room temperature. Water (2.5 L) was then added carefully at 20 to 35° C. The reaction mixture was then charged with Ethyl acetate (1.25 L). After complete addition of ethyl acetate, reaction mixture turned to clear solution. At room temperature it was stirred for 5 to 10 minutes and separated aqueous layer. Aqueous layer then again extracted with ethyl acetate (1.25 L) and separated aqueous layer. Combined organic layer then washed with twice 10% sodium bicarbonate solution (2×1.25 L) and twice process water (2×1.25L) and separated aqueous layer. Organic layer then washed with 30% brine solution (2.5 L) and separated aqueous layer. Concentrated ethyl acetate in vacuo to get ethyl 2-iodobenzoate in 95% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 248.75 (M+H). ¹H NMR (CDCl ₃): 1.41-1.37 (t, 3H), 4.41-4.35 (q, 2H), 7.71-7.09 (m, 1H), 7.39-7.35 (m, 1H), 7.94-7.39 (m, 1H), 7.96-7.96 (d, 1H). HPLC Purity: 99.27%

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, toluene (1.5 L) was charged at room temperature. Copper (I) iodide (15.3 g, 0.08 mol) was added in one lot at room temperature. Glycine (39.1 g, 0.520 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Ethyl 2-iodobenzoate (221.2 g, 0.801 mol) was added in one lot at room temperature. Tert-butyl (cyclopropylmethoxy)carbamate (150 g, 0.801 mol) was added in one lot at room temperature. Reaction mixture was stirred for 20 minutes at room temperature. Potassium carbonate (885.8 g, 6.408 mol) and ethanol (0.9 L) were added at 25° C. to 35° C. Reaction mixture was stirred for 30 minutes. The reaction mixture was refluxed at 78 to 85° C. for 24 hours. Reaction mixture was cooled to room temperature and stirred for 30 minutes. The reaction mixture was then charged with ethyl acetate (1.5 L). After complete addition of ethyl acetate, reaction mixture turned to thick slurry. At room temperature it was stirred for 30 minutes and the solid inorganic material was filtered off through hyflow supercel bed. Inorganic solid impurity was washed with ethyl acetate (1.5 L), combined ethyl acetate layer was washed with twice water (2×1.5 L) and separated aqueous layer. Organic layer washed with 30% sodium chloride solution (1.5 L) and separated aqueous layer. Ethyl acetate was concentrated in vacuo to get ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate in 89% yield, as an oil, which was used in next the reaction, without any further purification. MS (ESI-MS): m/z 357.93 (M+Na). ¹H NMR (CDCl ₃): 0.26-0.23 (m, 2H), 0.52-0.48 (m, 2H), 1.10-1.08 (m, 1H), 1.38-1.35 (t, 3H), 1.51 (s, 9H), 3.78-3.76 (d, J=7.6 Hz, 2H), 4.35-4.30 (q, J=6.8 Hz, 2H), 7.29-7.25 (m, 1H), 7.49-7.47 (m, 2H), 7.78-7.77 (d, 1H). HPLC Purity: 88.07%

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

(MOL) (CDX)

In a 10 L fixed glass assembly, dichloromethane (2.4 L) was charged at room temperature. Ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)amino)benzoate (200 g, 0.596 mol) was charged and cooled externally with ice-salt at 0 to 10° C. Methanolic HCl (688.3 g, 3.458 mol, 18.34% w/w) solution was added slowly drop wise, over a period of 15 minutes, while maintaining internal temperature below 10° C. Reaction mixture was warmed to 20 to 30° C., and stirred at 20 to 30° C. for 3 hours. The reaction mixture was quenched with addition of water (3.442 L). Upon completion of water addition, the reaction mixture turn out to light yellow coloured solution. At room temperature it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with Dichloromethane (0.8 L). Combined dichloromethane layer then washed with 20% sodium chloride solution (1.0 L) and separated aqueous layer. Concentrated dichloromethane vacuo to get Ethyl 2-((cyclopropylmethoxy)amino)benzoate in 92% yield, as an oil. MS (ESI-MS): m/z 235.65 (M+H) ⁺. ¹H NMR (CDCl ₃): 0.35-0.31 (m, 2H), 0.80-0.59 (m, 2H), 0.91-0.85 (m, 1H), 1.44-1.38 (t, 3H), 3.76-3.74 (d, 2H), 4.36-4.30 (q, 2H), 6.85-6.81 (t, 1H), 7.36-7.33 (d, 1H), 7.92-7.43 (m, 1H), 7.94-7.93 (d, 1H), 9.83 (s, 1H). HPLC Purity: 87.62%

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

(MOL) (CDX)

In a 2 L fixed glass assembly, Acetonitrile (0.6 L) was charged at room temperature. Ethyl 2-((cyclopropylmethoxy)amino)benzoate (120 g, 0.510 mol) was charged at room temperature. Ethyl hydrogen malonate (74.1 g, 0.561 mol) was charged at room temperature. Pyridine (161.4 g, 2.04 mol) was added carefully in to reaction mass at room temperature and cooled externally with ice-salt at 0 to 10° C. Phosphorous oxychloride (86.0 g, 0.561 mol) was added slowly drop wise, over a period of 2 hours, while maintaining internal temperature below 10° C. Reaction mixture was stirred at 0 to 10° C. for 45 minutes. The reaction mixture was quenched with addition of water (1.0 L). Upon completion of water addition, the reaction mixture turns out to dark red coloured solution. Dichloromethane (0.672 L) was charged at room temperature and it was stirred for another 15 minutes and separated aqueous layer. Aqueous layer was again extracted with dichloromethane (0.672 L). Combined dichloromethane layer then washed with water (0.400 L) and 6% sodium chloride solution (0.400 L) and separated aqueous layer. Mixture of acetonitrile and dichloromethane was concentrated in vacuo to get Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate in 95% yield, as an oil. MS (ESI-MS): m/z 350.14 (M+H) ^l. ¹H NMR (DMSO-d ₆): 0.3-0.2 (m, 2H), 0.6-0.4 (m, 2H), 1.10-1.04 (m, 1H), 1.19-1.15 (t, 3H), 1.29-1.25 (t, 3H), 3.72-3.70 (d, 2H), 3.68 (s, 2H), 4.17-4.12 (q, 2H), 4.25-4.19 (q, 2H), 7.44-7.42 (d, 1H), 7.50-7.46 (t, 1H), 7.68-7.64 (m, 1H), 7.76-7.74 (d, 1H). HPLC Purity: 86.74%

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

(MOL) (CDX)

In a 10 L fixed glass assembly under Nitrogen atmosphere, Methanol (0.736 L) was charged at room temperature. Ethyl 2-(N-(cyclopropylmethoxy)-3-ethoxy-3-oxopropanamido)benzoate (160 g, 0.457 mol) was charged at room temperature. Sodium methoxide powder (34.6 g, 0.641 mol) was added portion wise, over a period of 30 minutes, while maintaining internal temperature 10 to 20° C. Reaction mixture was stirred at 10 to 20° C. for 30 minutes. The reaction mixture was quenched with addition of ˜1N aqueous hydrochloric acid solution (0.64 L) to bring pH 2, over a period of 20 minutes, while maintaining an internal temperature 10 to 30° C. Upon completion of aqueous hydrochloric acid solution addition, the reaction mixture turned to light yellow coloured slurry. Diluted the reaction mass with water (3.02 L) and it was stirred for another 1 hour. Solid material was filtered off and washed twice with water (2×0.24 L). Dried the compound in fan dryer at temperature 50 to 55° C. for 6 hours to get crude ethyl 1-(cyclopropylmetboxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate as a solid.

Purification

In a 10 L fixed glass assembly, DMF (0.48 L) was charged at room temperature. Crude ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (120 g) was charged at room temperature. Upon completion of addition of crude compound, clear reaction mass observed. Reaction mixture stirred for 30 minutes at room temperature. Precipitate the product by addition of water (4.8 L), over a period of 30 minutes, while maintaining an internal temperature 25 to 45° C. Upon completion of addition of water, the reaction mixture turned to light yellow colored slurry. Reaction mixture was stirred at 25 to 45° C. for 30 minutes. Solid material was filtered off and washed with water (0.169 L). Dried the product in fan dryer at temperature 50 to 55° C. for 6 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 81% yield, as a solid. MS (ESI-MS): m/z 303.90 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.37-0.35 (m, 2H), 0.59-0.55 (m, 2H), 1.25-1.20 (m, 1H), 1.32-1.29 (t, 3H), 3.97-3.95 (d, 2H), 4.36-4.31 (q, 2H), 7.35-7.31 (in, 1H), 7.62-7.60 (dd, 1H), 7.81-7.77 (m, 1H), 8.06-7.04 (dd, 1H). HPLC Purity: 95.52%

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, tetrahydrofuran (0.5 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (100 g, 0.329 mol) was charged at room temperature. Glycine ethyl ester HCl (50.7 g, 0.362 mol) was charged at room temperature. N,N-Diisopropylethyl amine (64 g, 0.494 mol) was added carefully in to reaction mass at room temperature and heated the reaction mass at 65 to 70° C. Reaction mixture was stirred at 65 to 70° C. for 18 hours. The reaction mixture was quenched with addition of water (2.5 L).

Upon completion of water addition, the reaction mixture turns out to off white to yellow coloured slurry. Concentrated tetrahydrofuran below 55° C. in vacuo and reaction mixture was stirred at 25 to 35° C. for 1 hour. Solid material was filtered off and washed with water (3×0.20 L). Dried the compound in fan dryer at temperature 55 to 60° C. for 8 hours to get crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate as a solid.

Purification

In a 2 L fixed glass assembly, Methanol (1.15 L) was charged at room temperature. Crude ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (100 g) was charged at room temperature. The reaction mass was heated to 65 to 70° C. Reaction mass was stirred for 1 h at 65 to 70° C. Removed heating and cool the reaction mass to 25 to 35° C. Reaction mass stirred for 1 h at 25 to 35° C. Solid material was filtered off and washed with methanol (0.105 L). The product was dried under fan dryer at temperature 55 to 60° C. for 8 hours to get pure ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in 80% yield, as a solid. MS (ESI-MS): m/z 360.85 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.39 (m, 2H), 0.60-0.54 (m, 2H), 1.23-1.19 (t, 3H), 1.31-1.26 (m, 1H), 4.04-4.02 (d, 2H), 4.18-4.12 (q, 2H), 4.20-4.18 (d, 2H), 7.40-7.36 (m, 1H), 7.70-7.68 (d, 1H), 7.87-7.83 (m, 1H), 8.08-8.05 (dd, 1H), 10.27-10.24 (t, 1H). HPLC Purity: 99.84%

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

(MOL) (CDX)

In a 5 L fixed glass assembly, methanol (0.525 L) was charged at room temperature. Ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (75 g, 0.208 mol) was charged at room temperature. Water (0.30 L) was charged at room temperature. Sodium hydroxide solution (20.8 g, 0.520 mol) in water (0.225 L) was added carefully at 30 to 40° C. Upon completion of addition of sodium hydroxide solution, the reaction mass turned to clear solution. Reaction mixture stirred for 30 minutes at 30 to 40° C. Diluted the reaction by addition of water (2.1 L). Precipitate the solid by addition of hydrochloric acid solution (75 mL) in water (75 mL). Upon completion of addition of hydrochloric acid solution, the reaction mass turned to off white colored thick slurry. Reaction mixture was stirred for 1 h at room temperature. Solid material was filtered off and washed with water (4×0.375 L). The compound was dried under fan dryer at temperature 25 to 35° C. for 6 hours and then dried for 4 hours at 50 to 60° C. to get (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl) glycine in 98% yield, as a solid. MS (ESI-MS): m/z 333.05 (M+H) ⁺. ¹H NMR (DMSO-d ₆): 0.44-0.38 (m, 2H), 0.62-0.53 (m, 2H), 1.34-1.24 (m, 1H), 4.06-4.04 (d, 2H), 4.14-4.13 (d, 2H), 7.43-7.39 (t, 1H), 7.72-7.70 (d, 1H), 7.89-7.85 (m, 1H), 8.11-8.09 (dd, 1H), 10.27-10.24 (t, 1H), 12.97 (bs, 1H), 16.99 (s, 1H). HPLC Purity: 99.85%

Polymorphic Data (XRPD):

References[edit]

^ “Zydus receives DCGI approval for new drug Oxemia; what you need to know”.
^ CDSCO, SEC Committee. “SEC meeting to examine IND proposals, dated 29.12.2021”. CDSCO website Govt of India. CDSCO. Retrieved 19 January 2022.
^ Kansagra KA, Parmar D, Jani RH, Srinivas NR, Lickliter J, Patel HV, et al. (January 2018). “Phase I Clinical Study of ZYAN1, A Novel Prolyl-Hydroxylase (PHD) Inhibitor to Evaluate the Safety, Tolerability, and Pharmacokinetics Following Oral Administration in Healthy Volunteers”. Clinical Pharmacokinetics. 57 (1): 87–102. doi:10.1007/s40262-017-0551-3. PMC 5766731. PMID 28508936.
^ Parmar DV, Kansagra KA, Patel JC, Joshi SN, Sharma NS, Shelat AD, Patel NB, Nakrani VB, Shaikh FA, Patel HV; on behalf of the ZYAN1 Trial Investigators. Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study. Am J Nephrol. 2019 May 21;49(6):470-478. doi: 10.1159/000500232.
^ “Zydus Cadila announces phase III clinical trials of Desidustat”. 17 April 2019. Retrieved 20 April 2019 – via The Hindu BusinessLine.
^ Jain MR, Joharapurkar AA, Pandya V, Patel V, Joshi J, Kshirsagar S, et al. (February 2016). “Pharmacological Characterization of ZYAN1, a Novel Prolyl Hydroxylase Inhibitor for the Treatment of Anemia”. Drug Research. 66 (2): 107–12. doi:10.1055/s-0035-1554630. PMID 26367279.
^ Joharapurkar AA, Pandya VB, Patel VJ, Desai RC, Jain MR (August 2018). “Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases”. Journal of Medicinal Chemistry. 61 (16): 6964–6982. doi:10.1021/acs.jmedchem.7b01686. PMID 29712435.
^ Jain M, Joharapurkar A, Patel V, Kshirsagar S, Sutariya B, Patel M, et al. (January 2019). “Pharmacological inhibition of prolyl hydroxylase protects against inflammation-induced anemia via efficient erythropoiesis and hepcidin downregulation”. European Journal of Pharmacology. 843: 113–120. doi:10.1016/j.ejphar.2018.11.023. PMID 30458168. S2CID 53943666.
^ Market, Capital (20 January 2020). “Zydus enters into licensing agreement with China Medical System Holdings”. Business Standard India. Retrieved 20 January 2020 – via Business Standard.
^ Joharapurkar, Amit; Patel, Vishal; Kshirsagar, Samadhan; Patel, Maulik; Savsani, Hardikkumar; Jain, Mukul (22 January 2021). “Prolyl hydroxylase inhibitor desidustat protects against acute and chronic kidney injury by reducing inflammatory cytokines and oxidative stress”. Drug Development Research. 82 (6): 852–860. doi:10.1002/ddr.21792. PMID 33480036. S2CID 231680317.
^ “Zydus’ trials of Desidustat shows positive results for Covid-19 management”. The Hindu Business Line. The Hindu. Retrieved 25 January 2021.
^ “Zydus receives approval from USFDA to initiate clinical trials of Desidustat in cancer patients receiving chemotherapy”. PipelineReview.com. La Merie Publishing. Retrieved 22 January 2021.
^ “Stock Share Price | Get Quote | BSE”.

ANALYSIS

https://patentscope.wipo.int/search/en/result.jsf?inchikey=IKRKQQLJYBAPQT-UHFFFAOYSA-N

Countries

Desidustat
Clinical data

Other names	ZYAN1
Identifiers
IUPAC name [show]
CAS Number	1616690-16-4
UNII	Y962PQA4KS
Chemical and physical data
Formula	C₁₆H₁₆N₂O₆
Molar mass	332.312 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] C1CC1CON2C3=CC=CC=C3C(=C(C2=O)C(=O)NCC(=O)O)O
InChI [hide] InChI=1S/C16H16N2O6/c19-12(20)7-17-15(22)13-14(21)10-3-1-2-4-11(10)18(16(13)23)24-8-9-5-6-9/h1-4,9,21H,5-8H2,(H,17,22)(H,19,20) Key:IKRKQQLJYBAPQT-UHFFFAOYSA-N

Date

CTID	Title	Phase	Status	Date
NCT04215120	Desidustat in the Treatment of Anemia in CKD on Dialysis Patients	Phase 3	Recruiting	2020-01-02
NCT04012957	Desidustat in the Treatment of Anemia in CKD	Phase 3	Recruiting	2019-12-24

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Remdesivir, レムデシビル , ремдесивир , ريمديسيفير , 瑞德西韦 ,

March 12, 2020 9:14 am / Leave a comment

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ChemSpider 2D Image | remdesivir | C27H35N6O8P

Remdesivir

Formula	C27H35N6O8P
CAS	1809249-37-3
Mol weight	602.576

レムデシビル

UNII:3QKI37EEHE

ремдесивир [Russian] [INN]

ريمديسيفير [Arabic] [INN]

瑞德西韦 [Chinese] [INN]

2-Ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydro-2-furanyl]methoxy}(phenoxy)phosphoryl]amino}propanoate (non-preferred name)

L-Alanine, N-((S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-D-altrononitrile

2-Ethylbutyl (2S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

2-Ethylbutyl (2S)-2-[[(S)-[[(2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy]phenoxyphosphoryl]amino]propanoate
2-Ethylbutyl (2S)-2-[[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl]methoxy]phenoxyphosphoryl]amino]propanoate
2-Ethylbutyl N-[(S)-[2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-D-altrononitril-6-O-yl]phenoxyphosphoryl]-L-alaninate
GS 5734
L-Alanine, N-[(S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester,6-ester with 2-C-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-D-altrononitrile

GS-5734

Treatment of viral infections

Phase III, clinical trials for the treatment of hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). National Institute of Allergy and Infectious Diseases (NIAID) is evaluating remdesivir in phase II/III clinical trials for the treatment of Ebola virus infection.

The compound has been evaluated in preclinical studies for the potential treatment of Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV) infections.

Remdesivir is a nucleoside analogue, with effective antiviral activity, with EC₅₀s of 74 nM for ARS-CoV and MERS-CoV in HAE cells, and 30 nM for murine hepatitis virus in delayed brain tumor cells.

Remdesivir (development code GS-5734) is a novel antiviral drug in the class of nucleotide analogs. It was developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections,^[1] though it has subsequently also been found to show antiviral activity against other single stranded RNA viruses such as respiratory syncytial virus, Junin virus, Lassa fever virus, Nipah virus, Hendra virus, and the coronaviruses (including MERS and SARS viruses).^[2]^[3] It is being studied for SARS-CoV-2 and Nipah and Hendra virus infections.^[4]^[5]^[6] Based on success against other coronavirus infections, Gilead provided remdesivir to physicians who treated an American patient in Snohomish County, Washington in 2020, infected with SARS-CoV-2^[7] and is providing the compound to China to conduct a pair of trials in infected individuals with and without severe symptoms.^[8]

Research usage

Laboratory tests suggest remdesivir is effective against a wide range of viruses, including SARS-CoV and MERS-CoV. The medication was pushed to treat the West African Ebola virus epidemic of 2013–2016. Although the drug turned out to be safe, it was not particularly effective against filoviruses such as the Ebola virus.

Ebola virus

Remdesivir was rapidly pushed through clinical trials due to the West African Ebola virus epidemic of 2013–2016, eventually being used in at least one human patient despite its early development stage at the time. Preliminary results were promising and it was used in the emergency setting during the Kivu Ebola epidemic that started in 2018 along with further clinical trials, until August 2019, when Congolese health officials announced that it was significantly less effective than monoclonal antibody treatments such as mAb114 and REGN-EB3. The trials, however, established its safety profile.^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16]

SARS-CoV-2

In response to the 2019–20 coronavirus outbreak induced by coronavirus SARS-CoV-2, Gilead provided remdesivir for a “small number of patients” in collaboration with Chinese medical authorities for studying its effects.^[17]

Gilead also started laboratory testing of remdesivir against SARS-CoV-2. Gilead stated that remdesivir was “shown to be active” against SARS and MERS in animals.^[3]^[18]

In late January 2020, remdesivir was administered to the first US patient to be confirmed to be infected by SARS-CoV-2, in Snohomish County, Washington, for “compassionate use” after he progressed to pneumonia. While no broad conclusions were made based on the single treatment, the patient’s condition improved dramatically the next day,^[7] and he was eventually discharged.^[19]

Also in late January 2020, Chinese medical researchers stated to the media that in exploratory research considering a selection of 30 drug candidates. Remdesivir and two other drugs, chloroquine and lopinavir/ritonavir, seemed to have “fairly good inhibitory effects” on SARS-CoV-2 at the cellular level. Requests to start clinical testing were submitted,^[20]^[21]. On February 6, 2020, a clinical trial of remdesivir began in China.^[22]

Other viruses

The active form of remdesivir, GS-441524, shows promise for treating feline coronavirus.^[23]

Mechanism of action and resistance

Remdesivir is a prodrug that metabolizes into its active form GS-441524. GS-441524 is an adenosine nucleotide analog that confuses viral RNA polymerase and evades proofreading by viral exoribonuclease (ExoN), causing a decrease in viral RNA production. It was unknown whether it terminates RNA chains or causes mutations in them.^[24]However, it has been learned that the RNA dependent RNA polymerase of ebolavirus is inhibited for the most part by delayed chain termination.^[25]

Mutations in the mouse hepatitis virus RNA replicase that cause partial resistance were identified in 2018. These mutations make the viruses less effective in nature, and the researchers believe they will likely not persist where the drug is not being used.^[24]

MORE SYNTHESIS COMING, WATCH THIS SPACE…………………..

SYNTHESIS

Remdesivir can be synthesized in multiple steps from ribose derivatives. The figure below is one of the synthesis route of remdesivir invented by Chun et al. from Gilead Sciences.^[26]In this method, intermediate a is firstly prepared from L-alanine and phenyl phosphorodichloridate in presence of triethylamine and dichloromethane; triple benzyl-protected ribose is oxidized by dimethyl sulfoxide with acetic anhydride and give the lactone intermediate b; pyrrolo[2,1-f][1,2,4]triazin-4-amine is brominated, and the amine group is protected by excess trimethylsilyl chloride. n-Butyllithium undergoes a halogen-lithium exchange reaction with the bromide at -78 °C to yield the intermediate c. The intermediate b is then added to a solution containing intermediate c dropwise. After quenching the reaction in a weakly acidic aqueous solution, a mixture of 1: 1 anomers was obtained. It was then reacted with an excess of trimethylsilyl cyanide in dichloromethane at -78 °C for 10 minutes. Trimethylsilyl triflate was added and reacts for an additional 1 hour, and the mixture was quenched in an aqueous sodium hydrogen carbonate. A nitrile intermediate was obtained. The protective group, benzyl, was then removed with boron trichloride in dichloromethane at -20 °C. The excess of boron trichloride was quenched in a mixture of potassium carbonate and methanol. A benzyl-free intermediate was obtained. The isomers were then separated via reversed-phase HPLC. The optically pure compound and intermediate a are reacted with trimethyl phosphate and methylimidazole to obtain a diastereomer mixture of remdesivir. In the end, optically pure remdesivir can be obtained through methods such as chiral resolution.

The synthesis of Remdesivir was invented by Byoung Kwon Chun et al. from Gilead Sciences, Inc. and claimed in the patent, WO2016069826A1.

中文: 瑞德西韋的合成方法是由吉利德科學公司的 Byoung Kwon Chun等人所發明，並在WO2016069826A1中聲明專利。

PATENT

WO 2018204198

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E7724EB6CA3959303E18B3D392E0219F.wapp1nA?docId=WO2018204198&tab=PCTDESCRIPTION

Prevention and treatment methods for some Arenaviridae , Coronaviridae , Filoviridae, Flaviviridae, and Paramyxoviridae viruses present challenges due to a lack of vaccine or post-exposure treatment modality for preventing or managing these infections. In some cases, patients only receive supportive and resource intensive therapy such as electrolyte and fluid balancing, oxygen, blood pressure maintenance, or treatment for secondary infections. Thus, there is a need for antiviral therapies having a potential for broad antiviral activity.

[0004] The compound (S)-2-ethylbutyl 2-(((S)-(((2R,3 S,4R,5R)-5-(4-aminopyrrolo[2, 1-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate, referred herein as Compound 1 or Formula I, is known to exhibit antiviral properties against Arenaviridae, Coronaviridae, Filoviridae, and

Paramyxoviridae viruses as described in Warren, T. et al., Nature (2016) 531 :381-385 and antiviral activities against Flaviviridae viruses as described in co-pending United States provisional patent application no. 62/325,419 filed April 20, 2016.

[0005] (S)-2-Ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)

propanoate or 2-ethylbutyl ((S)-(((2R,3 S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate, (Formula I), has the following structure:

Formula I

PATENT

WO 2017184668

https://patents.google.com/patent/WO2017184668A1/en

A. Preparation of Compounds

Example 1. (2S)-ethyl 2-(chloro(phenoxy)phosphorylamino)pro anoate (Chloridate A)

[0246] Ethyl alanine ester hydrochloride salt (1.69 g, 11 mmol) was dissolved in anhydrous CH₂CI₂ (10 mL) and the mixture stirred with cooling to 0 °C under N₂(g). Phenyl dichlorophosphate (1.49 mL, 10 mmol) was added followed by dropwise addition of Et₃N over 10 min. The reaction mixture was then slowly warmed to RT and stirred for 12 h. Anhydrous Et₂0 (50 mL) was added and the mixture stirred for 30 min. The solid that formed was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography eluting with 0-50% EtOAc in hexanes to provide intermediate A (1.13 g, 39%). H NMR (300 MHz, CDC1₃) δ 7.39-7.27 (m, 5H), 4.27 (m, 3H), 1.52 (m, 3H), 1.32 (m, 3H). ³¹P NMR (121.4 MHz, CDC1₃) δ 8.2, 7.8.

Example 2. (2S)-2-ethylbutyl 2-(chloro(phenoxy)phosphorylamino)propanoate

(Chloridate B

[0247] The 2-ethylbutyl alanine chlorophosphoramidate ester B was prepared using the same procedure as chloridate A except substituting 2-ethylbutyl alanine ester for ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.

Example 3. (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate

(Chloridate C)

[0248] The isopropyl alanine chlorophosphoramidate ester C was prepared using the same procedure as chloridate A except substituting isopropyl alanine ester for the ethyl alanine ester. The material is used crude in the next reaction. Treatment with methanol or ethanol forms the displaced product with the requisite LCMS signal.

Example 4. (2S)-2-ethylbutyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[l,2-firi,2,41triazin- 7-yl)-5-cvano-3,4-dihvdroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 9)

[0249] Compound 9 can be prepared by several methods described below. Procedure 1

[0250] Prepared from Compound 1 and chloridate B according to the same method as for the preparation of compound 8 as described in PCT Publication no. WO 2012/012776. 1H NMR (300 MHz, CD₃OD) δ 7.87 (m, 1H), 7.31-7.16 (m, 5H), 6.92-6.89 (m, 2H), 4.78 (m, 1H), 4.50-3.80 (m, 7H), 1.45-1.24 (m, 8H), 0.95-0.84 (m, 6H). ³¹P NMR (121.4 MHz, CD₃OD) δ 3.7. LCMS m/z 603.1 [M+H], 601.0 [M-H].

Procedure 2

[0251] (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7- yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate. (2S)-2-ethylbutyl 2-(((4-nitrophenoxy)(phenoxy)phosphoryl)amino)propanoate (1.08 g, 2.4 mmol) was dissolved in anhydrous DMF (9 mL) and stirred under a nitrogen atmosphere at RT. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (350 mg, 1.2 mmol) was added to the reaction mixture in one portion. A solution of i-butylmagnesium chloride in THF (1M, 1.8 mL, 1.8 mmol) was then added to the reaction drop wise over 10 minutes. The reaction was stirred for 2 h, at which point the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate solution (3 x 15 mL) followed by saturated aqueous sodium chloride solution (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil was purified with silica gel column chromatography (0-10% MeOH in DCM) to afford (2S)-2- ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2, l-f][l,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate (311 mg, 43%, 1 :0.4 diastereomeric mixture at phosphorus) as a white solid. H NMR (400 MHz, CD₃OD) δ 7.85 (m, 1H), 7.34 – 7.23 (m, 2H), 7.21 – 7.09 (m, 3H), 6.94 – 6.84 (m, 2H), 4.78 (d, / = 5.4 Hz, 1H), 4.46 – 4.33 (m, 2H), 4.33 – 4.24 (m, 1H), 4.18 (m, 1H), 4.05 – 3.80 (m, 3H), 1.52 – 1.39 (m, 1H), 1.38 – 1.20 (m, 7H), 0.85 (m, 6H). ³¹P NMR (162 MHz, CD₃OD) δ 3.71, 3.65. LCMS m/z 603.1 [M+H], 600.9 [M-H]. HPLC (2-98% MeCN-H₂0 gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) t_R = 5.544 min, 5.601 min

Separation of the (S) and (R) Diastereomers

[0252] (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)- 5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate was dissolved in acetonitrile. The resulting solution was loaded onto Lux Cellulose-2 chiral column, equilibrated in acetonitrile, and eluted with isocratic

acetonitrile/methanol (95 :5 vol/vol). The first eluting diastereomer had a retention time of 17.4 min, and the second eluting diastereomer had a retention time of 25.0 min.

[0253] First Eluting Diastereomer is (S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4- aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phos horyl)amino)propanoate:

!HNMR (400 MHz, CD₃OD) δ 8.05 (s, 1H), 7.36 (d, / = 4.8 Hz, 1H), 7.29 (br t, J = 7.8 Hz, 2H), 7.19 – 7.13 (m, 3H), 7.11 (d, / = 4.8 Hz, 1H), 4.73 (d, / = 5.2 Hz, 1H), 4.48 – 4.38 (m, 2H), 4.37 – 4.28 (m, 1H), 4.17 (t, / = 5.6 Hz, 1H), 4.08 – 3.94 (m, 2H), 3.94 – 3.80 (m, 1H), 1.48 (sep, / = 12.0, 6.1 Hz, 1H), 1.34 (p, / = 7.3 Hz, 4H), 1.29 (d, / = 7.2 Hz, 3H), 0.87 (t, / = 7.4 Hz, 6H). ³¹PNMR (162 MHz, CD₃OD) δ 3.71 (s). HPLC (2-98% MeCN-H₂0 gradient with 0.1 % TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 um 100 A, 4.6 x 100 mm ) i_s = 5.585 min. [0254] Second Eluting Diastereomer is (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4- aminopyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-yl)-5-cyano-3 ,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:

HNMR (400 MHz, CD₃OD) δ 8.08 (s, 1H), 7.36 – 7.28 (m, 3H), 7.23 – 7.14 (m, 3H), 7.08 (d, 7 = 4.8 Hz, 1H), 4.71 (d, 7 = 5.3 Hz, 1H), 4.45 – 4.34 (m, 2H), 4.32 – 4.24 (m, 1H), 4.14 (t, / = 5.8 Hz, 1H), 4.08 – 3.94 (m, 2H), 3.93 – 3.85 (m, 1H), 1.47 (sep, / = 6.2 Hz, 1H), 1.38 – 1.26 (m, 7H), 0.87 (t, / = 7.5 Hz, 6H). ³¹PNMR (162 MHz, CD₃OD) δ 3.73 (s). HPLC (2- 98% MeCN-H₂0 gradient with 0.1% TFA modifier over 8.5 min, 1.5mL/min, Column: Phenomenex Kinetex C18, 2.6 urn 100 A, 4.6 x 100 mm ) t_R = 5.629 min.

Example 5. (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolor2J- f|[l,2,41triazin-7-yl)-5-cvano-3,4-dihvdroxytetrahvdrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (32)

[0255] The preparation of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,l f][l,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate is described below.

Preparation of (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)dihydrofuran-2(3H)- one.

[0256] (3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)tetrahydrofuran-2-ol (15.0g) was combined with MTBE (60.0 mL), KBr (424.5 mg), aqueous K₂HP0₄solution (2.5M, 14.3 mL), and TEMPO (56 mg). This mixture was cooled to about 1 °C. Aqueous bleach solution (7.9%wt.) was slowly charged in portions until complete consumption of starting material as indicated through a starch/iodide test. The layers were separated, and the aqueous layer was extracted with MTBE. The combined organic phase was dried over MgS0₄ and concentrated under reduced pressure to yield the product as a solid.

Preparation (4-amino-7-iodopyrrolor2,l-fl ri,2,41triazine)

[0257] To a cold solution of 4-aminopyrrolo[2, l-f][l,2,4]-triazine (10.03 g; 74.8 mmol) in N,N-dimethylformamide (70.27 g), N-iodosuccinimide (17.01g; 75.6 mmol) was charged in portions, while keeping the contents at about 0 °C. Upon reaction completion (about 3 h at about 0 °C), the reaction mixture was transferred into a 1 M sodium hydroxide aqueous solution (11 g NaOH and 276 mL water) while keeping the contents at about 20-30 °C. The resulting slurry was agitated at about 22 °C for 1.5 h and then filtered. The solids are rinsed with water (50 mL) and dried at about 50 °C under vacuum to yield 4-amino-7- iodopyrrolo[2,l-f] [l,2,4]triazine as a solid. ^!H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.78 (br s, 2H), 6.98 (d, J = 4.4 Hz, 1H), 6.82 (d, J = 4.4 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d6) δ 155.7, 149.1, 118.8, 118.1, 104.4, 71.9. MS m/z = 260.97 [M+H].

Preparation (3R,4R,5R)-2-(4-aminopyrrolor2, l-firi,2,41triazin-7-yl)-3,4-bis(benzyloxy)-5- ((benzyloxy)methyl)tetrahvdrofuran-2-ol via (4-amino-7-iodopyrrolor2,l-fl ri,2,41triazine)

[0258] To a reactor under a nitrogen atmosphere was charged iodobase 2 (81 g) and THF (1.6 LV). The resulting solution was cooled to about 5 °C, and TMSC1 (68 g) was charged. PhMgCl (345mL, 1.8 M in THF) was then charged slowly while maintaining an internal temperature at about < 5°C. The reaction mixture was stirred at about 0°C for 30 min, and then cooled to about -15 °C. z^‘PrMgCl-LiCl (311 mL, 1.1 M in THF) was charged slowly while maintaining an internal temperature below about -12 °C. After about 10 minutes of stirring at about -15 °C, the reaction mixture was cooled to about -20 °C, and a solution of lactone 1 (130 g) in THF (400 mL) was charged. The reaction mixture was then agitated at about -20 °C for about 1 h and quenched with AcOH (57 mL). The reaction mixture was warmed to about 0 °C and adjusted to pH 7-8 with aqueous NaHCC>3 (5 wt%, 1300 mL). The reaction mixture was then diluted with EtOAc (1300 mL), and the organic and aqueous layers were separated. The organic layer was washed with IN HC1 (1300 mL), aqueous NaHCC>3 (5 wt%, 1300 mL), and brine (1300 mL), and then dried over anhydrous Na₂S0₄ and concentrated to dryness. Purification by silica gel column chromatography using a gradient consisting of a mixture of MeOH and EtOAc afforded the product.

Preparation ((2S)-2-ethylbutyl 2- (((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate) (mixture of Sp and Rp):

1 ) phenyl dichlorophosphate

CH₂CI₂, -78 °C to ambient

2) pentafluorophenol

Et₃N, 0 °C to ambient

[0259] L- Alanine 2-ethylbutyl ester hydrochloride (5.0 g, 23.84 mmol) was combined with methylene chloride (40 mL), cooled to about -78 °C, and phenyl dichlorophosphate (3.65 mL, 23.84 mmol) was added. Triethylamine (6.6 mL, 47.68 mmol) was added over about 60 min at about -78 °C and the resulting mixture was stirred at ambient temperature for 3h. The reaction mixture was cooled to about 0 °C and pentafluorophenol (4.4 g, 23.84 mmol) was added. Triethylamine (3.3 mL, 23.84 mmol) was added over about 60 min. The mixture was stirred for about 3h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with an aqueous sodium carbonate solution several times, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of EtOAc and hexanes (0 to 30%). Product containing fractions were concentrated under reduced pressure to give (2S)-2-ethylbutyl 2-(((perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate as a solid. H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.32 (m, 4H), 7.30 – 7.17 (m, 6H), 4.24 – 4.16 (m, 1H), 4.13 – 4.03 (m, 4H), 4.01 – 3.89 (m, 1H), 1.59 – 1.42 (m, 8H), 1.40 – 1.31 (m, 8H), 0.88 (t, J = 7.5 Hz, 12H). ³¹P NMR (162 MHz, Chloroform-d) δ – 1.52. ¹⁹F NMR (377 MHz, Chloroform-d) δ – 153.63, – 153.93 (m), – 160.05 (td, J = 21.9, 3.6 Hz), – 162.65 (qd, J = 22.4, 20.5, 4.5 Hz). MS m/z = 496 [M+H]. Preparation of Title Compound (mixture of Sp and Rp):

[0260] The nucleoside (29 mg, 0.1 mmol) and the phosphonamide (60 mg, 0.12 mmol) and N,N-dimethylformamide (2 mL) were combined at ambient temperature. 7¾ri-Butyl magnesiumchloride (1M in THF, 0.15 mL) was slowly added. After about lh, the reaction was diluted with ethyl acetate, washed with aqueous citric acid solution (5%wt.), aqueous saturated NaHC0₃ solution and saturated brine solution. The organic phase was dried over Na₂S0₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and CH₂CI₂ (0 to 5%). Product containing fractions were concentrated under reduced pressure to provide the product.

Preparation of (3aR,4R,6R,6aR)-4-(4-aminopyrrolor2, l-firi,2,41triazin-7-yl)-6- (hvdroxymethyl)-2,2-dimethyltetrahydrofuror3,4-diri,31dioxole-4-carbonitrile:

[0261] To a mixture of (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4- dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-carbonitrile (5.8g, 0.02 mol), 2,2- dimethoxypropane (11.59 mL, 0.09 mol) and acetone (145 mL) at ambient temperature was added sulfuric acid (18M, 1.44 mL). The mixture was warmed to about 45 °C. After about 30 min, the mixture was cooled to ambient temperature and sodium bicarbonate (5.8 g) and water 5.8 mL) were added. After 15 min, the mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over sodium sulfate and concentrated under reduced pressure to give crude (2R,3R,4S,5R)-2-(4-aminopyrrolo[2, l-f] [l,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile. ^!H NMR (400 MHz, CD₃OD) δ 7.84 (s, 1H), 6.93 (d, / = 4.6 Hz, 1H), 6.89 (d, / = 4.6 Hz, 1H), 5.40 (d, / = 6.7 Hz, 1H), 5.00 (dd, / = 6.7, 3.3 Hz, 1H), 4.48 – 4.40 (m, 1H), 3.81 – 3.72 (m, 2H), 1.71 (s, 3H), 1.40 (s, 3H). MS m/z = 332.23 [M+l].

Preparation of (2S)-2-ethylbutyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolor2,l-firi,2,41triazin- 7-yl)-5-cvano-3,4-dihvdroxytetrahydrofuran-2- yl)methoxy)(phenoxy)phosphoryl)amino)propanoate:

[0262] Acetonitrile (100 mL) was combined with (2S)-2-ethylbutyl 2-(((4- nitrophenoxy)(phenoxy)phosphoryl)-amino)propanoate (9.6 g, 21.31 mmol), the substrate alcohol (6.6 g, 0.02 mol), magnesium chloride (1.9 g, 19.91 mmol) at ambient temperature. The mixture was agitated for about 15 min and N,N-diisopropylethylamine (8.67 mL, 49.78 mmol) was added. After about 4h, the reaction was diluted with ethyl acetate (100 mL), cooled to about 0 °C and combined with aqueous citric acid solution (5%wt., 100 mL). The organic phase was washed with aqueous citric acid solution (5%wt., 100 mL) and aqueous saturated ammonium chloride solution (40 mL), aqueous potassium carbonate solution

(10%wt., 2 x 100 mL), and aqueous saturated brine solution (100 mL). The organic phase was dried with sodium sulfate and concentrated under reduced pressure to provide crude product. ^!H NMR (400 MHz, CD₃OD) δ 7.86 (s, 1H), 7.31 – 7.22 (m, 2H), 7.17 – 7.09 (m, 3H), 6.93 – 6.84 (m, 2H), 5.34 (d, / = 6.7 Hz, 1H), 4.98 (dd, / = 6.6, 3.5 Hz, 1H), 4.59 – 4.50 (m, 1H), 4.36 – 4.22 (m, 2H), 4.02 (dd, / = 10.9, 5.7 Hz, 1H), 3.91 (dd, / = 10.9, 5.7 Hz, 1H), 3.83 (dq, / = 9.7, 7.1 Hz, 1H), 1.70 (s, 3H), 1.50 – 1.41 (m, 1H), 1.39 (s, 3H), 1.36 – 1.21 (m, 7H), 0.86 (t, / = 7.4 Hz, 6H). MS m/z = 643.21 [M+l]. Preparation of (S)-2-ethylbutyl 2-(((S)-(((2R.3S.4R.5R)-5-(4-aminopyrrolor2.1- firi,2,41triazin-7-yl)-5-cvano-3,4-ditivdroxytetratiydrofuran-2- yl)methoxy)( henoxy)phosphoryl)amino)propanoate (Compound 32)

Compound 32

[0263] The crude acetonide (12.85 g) was combined with tetrahydrofuran (50 mL) and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (100 mL), cooled to about 0 °C and concentrated HC1 (20 mL) was slowly added. The mixture was allowed to warm to ambient temperature. After consumption of the starting acetonide as indicated by HPLC analysis, water (100 mL) was added followed by aqueous saturated sodium bicarbonate solution (200 mL). The mixture was extracted with ethyl acetate (100 mL), the organic phase washed with aqueous saturated brine solution (50 mL), dried over sodium sulfated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol and ethyl acetate (0 to 20%).

Product containing fractions were concentrated under reduced pressure to provide the product.

PATENT

US 20170071964

US 20160122374

PAPER

Journal of Medicinal Chemistry (2017), 60(5), 1648-1661.

https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.6b01594

The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded in history with over 28,000 cases, resulting in >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) with anti-EBOV EC₅₀ = 86 nM in macrophages as the clinical candidate. Structure activity relationships established that the 1′-CN group and C-linked nucleobase were critical for optimal anti-EBOV potency and selectivity against host polymerases. A robust diastereoselective synthesis provided sufficient quantities of 4b to enable preclinical efficacy in a non-human-primate EBOV challenge model. Once-daily 10 mg/kg iv treatment on days 3–14 postinfection had a significant effect on viremia and mortality, resulting in 100% survival of infected treated animals [ Nature 2016, 531, 381−385]. A phase 2 study (PREVAIL IV) is currently enrolling and will evaluate the effect of 4b on viral shedding from sanctuary sites in EBOV survivors.

(S)-2-Ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (4b)

Compound 4b was prepared from 4 and 22b as described previously.(17)¹H NMR (400 MHz, methanol-d₄): δ 7.86 (s, 1H), 7.33–7.26 (m, 2H), 7.21–7.12 (m, 3H), 6.91 (d, J = 4.6 Hz, 1H), 6.87 (d, J = 4.6 Hz, 1H), 4.79 (d, J = 5.4 Hz, 1H), 4.43–4.34 (m, 2H), 4.28 (ddd, J = 10.3, 5.9, 4.2 Hz, 1H), 4.17 (t, J = 5.6 Hz, 1H), 4.02 (dd, J = 10.9, 5.8 Hz, 1H), 3.96–3.85 (m, 2H), 1.49–1.41 (m, 1H), 1.35–1.27 (m, 8H), 0.85 (t, J = 7.4 Hz, 6H).

¹³C NMR (100 MHz, methanol-d₄): δ 174.98, 174.92, 157.18, 152.14, 152.07, 148.27, 130.68, 126.04, 125.51, 121.33, 121.28, 117.90, 117.58, 112.29, 102.60, 84.31, 84.22, 81.26, 75.63, 71.63, 68.10, 67.17, 67.12, 51.46, 41.65, 24.19, 20.56, 20.50, 11.33, 11.28.

³¹P NMR (162 MHz, methanol-d₄): δ 3.66 (s).

HRMS (m/z): [M]⁺ calcd for C₂₇H₃₅N₆O₈P, 602.2254; found, 602.2274.

[α]²¹_D – 21 (c 1.0, MeOH).

PAPER

Nature (London, United Kingdom) (2016), 531(7594), 381-385.

https://www.nature.com/articles/nature17180

Remdesivir
Clinical data

Other names	GS-5734
Routes of administration	By mouth, insufflation
ATC code	None
Legal status
Legal status	US: Investigational New Drug
Identifiers
IUPAC name [show]
CAS Number	1809249-37-3
DrugBank	DB14761
ChemSpider	58827832
UNII	EW5GL2X7E0
KEGG	D11472
Chemical and physical data
Formula	C₂₇H₃₅N₆O₈P
Molar mass	602.585 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Nc1ncnn2c1ccc2C3(C#N)C(O)C(O)C(O3)COP(=O)(Oc4ccccc4)NC(C)C(=O)OCC(CC)CC

Remdesivir
Clinical data

Other names	GS-5734
Routes of administration	By mouth, insufflation
ATC code	None
Legal status
Legal status	US: Investigational New Drug
Identifiers
IUPAC name [show]
CAS Number	1809249-37-3
DrugBank	DB14761
ChemSpider	58827832
UNII	EW5GL2X7E0
KEGG	D11472
Chemical and physical data
Formula	C₂₇H₃₅N₆O₈P
Molar mass	602.585 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] Nc1ncnn2c1ccc2C3(C#N)C(O)C(O)C(O3)COP(=O)(Oc4ccccc4)NC(C)C(=O)OCC(CC)CC

//////////////Remdesivir, レムデシビル , UNII:3QKI37EEHE, ремдесивир , ريمديسيفير , 瑞德西韦 , GS-5734 , GS 5734, PHASE 3 , CORONOVIRUS, COVID-19

CCC(CC)COC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@](C#N)([C@H](O)[C@@H]1O)c2ccc3c(N)ncnn23)Oc4ccccc4

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Uprifosbuvir

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods†

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Roluperidone

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Ranjit Desai

Step 1′a Process for Preparation of ethyl 2-iodobenzoate (XI-a)

Step-2 Process for the Preparation of ethyl 2-((tert-butoxycarbonyl)(cyclopropylmethoxy)aminolbenzoate (XII-a)

Step 3 Process for the Preparation of ethyl 2-((cyclopropylmethoxy)amino)benzoate (XIII-a)

Step 4 Process for the Preparation of ethyl 24N-(cyclopropylinethoxy)-3-ethoxy-3-oxopropanamido)benzoate (XIV-a)

Step 5: Process for the Preparation of ethyl 1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2 dihydroquinolline-3-carboxylate (XY-a)

Purification

Step 6 Process for the Preparation of ethyl (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycinate (XVI-a)

Purification

Step 7: Process for the Preparation of (1-(cyclopropylmethoxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbonyl)glycine (I-a)

Polymorphic Data (XRPD):

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ANALYSIS

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L-Alanine, N-((S)-hydroxyphenoxyphosphinyl)-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-2,5-anhydro-D-altrononitrile

2-Ethylbutyl (2S)-2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo(2,1-f)(1,2,4)triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate

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Ebola virus

SARS-CoV-2

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