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Landiolol

April 20, 2025 2:57 am / Leave a comment

Landiolol

133242-30-5
ONO-1101
Ono 1101
WHO 7516

FDA APPROVED 11/22/2024, Rapiblyk, To treat supraventricular tachycardia

C25H39N3O8
509.6 g/mol

[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl 3-[4-[(2S)-2-hydroxy-3-[2-(morpholine-4-carbonylamino)ethylamino]propoxy]phenyl]propanoate

Landiolol hydrochloride
144481-98-1
Landiolol HCl
ONO 1101 hydrochloride
Onoact

Landiolol, sold under the brand name Onoact among others, is a medication used for the treatment of tachycardia, atrial fibrillation, and atrial flutter.^[1]^[4] It is a beta-adrenergic blocker;^[4] an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility.^[6]^[7] In comparison to other beta blockers, landiolol has the shortest elimination half-life (3 to 4 minutes), ultra-rapid onset of effect (heart rate begins to decrease immediately after completion of administration), and predictable effectiveness with inactive metabolites (heart rate returns to baseline levels at 30 min after completion of landiolol hydrochloride administration).^[8] The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired.^[9] It is used as landiolol hydrochloride.

Landiolol was approved for medical use in Japan in 2002,^[10]^[11] in Canada in November 2023,^[1] and in the United States in November 2024.^[12]^[13]^[14]

Syn

Landiolol 1 is a potent cardioselective beta-blocker with ultrarapid action, used as an arrhythmic agent in the form of the hydrochloride salt.
[0004]The synthesis of Landiolol 1 is disclosed in US 5013734 , JP 3302647 , CN 100506814 , JP 2539734 and Chemical & Pharmaceutical Bulletin 1992, 40 (6) 1462-1469. The main synthetic route for the preparation of Landiolol is reported in the following scheme:

The synthesis of landiolol appeared in an earlier patent in 1990. Esterification of 3- (4-hydroxyphenyl)propionic acid (141) with 2,2-dimethyl- 1,3-dioxolan-4-ylmethyl chloride (142) in DMSO gave desired ester 143 in 57% yield. Treatment of phenol 143 with bromo epoxide 144 in the present of K2CO3 afforded ether 145 in 76% yield. Epoxide 145 was then reacted with free amine 146 via a neucleophilic ring opening process to provide landiolol (14).

Yield:144481-98-1 95.9%

Reaction Conditions:

with hydrogenchloride in ethyl acetate at 5 – 10; for 2 h;

Steps:

1.6 Preparation of Lantilolol Hydrochloride

Add Lantilolol (10g, 19.62mmol) and 100mL of ethyl acetate to the reaction flask. The temperature of the ice-water bath is lowered below 5 ° C, and a temperature of 10-18 ° C is added dropwise to a 15-18% HCl-ethyl acetate solution 4.63g A large amount of solid was gradually precipitated, dripped, stirred below 10 ° C for 2h, filtered, washed with ethyl acetate, and dried under vacuum at 50 ° C to obtain 10.28 g of a white solid with a yield of 95.9% and an HPLC purity of 99.85%.

References:

CN110483470,2019,A Location in patent:Paragraph 0031; 0045-0047

EP2687521,2014,A1

https://patents.google.com/patent/EP2687521B1/en

[0025]Typically, to activate the salen catalyst, preferably (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt 16 is reacted with 1.0 ÷ 3.0 equivalents of a carboxylic acid, preferably 4-nitrobenzoic acid 17, preferably 1.5 ÷ 2.5 equivalents. The reaction is carried out in a polar aprotic solvent, preferably dichloromethane, at a temperature of 10 ÷ 40°C, preferably at a temperature of 20 ÷ 30°C. 4 ÷ 15 Volumes of solvent are used, preferably 7 ÷ 12 volumes with respect to the amount of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt 16. After a dark brown color appears, the solvent is removed thereby obtaining the catalyst the in active form. This is then added with 10 ÷ 100 equivalents of starting product (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate 3, preferably 20 ÷ 50 equivalents, then with a polar aprotic solvent, preferably methyl tert-butyl ether (MTBE). 1 ÷ 5 Volumes of solvent are used, preferably 2 ÷ 3 volumes with respect to the amount of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate 3. Afterwards, 2.0 ÷ 3.0 equivalents of a compound of formula 4, typically epichlorohydrin, are added, preferably 2.0 ÷ 2,5 equivalents. The reaction is carried out at a temperature of 10 ÷ 40°C, preferably at a temperature of 20 ÷ 30°C. The reaction is monitored by UPLC analysis using a C18 column and water / acetonitrile containing 1% formic acid as the eluent phase. After completion of the reaction, water and toluene are added and phases are separated. The organic phase is then distilled to recover (S)-epichlorohydrin and washed with dilute sodium hydroxide. The organic phase is then concentrated to small volume, added with a polar solvent, acetonitrile or methanol, preferably acetonitrile, concentrated again to small volume to remove toluene and finally added with 5 ÷ 30 volumes of a polar solvent, such as acetonitrile or methanol, preferably acetonitrile. The suspension is filtered thus recovering the catalyst and the resulting solution can be directly used in step b, or (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)-propanoate 5 can be isolated as an oil that can be stored at room temperature for some days. In order to obtain (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate 5 as an oil, the solution in the polar solvent is added with decolorizing filter aid, the obtained suspension is filtered and the resulting solution is evaporated to dryness. (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxy-propoxy)phenyl)propanoate 5 is obtained as an oil.
[0026]Typically, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate 5 obtained in step a, either isolated as an oil or directly from the polar solvent solution, is reacted with an inorganic base, preferably potassium carbonate, in an amount of 1.0 ÷ 6.0 equivalents, 3.0 ÷ 4.0 equivalents, in the presence of a ionic inorganic catalyst, preferably potassium iodide, in catalytic amounts (0.05 ÷ 0.20 eq). Thereafter, 2-(morpholine-4-carboxamido)ethanamine as base or a salt thereof, such as the oxalate or the hydrochloride, preferably the oxalate, is added in an amount of 1.0 ÷ 4.0 equivalents, preferably 2.0 ÷ 3.0 equivalents. The reaction is carried out in a polar solvent, preferably acetonitrile, at a temperature 20 ÷ 85°C, preferably 60 ÷ 85°C. 5 ÷ 30 Volumes of solvent are used, preferably 10 ÷ 20 volumes with respect to the amount of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)-phenyl)propanoate 5. The reaction is monitored by UPLC analysis using a C 18 column and water / acetonitrile containing 1% formic acid as the eluent. After completion of the reaction, ethyl acetate and water are added and the phases separated. The organic phase is then extracted with water at pH 2 ÷ 5, preferably 3 ÷ 4. The phases are separated and the aqueous phase is extracted again with ethyl acetate at pH 8 ÷ 13, preferably 9 ÷ 12. The solvent of the organic phase is then replaced with 2 ÷ 20 volumes of a polar solvent, such as isopropanol, and the resulting solution can be directly used in step c, or Landiolol 1 can be isolated. For this purpose, the solvent is removed or replaced with a polar solvent, for example diisopropyl ether, to promote solidification, then the solvent is stripped from the resulting suspension thereby obtaining Landiolol 1 as an oil which solidifies in time.
[0027]Typically, Landiolol 1 obtained in step b directly from the polar solvent solution or by dissolution of the isolated product is directly salified to give Landiolol hydrochloride 2, preferably with hydrochloric acid. Salification is carried out in a polar solvent, preferably isopropanol, in amounts of 2 ÷ 20 volumes of solvent, preferably 5 ÷ 10 volumes with respect to the amount of Landiolol 1. After addition of the acid, the solvent is evaporated off and the product is crystallized by adding 1 ÷ 20 volumes of a polar solvent, preferably acetone. The suspension is filtered and the solid is dried at 25 ÷ 35°C under vacuum for 12 hours to obtain Landiolol hydrochloride 2. The enantiomeric excess of the final product is analyzed using a Chiralcel OD column and hexane / ethanol as the eluent phase containing diethylamine.
[0028]The process of the invention is particularly advantageous in that is effected without isolating any intermediates. Intermediate 5 is obtained with high purity in very high yields under very mild reactions conditions. Furthermore, the starting material 4 in which X is chlorine (epichlorohydrin), is very inexpensive and easily commercially available. The catalysts used are commercially available at low costs and can be easily recovered by simple filtration. Surprisingly, the reaction to give Landiolol 1 starting from the novel intermediate 5 in which X is chlorine provides a markedly higher yield than those obtained with most processes mentioned in the background of the invention, which conversely start from intermediate 7. The resulting Landiolol 1 can be directly converted to Landiolol hydrochloride 2 in good overall yields, with no further purifications neither intermediate steps. The resulting Landiolol hydrochloride 2 has very high enantiomeric purity.
[0029]Furthermore, the process of the invention allows to recover (S)-epichlorohydrin 12, which is a high added value product that can also be used in the synthesis of Landiolol 1 according to the following scheme, to prepare compound 3:
[0030]The synthesis of intermediate 15 from 12 in very high yields is described in literature in a number of publications. Some publications which the disclose it are the following: Catalysis Communications, 8(12), 2087-2095; 2007; CN100506814 ; Journal of Molecular Catalysis A: Chemical, 236(1-2), 72-76; 2005; Chinese Journal of Chemistry, 23(9), 1275-1277; 2005; Synthetic Communications, 35(11), 1441-1445; 2005; Synthetic Communications, 31(22), 3411-3416; 2001; Chemistry Letters, (11), 2019-22; 1990; Khimiya Geterotsiklicheskikh Soedinenii, (1), 33-6; 1991. The synthesis of 3 in high yields starting from 15 and 19 is described in CN100506814 . A further publication disclosing it is US5013734 . Both publications have already been mentioned in the background of the invention for the synthesis of Landiolol 1.
[0031]The invention is illustrated in detail by the following examples.
[0032]
[0033]A suspension of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt (16) (50 mg, 0.0828 mmol) in MTBE (1 ml) is added with acetic acid (10 mg, 0.166 mmol). The mixture is left under stirring for 1 h at 20-25°C until a dark color appears. Afterwards, (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate (3), (500 mg, 1.78 mmol), then epichlorohydrin (compound of formula 4 in which X is chlorine) (340 mg, 3.56 mmol) are added thereto. The mixture is left under stirring at 20-25°C, monitoring by UPLC. After completion of the reaction, water (5 ml) and toluene (5 ml) are added, the phases are separated and the solvent and (S)-epichlorohydrin are removed from the organic phase under reduced pressure to obtain 600 mg (90.4%) of a dark oil.
[0034]
[0035]A suspension of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt (16) (1,9 g, 3.19 mmol) in dichloromethane (20 ml) is added with 4-nitrobenzoic acid 17 (1.1 g, 6.38 mmol). The mixture is left under stirring for 1 h at 20-25°C until a dark color appears. The solvent is replaced with MTBE (30 ml), subsequently (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate (3), (18 g, 63,8 mmol) and then epichlorohydrin (compound of formula 4 in which X is chlorine) (13,4 g, 140 mmol) are added. The mixture is left under stirring at 20-25°C, monitoring by UPLC. After completion of the reaction, toluene (300 ml) and water (150 ml) are added and the phases are separated. The organic phase is evaporated to dryness thereby recovering the enriched (S)-epichlorohydrin. Toluene (300 ml) and 10% NaOH (100 ml) are added. The phases are separated, the resulting solution is concentrated to a volume of about 50 ml, added with 100 ml of acetonitrile, concentrated to a volume of 50 ml and finally added with 250 ml of acetonitrile. Decolorizing filter aid (2.5 g) is added, the mixture is left under stirring for 15′ and the suspension is filtered. The filtrate is evaporated to dryness to obtain 23.7 g (99,6%) of a red-brownish oil.
[0036]A suspension of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt (16) (470 mg, 0.780 mmol) in dichloromethane (5 ml) is added with 4-nitrobenzoic acid 17 (270 mg, 1.56 mmol). The mixture is left under stirring for 45′ at 20-25°C until a dark color appears. The resulting solution is concentrated to a volume of about 2 ml, added with 5 ml of MTBE, concentrated to a volume of 2 ml and finally added with 6 ml of MTBE, subsequently with (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate (3), (5 g, 17.7 mmol) and then with epichlorohydrin (compound of formula 4 in which X is chlorine) (3.7 g, 38.9 mmol). The mixture is left under stirring at 20-25°C, monitoring by UPLC. After completion of the reaction, toluene (25 ml) and water (25 ml) are added and the phases are separated. The organic phase is evaporated to dryness thereby recovering the enriched (S)-epichlorohydrin. Acetonitrile (25 ml) is added and the suspension is filtered thereby recovering the catalyst. The resulting solution is concentrated to a volume of about 5 ml, added with 15 ml of toluene, then concentrated to a volume of 5 ml and finally added with 20 ml of toluene and decolorizing filter aid (20.0 g). The mixture is left under stirring for 15′ and the suspension is filtered. The filtrate is evaporated to dryness to obtain 6.1 g (92.4%) of a yellow oil.
LC-MS (ESI+) [M+H]⁺ = 373
¹H-NMR (CDCl₃) (chemical shifts expressed in ppm with respect to TMS): 1,37 (3H, s, CH₃); 1,43 (3H, s, CH₃); 2,65 (2H, t, J = 7 Hz, CH₂-Ar); 2,83 (1H, bs, OH); 2,91 (2H, t, J = 7 Hz, CH₂-CO); 3,66 – 3,81 (3H, m, CH in 4 oxolane and CH₂-Cl); 4.00 – 4,25 (6H, m, CH in 4 oxolane, CH₂-OCO, CH₂-OAr and CH in 5 oxolane); 4,25 (1H, m, CH-OH); 6,84 and 7,13 (4H, system AA’XX’, aromatics).
¹³C-NMR (CDCl₃) (ppm): 25,3 (CH₃); 26,6 (CH₃); 29,9 (CH₂); 35,8 (CH₂); 45,9 (CH₂-Cl); 64,6 (CH₂); 66,2 (CH₂); 68,5 (CH₂); 69,7 (CH); 73,4 (CH); 109,7; 114,5 (CH); 129,3 (CH); 133,1; 156,7; 172,6 (COOR).
Elemental analysis: C, 58.3%; H, 6.9%; Cl, 9.3%; O, 25.5%. (% calculated: C, 58.0; H, 6.8; Cl, 9.5; O, 25.7).
FT-IR (UATR, cm^-1): 3456, 2987, 2936, 1733, 1612, 1512, 1372, 1241, 1154, 1041,828,741,720.
[0037]
[0038]A suspension of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate (5) prepared according Example 3 (0.50 g, 0.00134 mol) in isopropanol (10 ml) is added with 2-(morpholine-4-carboxamido)ethanamino hydrochloride (18) (1.4 g, 0.00670 mol), heated to 30-35°C and dropwise added with 30% NaOH, keeping pH at 10-11. The mixture is left under stirring at 35-40°C, monitoring by UPLC. After completion of the reaction, ethyl acetate (20 ml) and water (20 ml) are added and the phases are separated. The organic phase is added with water (20 ml) and adjusted to pH 3-4 with hydrochloric acid. The phases are separated and the resulting aqueous phase is then adjusted to pH 10-11 with sodium hydroxide and re-extracted with ethyl acetate (20 ml). The solvent is then evaporated off under reduced pressure to obtain 0.38 g (55.6%) of a pale yellow oil which solidifies in time to a pale yellow solid.
[0039]
[0040]A solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate (5) prepared according to Example 3 (0.30 g, 0.805 mmol) in acetonitrile (6.0 ml) is added with potassium carbonate 0.45 g (3.22 mmol), and KI 0.013 g (0.0805 mmol), then refluxed for 2 h and added with 2-(morpholine-4-carboxamido)ethanamino oxalate (6) (0.64 g, 2.42 mmol). The mixture is refluxed under stirring, monitoring by UPLC. After completion of the reaction, ethyl acetate (10 ml) and water (10 ml) are added and the phases are separated. The organic phase is added with water (10 ml) and adjusted to pH 4-5 with hydrochloric acid, the phases are separated and the resulting aqueous phase is then adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (10 ml). Then the solvent is evaporated off under reduced pressure to obtain 0.29 g (70.7%) of a pale yellow oil which solidifies in time to a pale yellow solid.
LC-MS (ESI+) [M+H]⁺ = 510
¹H-NMR (CDCl₃) (chemical shifts expressed in ppm with respect to TMS) (assigned based on the hetero correlation HSQC spectrum): 1.36 (3H, s, CH₃); 1.42 (3H, s, CH₃); 2.63 (2H, t, J = 7 Hz, CH₂-Ar); 2.75 – 2.93 (8H, m, CH₂-CO, CH-CH ₂-NH, CH₂-CH ₂-NH, NH and OH); 3.35 (6H, m, 2CH₂-N morpholine and CH ₂-NH); 3.65 (4H, m, 2CH₂-O morpholine), 3.68 (1H, m, CH in 4 oxolane); 3.94 (2H, bd, CH₂-OAr); 4.00 – 4.20 (4H, m, CH in 4 oxolane, CH₂-OCO and CH in 5 oxolane); 4.25 (1H, m, CH-OH); 5.21 (1H, bt, NH carbamate); 6.83 and 7.11 (4H, system AA’XX’, aromatics).
¹³C-NMR (CDCl₃) (ppm) (multiplicity was assigned by DEPT-135): 25.3 (CH₃); 26.6 (CH₃); 29.9 (CH₂); 35.8 (CH₂); 40.2 (CH₂); 43.8 (CH₂-N morpholine); 49.2 (CH₂); 51.5 (CH₂); 64.6 (CH₂); 66.2 (CH₂); 66.4 (CH₂-O morpholine); 68.3 (CH); 70.3 (CH₂); 73.4 (CH); 109.7; 114.4 (CH); 129.2 (CH); 132.8; 157.0; 158.0; 172.5 (COOR).
FT-IR (UATR, cm^-1): 3350. 2858, 1735, 1626, 1512, 1454, 1371, 1244, 1153, 1115, 1040. 829, 733.
[0041]
[0042]A solution of Landiolol (1) prepared according to Example 5 (100 mg, 0.196 mmol) in isopropanol (6.0 ml) is added with 18% isopropanol hydrochloric acid (40 mg, 0.197 mmol). The solvent is then evaporated off under reduced pressure and the residue is crystallized from acetone (2 ml). The suspension is filtered and the crystal is dried at 25°C for 12 h to obtain 80 mg (74.7%) of a white solid.
[0043]
[0044]A suspension of (R,R)-N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ciclohexanediamino cobalt (16) (47 mg, 0.0780 mmol) in dichloromethane (1 ml) is added with 4-nitrobenzoic acid 17 (27 mg, 0.156 mmol). The mixture is left under stirring for 45′ at 20-25°C until a dark color appears. The resulting solution is concentrated to a volume of about 0.5 ml, added with 0.5 ml of MTBE, concentrated to a volume of 0.5 ml and finally added with 0.5 ml of MTBE, then with (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate (3), (0.5 g, 1,77 mmol) and then with epichlorohydrin (compound of formula 4 in which X is chlorine) (0.37 g, 3,89 mmol). The mixture is left under stirring at 20-25°C, monitoring by UPLC. After completion of the reaction, toluene (10 ml) and water (10 ml) are added and the phases are separated. The organic phase is evaporated recovering the enriched (S)-epichlorohydrin, then added again with toluene (10 ml) and washed with 10% NaOH (10 ml). The resulting solution is concentrated to a volume of about 2 ml, added with 5 ml of acetonitrile, concentrated to a volume of 2 ml and finally added with 10 ml of acetonitrile). The suspension is filtered thus recovering the catalyst and the solution is added with potassium carbonate 0.79 g (5,64 mmol), and KI 0.026 g (0.161 mmol), refluxed for 2 h, then added with 2-(morpholine-4-carboxamido)ethanamino oxalate (6) (1.07 g, 4.03 mmol). The mixture is refluxed under stirring, monitoring by UPLC. After completion of the reaction, ethyl acetate (20.0 ml) and water (20 ml) are added and the phases are separated. The organic phase is then adjusted to pH 4-5 with hydrochloric acid and extracted with water (20 ml). The phases are separated and the resulting aqueous phase is then adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (20 ml). The resulting solution is concentrated to a volume of about 5 ml, added with 20 ml of isopropanol, concentrated to a volume of 5 ml and finally added with 30 ml of isopropanol, then 18% isopropanol hydrochloric acid (0.24 g, 1.18 mmol). The solvent is then evaporated off under reduced pressure and the residue is crystallized from acetone (10 ml). The suspension is filtered and the crystal is dried at 25°C for 12 h to obtain 0.48 g (49.7% total, enantiomeric purity: 99.8%) of a white solid.
m.p.: 126°C (from literature 123-127°C)
LC-MS (ESI+) [M+H]⁺ = 510
FT-IR (UATR, cm^-1): 3265, 2941, 2789, 2419, 1723, 1615, 1538, 1515, 1435, 1371, 1260. 1242, 1196, 1118, 1047, 887, 838, 821, 771.

Medical uses

Landiolol is indicated as an antiarrhythmic agent to treat

Supraventricular tachycardia and for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other circumstances where short-term control of the ventricular rate with a short acting agent is desirable.
Non-compensatory sinus tachycardia where, in the physician’s judgment the rapid heart rate requires specific intervention.

Landiolol has been approved for the treatment of ventricular fibrillation or ventricular tachycardia in Japan.

In the United States, landiolol is indicated for the short-term reduction of ventricular rate in adults with supraventricular tachycardia including atrial fibrillation and atrial flutter.^[4]

Landiolol can be used as first-line treatment for acute ventricular rate control in patients with atrial fibrillation (Level I recommendation- 2020 Guidelines of the European Society of Cardiology^[15]).

Mode of action

The drug acts as an ultra-short-acting β1-selective blocking agent. It is rapidly hydrolyzed to an inactive form by both carboxylesterase in the liver and pseudocholinesterase in the plasma, resulting in an elimination half-life of about four minutes.^[16] Landiolol is a highly selective beta-1-adrenoreceptor antagonist (the selectivity for beta-1-receptor blockade is 255 times higher than for beta-2-receptor blockade) that inhibits the positive chronotropic effects of the catecholamines adrenaline and noradrenaline on the heart, where beta-1-receptors are predominantly located. Landiolol, as other beta-blockers, is thought to reduce the sympathetic drive, resulting in reduction in heart rate, decrease in spontaneous firing of ectopic pacemakers, slowing the conduction and increase the refractory period of the AV node. Landiolol does not exhibit any membrane-stabilizing activity or intrinsic sympathomimetic activity in vitro. In preclinical and clinical studies, landiolol controlled tachycardia in an ultra-short acting manner with a fast onset and offset of action and further demonstrated anti-ischaemic and cardioprotective effects.^[17] To date, landiolol has the shortest plasma half-time and the highest cardio-selectivity among β-blockers in clinical use. The selectivity of landiolol for β1-receptor blockade is 255 times higher than for β2-receptor blockade. In comparison, Metoprolol, has a much less cardioselectivity (landiolol is 100 times more cardioselective than metoprolol,^[18] and 8 times more cardioselectove than esmolol^[19]), and sixty times longer half-life (3–4 hours comparing to 3–4 minutes in case of landiolol). FDA points out that CYP2D6 poor metabolizers will have decreased cardioselectivity for metoprolol due to increased metoprolol blood levels, since the gene variation reduces the conversion of metoprolol to inactive metabolites leading to almost 5-fold higher plasma concentrations of metoprolol.^[20]

Activation of β2 adrenergic receptors contributes to bronchial dilation and acceleration of alveolar fluid clearance in the pulmonary airway system. Consequently, a cardio-selective β1-blocker with limited effect on β2-receptor decreases the heart rate without the pulmonary adverse effects in patients with COPD or Asthma. Pharmacological stimulation of β2 receptors increases coronary blood flow in healthy humans and in patients with mildly atherosclerotic coronary arteries. Thus, not only does a cardio-selective β1-blocker reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia, while reducing the heart rate selectively. Interestingly, landiolol does not possess any sodium and calcium antagonistic properties, which makes it a more suitable cardio-selective β-blocker for patients with heart failure due to its lesser potency for negative inotropy, while offering higher potency for heart rate reduction. Contrary to landiolol, exposure to other β-blockers such as esmolol amplifies the re-expression of β-receptors which explains the drug tolerance effect seen during long-term esmolol infusion. Long term exposure of cells to betablockers which act as pharmacochaperones will raise the total surface level of β1-adrenergic receptors, resulting in exaggerating responses to endogenous agonists such as catecholamines, if the treatment is suddenly stopped. This phenomenon has been described as the betablocker withdrawal rebound. However, landiolol lacks appreciable pharmacochaperoning activity, as landiolol can hardly permeate cell membranes due to its large polar surface area.

Biotransformation

Landiolol is metabolised via hydrolysis of the ester moiety. In vitro and in vivo data suggest that landiolol is mainly metabolised in the plasma by pseudocholinesterases and carboxylesterases. Hydrolysis releases a ketal (the alcoholic component) that is further cleaved to yield glycerol and acetone, and the carboxylic acid component (metabolite M1), which subsequently undergoes beta-oxidation to form metabolite M2 (a substituted benzoic acid). The beta-1-adrenoreceptor blocking activity of landiolol metabolites M1 and M2 is 1/200 or less of the parent compound indicating a negligible effect on pharmacodynamics taking into account the maximum recommended landiolol dose and infusion duration.

Neither landiolol nor the metabolites M1 and M2 showed inhibitory effects on the metabolic activity of different cytochrome P450 molecular species (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The cytochrome P450 content was not affected in rats after repeated intravenous administration of landiolol. There are no data on a potential effect of landiolol or its metabolites on CYP P450 induction or time dependent inhibition available.

IV β-Blocker	max. elimination half-life (min)	cardio-selectivity (β1/β2)	metabilization
Landiolol	4	250	pseudocholinesterases
Esmolol	9	30	ery-esterases
Metoprolol	420	3	cytochrom P2D6 (Leber)

History

The beneficial effects of landiolol have been demonstrated in over sixty clinical trials (pubmed search -August 2018). Landiolol was generally well tolerated, with a relatively low risk of hypotension and bradycardia. Most clinical trials with landiolol have been conducted in peri-operative settings for the treatment or prophylaxis of supraventricular tachycardia or tachyarrhythmia before or after cardiac and non-cardiac surgeries. Randomized clinical trials have been published to compare landiolol with placebo<^[21]^[22]^[23] diltiazem,^[24] and amiodaron^[25] in patients with or without heart failure. Case reports on the use of landiolol after myocardial infarction,^[26] refractory electrical storm^[27] have been published. The fast turnover of landiolol will diminish most adverse events due to self-limiting administration. Landiolol may be cardio-protective in septic rats by normalizing coronary microcirculation through blockage of sepsis-induced decrease in expression of VEGF signaling system but independent of inflammatory cytokines.

The efficacy and safety of landiolol in septic shock has been investigated in a multi-center prospective randomized controlled trial, and the results of the study have been published in the renown Journal Lancet Respiratory in 2020, demonstrating clinical impact of landiolol in sepsis patients through significant reduction of new-onset arrhythmia and keeping the patients within the target heart rate range.

Furthermore, landiolol demonstrated a positive clinical impact regarding ventilation-free days, ICU-free days and hospital-free days. Patients in the landiolol group had a survival rate of 88% by day 28, in contrast to a mortality rate of 20% in the control group by day 28. These are very important findings which may include landiolol in the standard of care for sepsis patients, since tachycardia and atrial fibrillation are key prognostic factors for sepsis. Additionally, tachycardia exceeding 100 beats per min (bpm) on admission to an intensive care unit (ICU) is a risk factor for worsening prognosis.^[28]

A publication in the Journal of Cardiology illustrated in a prospective real-world setting, the safety and effectiveness of landiolol for the treatment of atrial fibrillation or atrial flutter in chronic heart failure (over one thousand patients at 209 medical institutions throughout Japan). In this survey, which is one of the largest studies ever performed in patients with chronic heart failure requiring intravenous rate control, report of serious hypotension was in less than 1% of patients, which highlights the cardio-selectivity of landiolol with limited effect on blood pressure. Noteworthy, over 70% of patients were in the NYHA class III or IV (35% NYHA IV), and close to 50% had a LVEF below 40%. The median time to first return to sinus rhythm after administration of landiolol was 14 hours, and the median highest infusion rate was 3 μg/kg/min.^[29]

The excellent tolerance of landiolol at lower dosage (3–5 μg/kg/min) allows to initiate prophylactic use during surgery and post-operatively. Landiolol prophylaxis is associated with reduced incidence of postoperative atrial fibrillation without triggering adverse events related to a beta-blockade. Optimized infusion scheme with continuing landiolol infusion in the post-operative period seems to be associated with better response, while infusion limited to the intraoperative period may not be sufficient^[30]

Society and culture

Legal status

Landiolol was approved for medical use in Japan in 2002,^[10] in Canada in November 2023,^[1] and in the United States in November 2024.^[13]

Brand names

It is sold under various brand names including Rapibloc, Raploc, Runrapiq, Landibloc, Onoact, Corbeta, and Rapiblyk.

References

^ Jump up to:^a ^b ^c ^d “Summary Basis of Decision for Sibboran”. Health Canada. 2 July 2024. Retrieved 12 October 2024.
^ “Details for: Sibboran”. Health Canada. 20 November 2023. Retrieved 3 March 2024.
^ “Regulatory Decision Summary for Sibboran”. Drug and Health Products Portal. 21 December 2022. Retrieved 2 April 2024.
^ Jump up to:^a ^b ^c ^d https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217202s000lbl.pdf
^ “List of nationally authorised medicinal products Active substance: landiolol” (PDF). Procedure no.: PSUSA/00010570/201802. Retrieved 12 October 2024.
^ Ikeshita K, Nishikawa K, Toriyama S, Yamashita T, Tani Y, Yamada T, et al. (2008). “Landiolol has a less potent negative inotropic effect than esmolol in isolated rabbit hearts”. Journal of Anesthesia. 22 (4): 361–6. doi:10.1007/s00540-008-0640-4. PMID 19011773. S2CID 5731527.
^ Wada Y, Aiba T, Tsujita Y, Itoh H, Wada M, Nakajima I, et al. (April 2016). “Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction”. Journal of Arrhythmia. 32 (2): 82–8. doi:10.1016/j.joa.2015.09.002. PMC 4823575. PMID 27092187.
^ Atarashi H, Kuruma A, Yashima M, Saitoh H, Ino T, Endoh Y, et al. (August 2000). “Pharmacokinetics of landiolol hydrochloride, a new ultra-short-acting beta-blocker, in patients with cardiac arrhythmias”. Clinical Pharmacology and Therapeutics. 68 (2): 143–50. doi:10.1067/mcp.2000.108733. PMID 10976545. S2CID 46146913.
^ Iguchi S, Iwamura H, Nishizaki M, Hayashi A, Senokuchi K, Kobayashi K, et al. (June 1992). “Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101”. Chemical & Pharmaceutical Bulletin. 40 (6): 1462–9. doi:10.1248/cpb.40.1462. PMID 1356643.
^ Jump up to:^a ^b “Ono Submits an Application of Onoact for Intravenous Infusion 50mg/150mg, a Short-Acting Selective β1 Blocker, in Japan for Additional Indication of Tachyarrhythmia in Pediatric Patients with Low Cardiac Function for a Partial Change in Approved Items of”. Ono Pharmaceutical. 28 October 2021. Retrieved 29 November 2024.
^ “A Short-Acting Selective β1 Blocker, Onoact for Intravenous Infusion 50mg/150mg Approved for Additional Indication of Tachyarrhythmia in Pediatric Patients with Low Cardiac Function in Japan”. Ono Pharmaceutical (Press release). 24 August 2022. Retrieved 28 November 2024.
^ “U.S. FDA Approves AOP Health’s Rapiblyk (landiolol) for Atrial Fibrillation and Atrial Flutter in the Critical Care Setting” (Press release). AOP Health. 27 November 2024. Retrieved 28 November 2024 – via Business Wire.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. (February 2021). “2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC”. European Heart Journal. 42 (5): 373–498. doi:10.1093/eurheartj/ehaa612. hdl:1887/3279676. PMID 32860505.
^ Circ J. 2016 Apr 25;80(5):1106-7
^ “Rapibloc Summary of Product Characteristics” (PDF). Archived from the original (PDF) on 16 June 2019. Retrieved 11 September 2018.
^ Baker JG (February 2005). “The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors”. British Journal of Pharmacology. 144 (3): 317–22. doi:10.1038/sj.bjp.0706048. PMC 1576008. PMID 15655528.
^ Okajima M, Takamura M, Taniguchi T (August 2015). “Landiolol, an ultra-short-acting β1-blocker, is useful for managing supraventricular tachyarrhythmias in sepsis”. World Journal of Critical Care Medicine. 4 (3): 251–7. doi:10.5492/wjccm.v4.i3.251. PMC 4524822. PMID 26261777.
^ Dean L (2017). “Metoprolol Therapy and CYP2D6 Genotype”. In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520381. Bookshelf ID: NBK425389.
^ Ojima T, Nakamori M, Nakamura M, Katsuda M, Hayata K, Kato T, et al. (July 2017). “Randomized clinical trial of landiolol hydrochloride for the prevention of atrial fibrillation and postoperative complications after oesophagectomy for cancer”. The British Journal of Surgery. 104 (8): 1003–1009. doi:10.1002/bjs.10548. PMID 28444964. S2CID 1079409.
^ Xiao J, He P, Zou Q, Zhao Y, Xue Z, Deng X, et al. (March 2015). “Landiolol in the treatment of the intraoperative supraventricular tachycardia: a multicenter, randomized, double-blind, placebo-controlled study”. Journal of Clinical Anesthesia. 27 (2): 120–8. doi:10.1016/j.jclinane.2014.07.003. PMID 25434501.
^ Sezai A, Minami K, Nakai T, Hata M, Yoshitake I, Wakui S, et al. (June 2011). “Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: new evidence from the PASCAL trial”. The Journal of Thoracic and Cardiovascular Surgery. 141 (6): 1478–87. doi:10.1016/j.jtcvs.2010.10.045. PMID 21269646.
^ Sakamoto A, Kitakaze M, Takamoto S, Namiki A, Kasanuki H, Hosoda S (2012). “Landiolol, an ultra-short-acting β₁-blocker, more effectively terminates atrial fibrillation than diltiazem after open heart surgery: prospective, multicenter, randomized, open-label study (JL-KNIGHT study)”. Circulation Journal. 76 (5): 1097–101. doi:10.1253/circj.CJ-11-1332. PMID 22361918.
^ Shibata SC, Uchiyama A, Ohta N, Fujino Y (April 2016). “Efficacy and Safety of Landiolol Compared to Amiodarone for the Management of Postoperative Atrial Fibrillation in Intensive Care Patients”. Journal of Cardiothoracic and Vascular Anesthesia. 30 (2): 418–22. doi:10.1053/j.jvca.2015.09.007. PMID 26703973.
^ Kiyokuni M, Konishi M, Sakamaki K, Kawashima C, Narikawa M, Doi H, et al. (October 2016). “Beneficial effect of early infusion of landiolol, a very short-acting beta-1 adrenergic receptor blocker, on reperfusion status in acute myocardial infarction”. International Journal of Cardiology. 221: 321–6. doi:10.1016/j.ijcard.2016.07.076. PMID 27404699.
^ Kanamori K, Aoyagi T, Mikamo T, Tsutsui K, Kunishima T, Inaba H, et al. (2015). “Successful Treatment of Refractory Electrical Storm With Landiolol After More Than 100 Electrical Defibrillations”. International Heart Journal. 56 (5): 555–7. doi:10.1536/ihj.15-102. PMID 26346519.
^ Kakihana Y, Nishida O, Taniguchi T, Okajima M, Morimatsu H, Ogura H, et al. (2020). “Efficacy and safety of landiolol, an ultra-short-acting β1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): A multicentre, open-label, randomised controlled trial”. The Lancet Respiratory Medicine. 8 (9): 863–872. doi:10.1016/S2213-2600(20)30037-0. PMID 32243865.
^ Yamashita T, Nakasu Y, Mizutani H, Sumitani K (2019). “A prospective observational survey on landiolol in atrial fibrillation/Atrial flutter patients with chronic heart failure – AF-CHF landiolol survey”. Journal of Cardiology. 74 (5): 418–425. doi:10.1016/j.jjcc.2019.05.012. PMID 31255463.
^ Balik M, Sander M, Trimmel H, Heinz G (2018). “Landiolol for managing post-operative atrial fibrillation”. European Heart Journal Supplements. 20 (Suppl A): A10 – A14. doi:10.1093/eurheartj/sux036. PMC 5909769. PMID 30188958.


Clinical data
Trade names	Onoact, others
Other names	ONO-1101
AHFS/Drugs.com	Rapiblyk
License data	US DailyMed: Landiolol
Routes of administration	Intravenous
Drug class	Antiarrhythmic
ATC code	C07AB14 (WHO)
Legal status
Legal status	CA: ℞-only^[1]^[2]^[3]US: ℞-only^[4]Rx-only^[5]
Identifiers
showIUPAC name
CAS Number	133242-30-5144481-98-1
PubChem CID	114905 164457
ChemSpider	102855
UNII	62NWQ924LH G8HQ634Y17
KEGG	D12410D01847
CompTox Dashboard (EPA)	DTXSID10158026
Chemical and physical data
Formula	C₂₅H₃₉N₃O₈
Molar mass	509.600 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

Bivamelagon

April 19, 2025 9:03 am / Leave a comment

Bivamelagon

CAS 2641595-54-0

NO1Y8WRA8N, 629.3 g/mol, C₃₅H₅₃ClN₄O₄

MC-4R Agonist 2

N-[(3S,5S)-1-[[(3S,4R)-4-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-3-pyrrolidinyl]carbonyl]-5-(4-morpholinylcarbonyl)-3-pyrrolidinyl]-2-methyl-N-(cis-4-methylcyclohexyl)propanamide
N-((3S,5S)-1-((3S,4R)-1-(tert-Butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-(cis-4-methylcyclohexyl)isobutyramide
N-[(3S,5S)-1-[(3S,4R)-1-tert-butyl-4-(4-chlorophenyl)pyrrolidine-3-carbonyl]-5-(morpholine-4-carbonyl)pyrrolidin-3-yl]-2-methyl-N-(4-methylcyclohexyl)propanamide

LB54640; LB-54640; LR-19021; LR19021

MC-4R Agonist 2 (Example 1) is a MC4R agonist. MC-4R Agonist 2 can be used in the study of obesity, diabetes, inflammation, and erectile dysfunction^[1].

SCHEME

PATENT

WO2021091283A1.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021091283&_cid=P21-M9NZN0-90342-1

Step D: Preparation of N -((3 S ,5 S )-1-((3 S ,4 R )-1-( tert -butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide hydrochloride

[173]

N -((3 S ,5 S )-1-((3 S ,4 R )-1-( tert -butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)- N -((1 s ,4 R )-4-methylcyclohexyl)isobutyramide (5.0 g, 7.95 mmol) obtained in Step C was dissolved in ethyl acetate (50 ml), and a 2N hydrochloric acid ethyl acetate solution (3.97 ml, 15.89 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration using hexane and diethyl ether to obtain the title compound (5.23 g, 99%).

[174]

MS [M+H] = 630 (M+1)

[175]

¹H NMR (500 MHz, CD ₃OD) δ 7.49-7.44 (m, 4H), 4.83 (m, 1H), 4.23-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.79-3.47 (m, 14H), 3.03-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.14 (m, 1H), 1.97 (m, 1H), 1.80-1.62 (m, 5H), 1.50 (s, 9H), 1.44-1.27 (m, 3H), 1.06-1.04 (m, 9H)

PATENT

WO2022235103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022235103&_cid=P21-M9NZHZ-87240-1

Preparation of cyclohexyl-3-carbonyl-l)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (MC70)

[141]

[142]The title compound was obtained through the following steps A, B, and C.

[143]

Step A: Preparation of methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate

[144]Methyl (2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate hydrochloride (28.7 g, 82.73 mmol) obtained in Manufacturing Example 1, (3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (24.5 g, 86.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 g, 115.83 mmol) and 1-hydroxybenzotriazole hydrate (15.7 g, 115.83 mmol) obtained in Manufacturing Example 2 were dissolved in N,N’-dimethylformamide (400 ml) and N,N’-diisopropylethylamine (72.0 ml, 413.66 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours and the reaction solvent was concentrated under reduced pressure. A 0.5 N aqueous sodium hydroxide solution was added, and extraction was performed twice with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate (41.19 g, 87%).

[145]

MS [M+H] = 575 (M+1)

[146]

Step B: Preparation of (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid

[147]Methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) obtained in the above step A was dissolved in methanol (450 ml), and 6N sodium hydroxide aqueous solution (57.2 ml, 343.09 mmol) was added. The mixture was stirred at room temperature for 16 hours, and the pH was adjusted to about 5 with 6N hydrochloric acid aqueous solution, and then the reaction solution was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane, and the insoluble solid was filtered through a paper filter. The filtrate was concentrated under reduced pressure to obtain the crude title compound (38.4 g, 99%), which was used in the next step without purification.

[148]

MS [M+H] = 561 (M+1)

[149]

Step C: Preparation of N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide

[150](2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid (38.4 g, 68.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4 g, 96.04 mmol) and 1-hydroxybenzotriazole hydrate (13.0 g, 96.04 mmol) obtained in the above step B were dissolved in N,N’-dimethylformamide (200 ml), and then morpholine (5.9 ml, 68.80 mmol) and N,N’-diisopropylethylamine were sequentially added. (59.7 ml, 343.02 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours and the reaction solution was concentrated under reduced pressure, 0.5 N aqueous sodium hydroxide solution was added, and extraction was performed twice with ethyl acetate. The organic layer was washed twice with aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (37.05 g, 86%,

MC70 ).

[151]

MS [M+H] = 630 (M+1)

Bivamelagon (INNTooltip International Nonproprietary Name; developmental code names LB54640, LR-19021) is a small-molecule melanocortin MC₄ receptor agonist under development by LG Chem Life Sciences for the treatment of hypothalamic obesity, .^[1]^[2] Unlike the older drug with the same mechanism of action, setmelanotide, it can be taken orally.^[3]^[4]^[5] As of March 2024, it is in phase 2 clinical trials.^[1]

References

^ Jump up to:^a ^b “Rhythm Pharmaceuticals”. AdisInsight. 13 March 2024. Retrieved 25 February 2025.
^ “Delving into the Latest Updates on Bivamelagon with Synapse”. Synapse. 23 January 2025. Retrieved 25 February 2025.
^ Aronne, Sarah R. Barenbaum, Louis J. (2023). “Antiobesity Medications on the Horizon”. Handbook of Obesity – Volume 2 (5 ed.). CRC Press. pp. 394–401. doi:10.1201/9781003432807-42. ISBN 978-1-003-43280-7.
^ First-in-Human Study of Safety, Pharmacodynamics of LB54640, An Oral Melanocortin-4 Receptor Agonist Mirza, Victoria, MD, MPH; Lee, Jisoo, MD; Gwak, Heemin; Yang, Yunjeong; Kim, Mina. Obesity; Silver Spring Vol. 30, (Nov 2022): 145-146.
^ Piper, Noah B.C.; Whitfield, Emily A.; Stewart, Gregory D.; Xu, Xiaomeng; Furness, Sebastian G.B. (August 2022). “Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors”. Biochemical Pharmacology. 202: 115115. doi:10.1016/j.bcp.2022.115115. PMID 35671790. S2CID 249452717.

Clinical data

Other names	LB54640; LB-54640; LR-19021; LR19021
Routes of administration	Oral
Drug class	Melanocortin MC₄ receptor agonist
Legal status
Legal status	Investigational
Identifiers
showIUPAC name
CAS Number	2641595-54-0
PubChem CID	165152355
DrugBank	DB18331
ChemSpider	129440355
UNII	NO1Y8WRA8N
Chemical and physical data
Formula	C₃₅H₅₃ClN₄O₄
Molar mass	629.28 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

[1]. Seung Wan Kang, et al. Melanocortin-4 receptor agonists. Patent WO2021091283A1.

////////Bivamelagon, LB54640, LB-54640, LR-19021, LR19021, NO1Y8WRA8N

Iomeprol

April 19, 2025 2:53 am / Leave a comment

Iomeprol

78649-41-9
Iomeprolum
Iomeron
Iomeprolo

WeightAverage: 777.089
Monoisotopic: 776.8541

Chemical FormulaC₁₇H₂₂I₃N₃O₈

FDA APPROVED, 11/27/2024, Iomervu, For use as a radiographic contrast agent

1-N,3-N-bis(2,3-dihydroxypropyl)-5-[(2-hydroxyacetyl)-methylamino]-2,4,6-triiodobenzene-1,3-dicarboxamide

Iomeprol, sold under the brand name Imeron among others, is a medication used as a radiocontrast agent in X-ray imaging.^[1]^[2]^[3]

Iomeprol was approved for medical use in the United States in November 2024.^[1]^[4]^[5]

Experimental Properties

Property	Value	Source
melting point (°C)	285-291	https://www.chemos.de/import/data/msds/GB_en/78649-41-9-A0017152-GB-en.pdf
boiling point (°C)	198	https://datasheets.scbt.com/sds/eghs/en/sc-211652.pdf

European patent EP0026281a1 first discloses two synthetic methods of iomeprol, respectively:
the first synthesis method is to take 5-amino-2, 4, 6-triiodoisophthalic acid as a starting material, methylate amino to chlorinate the starting material to prepare diacyl chloride, then use acetoxy acetyl chloride to carry out acylation reaction, then carry out amidation reaction with 3-amino-1, 2-propylene glycol, and finally use sodium hydroxide to hydrolyze the product to obtain iomeprol, as shown in the synthesis scheme 1

U.S. Patent No. 4,364,921 discloses three preparation processes of iopromide. One of them is shown in the following reaction scheme 1.

[Reaction scheme 1]

U.S. patent No. 4,364,921 are those basically under the same concept as shown in the following reaction schemes 3 and 4.

[Reaction scheme 3]

[Reaction scheme 4]

References:

M F C Co., Ltd.;Park Yung-ho;Hwang Seong-gwan;Park Jang-ha;Seo Rak-seok;Kim Gyeong-deok KR2020/77762, 2020, A Location in patent:Paragraph 0133-0136

Yield:78649-41-9 95%

Reaction Conditions:

with sodium hydroxide in N,N-dimethyl acetamide at 10 – 60; for 16 h;

Steps:

6 Synthesis of Iomeprole
Prepared N,N-bis(2,3-dihydroxypropyl)-5-(2-hydroxyacetamido)-2,4,6-triiodoisophthalamide 20 g (0.026 mol) in a reactor and 60 g of N,N-dimethylacetamide was added, followed by heating and stirring at 60 °C to dissolve.1.3 g (0.033 mol) of caustic soda was added to the reactor and stirred to dissolve. The reactor was cooled to 10 °C or less, and 4.5 g (0.032 mol) of iodomethane was added to the reactor, followed by stirring at 25 °C for 14 to 16 hours. After confirming the completion of the reaction, acetic acid was added to neutralize the reaction solution.The solvent was removed through concentration under reduced pressure at 60 to 65 °C and 60 g of ethanol was added to crystallize. The wet body was obtained by filtration and dried under reduced pressure in an oven at 60 °C for 12 hours to obtain iomeprol (yield 95%, purity 99.8%).

Iomeprol (CAS NO.: ), with its systematic name of , N,N’-bis(2,3-dihydroxypropyl)-5-((hydroxyacetyl)methylamino)-2,4,6-triiodo-, could be produced through many synthetic methods.

Following is one of the synthesis routes:
Firstly, 5-Amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid (I) is treated with chloride to produce the dichloride (II). Secondly, compound (II) is treated with acetoxyacetyl chloride to afford compound (III), which is methylated with iodomethane. Lastly, condensation with 3-amino-1,2-propanediol of the N-methyl derivative (IV) thus obtained, followed by deacetylation with alkali metal hydroxide, yields iomeprol.

PATENT

https://patents.google.com/patent/WO2009134030A1/en

The process for preparing iopromide of formula (1) according to the present invention is shown in the following reaction scheme 5.

[Reaction scheme 5]

Step 1

5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) is used as a starting material. The compound of formula (2) is reacted with methoxyacetyl chloride in dimethylacetamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3) which is then used without an additional purification procedure for the next step. The compound of formula (3) is reacted with 2,3-dihydroxypropylamine in dimethylacetamide solvent in the presence of triethylamine to form 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride of formula (4), as shown in the following reaction scheme 6.

[Reaction scheme 6]

In the above reaction scheme, if 2,3-dihydroxypropylamine is used preferably in 0.6 to 1 equivalents, more preferably in 0.7 equivalents, the compound of formula (4) can be obtained in reasonable yield with minimizing the generation of the compound of formula (5) which is a bismer by-product.

In addition, since the unreacted compound of formula (3) existing in the filtrate obtained along with the compound of formula (4) can be recycled to the next batch without an additional recovery procedure, the loss of the yield of iopromide which occurs during the removal procedure of the bismer by-product generated in a large amount in conventional process can be prevented ultimately.

Step 2

The compound of formula (4) is reacted with acetic anhydride in acetic acid solvent in the presence of sulfuric acid as a catalyst to convert into the compound of formula (19). Sulfuric acid of preferably 0.01 to 0.2 moles, more preferably 0.05 to 0.1 moles per 1 molar reaction is added at a temperature of preferably from 0 to 30°C, more preferably from 5 to 25°C. Acetic anhydride of preferably 0.19 to 1 L, more preferably 0.35 to 0.7 L per 1 molar reaction is used.

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid-N,N’-bis-(2,3-diacetoxypropyl) diamide of the compound of following formula (21), which is generated by a simultaneous conversion of the bismer by-product of formula (5) already produced in the step 1 with the conversion of the compound of formula (4) into the compound of formula (19), is easily removed by the simple crystallization procedure of the compound of formula (19). That is, the by-product of the compound of formula (21) can be removed even without an additional removal procedure. It consequently means that the bismer by-product of the compound of formula (5) which is hard to remove according to conventional process can be effectively removed in the present invention even without any additional purification procedures.

[Formula 5]

[Formula 21]

Step 3

The compound of formula (19) is reacted with 2,3-dihydroxy-N-methypropylamine in dimethylacetamide solvent in the presence of triethylamine as a base to convert into the compound of formula (20). By the hydrolysis of the compound of formula (20) in aqueous NaOH solution without further purification therefor, iopromide of formula (1) can be obtained.

The present invention will be explained more specifically by the following examples. However, the examples are not intended to limit the scope of the present invention thereto.

Example 1: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (Formula 4)

5-amino-2,4,6-triiodoisophthalic acid dichloride (13.7 kg, 23 mol) was dissolved in dimethylacetamide (17.2 kg) and the mixture was cooled to 15 ℃ . Methoxyacetyl chloride (3.74 kg, 34.5 mol) was added dropwise thereto for 2 hours, and then the mixture was stirred for 15 hours. After confirming the disappearance of the starting material by HPLC analysis for reaction, methylene chloride (45.7 kg) and water (11.5 kg) were subsequently added to the reaction mixture upon being stirred, and then the stirring was stopped and the layers became separated. The obtained organic layer was washed with aqueous sodium bicarbonate solution and concentrated by distillation under reduced pressure. To a solution of the obtained concentrate dissolved in dimethylacetamide (43.1 kg), triethylamine (1.95 kg, 19.32 mol) was added and then a solution of 2,3-dihydroxypropylamine (1.47 kg, 16.13 mol) dissolved in dimethylacetamide (10.78 kg) was added dropwise thereto for 5 hours with maintaining 0 to 5 ℃ . After additional 3 hours with stirring, the reaction mixture was concentrated by distillation under reduced pressure and to the concentrate, methylene dichloride (213.33 kg) was added dropwise for 5 hours to form solid. The solid was filtered and the title compound was obtained as a white solid (10.98 kg, yield 66.1 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.2,10.06(2s, 1H); 8.79, 8.71, 8.63 (3t, 1H); 4.5~4.0(br, 2H); 4.04, 4.00(2s, 2H); 3.71~3.66(m, 1H); 3.48, 3.47(2s, 3H); 3.40~3.36(m, 2H); 3.36~3.27(m, 1H); 3.2~3.09 (m, 1H)

Example 2: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (Formula 19)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride (9.97 kg, 13.8 mol) was dispersed in acetic acid, and then anhydrous acetic acid (7.45 kg) was added thereto and the mixture was cooled to 5 ℃ . Sulfuric acid (135 g) was slowly added thereto and the mixture was stirred for 1 hour. To the obtained clear solution, sodium acetate trihydrate (376 g) was added and dissolved at 0 to 5 ℃ . And then water (96.6 kg) was added for 3 hours with maintaining 0 to 10 ℃ to produce solid. The produced solid was filtered and the title compound was obtained as a white solid (10.04 kg, yield 90.2 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.12, 9.99(2s, 1H); 8.91, 8.80(2t, 1H); 5.10~5.06(m, 1H); 4.32~4.27(m, 1H); 4.20~4.16(m, 1H); 4.01, 4.00(2s, 2H); 3.52~3.37(m, 2H); 3.47, 3.46(2s, 3H); 2.02(s, 6H)

Example 3: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-dihydroxypropyl)]diamide (iopromide)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (7.23 kg, 8.97 mol) was dissolved in dimethylacetamide (12.6 kg), and triethylamine (1.95 kg, 19.32 mol) was added thereto and a solution of 2,3-dihydroxy-N-methylpropylamine (943 g, 8.97 mol) dissolved in dimethylacetamide (4.2 kg) was added dropwise thereto at room temperature. After additional 2 hours with stirring, the solution was concentrated by distillation under reduced pressure. To an aqueous solution of the obtained 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-diacetoxypropyl)]diamide dissolved in water, a solution of sodium hydroxide (897 g, 22.43 mol) dissolved in water was added and the reaction mixture was stirred for 10 hours with maintaining 20 to 25 ℃ . The reaction solution was passed through cation exchange resin column and anion exchange resin column to produce a colorless and transparent aqueous solution. The obtained aqueous solution was distilled under reduced pressure to remove water completely, crystallized in ethanol and filtered to obtain a white crystalline iopromide (6.032 kg, yield 85 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.07, 10.03, 9.97, 9.90(4s,1H); 8.66, 8.57, 8.52(3t, 1H); 4.76~4.74(m, 1H); 4.72, 4.67(2t, 1H); 4.59~4.58(m, 1H); 4.54~4.44(m, 1H); 4.00(s, 2H); 3.89~3.88(m, 1H); 3.69~3.68(m, 2H); 3.47(s, 3H); 3.44~3.38(m, 4H); 3.23~3.17(m, 3H), 2.85~2.83(4s, 3H)

Example 4: Synthesis of 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-diacetoxypropyl)]diamide (Formula 20)

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-diacetoxypropyl)amide chloride (80.65 g, 0.1 mol) was dissolved in dimethylacetamide (140.5 g), and then triethylamine (11.13 g, 0.11 mol) was added thereto and a solution of 2,3-dihydroxy-N-methylpropylamine (10.5 g, 0.1 mol) dissolved in dimethylacetamide (46.9 g) was added dropwise thereto at room temperature. After additional 2 hours with stirring, the produced solid was filtered and then the filtrate was concentrated by distillation under reduced pressure. To the obtained concentrate, diethyl ether was added dropwise to form solid. The formed solid was filtered and the title compound was obtained as a white solid (85.8 g, yield 98 %).

¹ H NMR(dmso-d⁶, 500MHz) 10.10, 10.06, 10.00, 9.92(4s,1H); 8.93, 8.83, 8.78(3m, 1H); 5.09(br, 1H); 4.78~4.74(m, 1H); 4.62~4.58(m, 1H); 4.34~4.26(m, 1H); 4.22~4.16(m, 1H); 4.00(s, 2H); 3.89(br, 1H); 3.72~3.65,(m, 1H); 3.49~3.40(br, 2H);3.47(s, 3H); 3.48~3.38(m, 2H); 3.22~3.12,(m, 1H); 3.07~3.04(m, 1H); 2.87~2.82(m, 2H); 2.03(s, 3H); 2.02(s, 3H)

PATENT

https://patents.google.com/patent/RU2563645C2/ru

Scheme 3

Example 1Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH

₂ -CH(OH)CH

₂ OH groups using a starting solution heated to 60

° C.In a 2 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was heated to 60 °C and then solid I

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO

₃ (173.6 g; 0.494 mol) was slowly added over 2 h. The reaction mixture was maintained at 60 °C for an additional 4 h, during which time the pH spontaneously remained in the range of 5-5.5. The red solution was cooled to 25°C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached a stable negative value in the range from 0 to -20 mV.During quenching of the reaction mixture, the pH was maintained at 5 by adding minimal amounts of 30% (w/w) aqueous NaOH solution.HPLC analysis (the results of which are shown in Fig. 1) showed the degree of conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (by area % on the HPLC chromatogram), and the resulting solution was used in the next stage of the synthesis without any further processing.Example 2Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH

₂ -CH(OH)CH

₂ OH groups using a starting solution heated to 40

° CIn a 2 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, solid I

₂ (250.6 g, 0.988 mol) was added in one portion to an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution, 0.816 mol; pH 9.6) heated to 40 °C. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO

₃ (173.6 g, 0.494 mol) was slowly added over 3 h. The reaction mixture was then heated for 2 h at 40°C, 1 h at 50°C and 1 h at 60°C, during which time the pH spontaneously remained in the range of 5-5.5. The resulting red solution was cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution during quenching, which was carried out by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values in the range of -20 to -50 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 3Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH

₂ -CH(OH)CH

₂ OH groups using a stock solution heated to 30

° C and quenching the reaction mixture with bisulfite at pH5 in the final stepIn a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g of solution; 0.816 mol; pH 9.6) was diluted with H

_{2 O (1054 g), heated to 30 °C and then solid I}

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO

₃ (173.6 g; 0.494 mol) was slowly added over 4 h. The temperature of the reaction mixture was raised to 60°C and maintained at this temperature for a further 4 h, with the pH spontaneously remaining in the range of 5-5.5. The resulting red solution was cooled to 25°C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5 by adding 30% (w/w) aqueous NaOH solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values in the range of 0 to -20 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 4Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH

₂ -CH(OH)CH

₂ OH groups using a starting solution heated to 30

° C and quenching the reaction mixture with bisulfite at pH7 in the final stepIn a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of the sodium salt of 3,5-disubstituted phenol 1 corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was diluted with H

_{2 O (1054 g), heated to 30 °C and then solid I}

₂ (250.6 g; 0.988 mol) was added in one portion. When the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO

₃ (173.6 g; 0.494 mol) was slowly added over 4 h. The temperature of the reaction mixture was raised to 60°C and maintained at this temperature for a further 4 h, during which time the pH spontaneously remained in the range of 5-5.5. The resulting red solution was cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution during quenching, which was carried out by adding 18% (w/w) aqueous sodium bisulfite solution until the color was lost and the oxidation-reduction potential, measured with a suitable electrode, reached stable negative values in the range of -20 to -50 mV.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 5Preparation of a compound of formula 2, in which both substituents R and R’ are -NH-CH

₂ -CH(OH)CH

₂ OH groups, using a starting solution at room temperature (approximately 20

° C)In a 4 L four-necked jacketed reactor equipped with a mechanical stirrer, reflux condenser and combination pH/temperature electrode, an aqueous solution of 3,5-disubstituted phenol 1 sodium salt corresponding to a phenol concentration of 22.8% (w/w) (1175 g solution; 0.816 mol; pH 9.6) was first diluted with H

_{2 O (1054 g) maintaining the temperature at 20 °C, and then solid I}

_{2 (250.6 g; 0.988 mol) was added in one portion. The resulting solution was then heated to 40 °C and when the pH spontaneously dropped to 5, a 50% (w/w) aqueous solution of HIO}

₃ (173.6 g; 0.494 mol) was slowly added over 4 h . The temperature of the reaction mixture was raised to 60°C over 2 h and maintained at this temperature for a further 3 h, during which time the pH spontaneously remained in the range of 5-5.5. The red solution was then cooled to 25°C, the pH was adjusted to 7 and maintained at this level by adding 30% (w/w) aqueous NaOH solution, and quenched with sodium bisulfite (18% (w/w) aqueous solution) until color loss and stable negative values (in the range of -20 to -50 mV) of the oxidation-reduction potential were reached, measured with suitable redox electrodes.HPLC analysis showed the conversion of the starting compound to 3,5-disubstituted-2,4,6-triiodophenol 2b to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further treatment.Example 6Preparation of a compound of formula 2 in which the substituent R is a -NH-CH

₂ -CH(OH)CH

₂ OH group and R’ is -NH-CH(CH

₂ OH)

₂ using a starting solution heated to 60

° C.In a 1 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser, and combination pH/temperature electrode, N-(2,3-dihydroxypropyl)-N’-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-1,3-benzenedicarboxamide (100.3 g, 0.305 mol) was dissolved in H

₂ O (430 g) and converted to the corresponding sodium salt by adding 30% (w/w) NaOH (40.6 g, 0.305 mol) (pH 9.5). The solution was heated to 60 °C and solid I

₂ (93.1 g, 0.367 mol) was added in one portion; When the pH spontaneously dropped to 5, 50% (w/w) aqueous HIO3 (64.5 g, 0.183 mol) was added slowly over 2 h

_. The reaction temperature was maintained at 60 °C for a further 4 h, during which time the pH of the reaction mixture spontaneously remained in the range 5-5.5. The resulting red solution was cooled to 25 °C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5, by adding 30% (w/w) aqueous NaOH until colourlessness and a stable negative oxidation-reduction potential, measured with a suitable oxidation-reduction electrode, in the range 0 to -20 mV.HPLC analysis (Fig. 2) showed the degree of conversion of the starting compound to N-(2,3-dihydroxypropyl)-N’-[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide >98% (by area % on the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any additional processing.Example 7Preparation of a compound of formula 2 in which both substituents R and R’ are -NH-CH(CH

₂ OH)

₂ groups using a starting solution heated to 60

° C.In a 0.5 L jacketed four-neck reactor equipped with a mechanical stirrer, reflux condenser, and combination pH/temperature electrode, N,N’-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-1,3-benzenedicarboxamide (50 g, 0.152 mol) was dissolved in H

₂ O (215 g) and converted to the corresponding sodium salt by adding 30% (w/w) NaOH (20.3 g, 0.152 mol) (pH 9.5). The solution was heated to 60 °C and solid I

₂ (46.4 g, 0.183 mol) was added in one portion; When the pH spontaneously dropped to 5, 50% (w/w) aqueous HIO3 (32.2 g, 0.091 mol) was added slowly over 2 h

_. The reaction temperature was maintained at 60 °C for an additional 4 h, during which time the pH of the reaction mixture spontaneously remained in the range 5-5.5. The resulting red solution was cooled to 25 °C and quenched by adding 18% (w/w) aqueous sodium bisulfite solution, maintaining the pH at 5, with 30% (w/w) aqueous NaOH until colorlessness and a stable negative oxidation-reduction potential (in the range of -20 to -50 mV), as measured by a suitable oxidation-reduction electrode.HPLC analysis showed the conversion of the starting compound to N,N’-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-hydroxy-2,4,6-triiodo-1,3-benzenedicarboxamide to be >98% (based on area % of the HPLC chromatogram), and the resulting solution was used in the next step of the synthesis without any further processing.Comparative example 1This test was carried out to evaluate the efficiency of the iodination reaction disclosed by Patil et al., in ARKIVOC, 2006, 104 and Tetrahedron Lett., 2005, 46, 7179.In a 50 mL three-necked round-bottomed flask equipped with a thermometer and a reflux condenser, solid 3,5-disubstituted phenol 1 (16.4 g, 50 mmol) was suspended in ethanol (30 mL). Then, to the resulting suspension, heated to 38-40 °C, solid I

₂ (15.2 g, 60 mmol) was added in one portion and a solution of HIO

₃ (5.3 g, 30 mmol) in H

₂ O (3 mL) was added in the indicated order over 5 min. The resulting dark brown mixture was stirred at 38-40 °C for about 1 h and then the change in appearance of the reaction mixture was recorded, which turned into a clear dark brown solution. The reaction mixture was maintained at the above temperature for a total of 3.5 h, then cooled to room temperature, which caused crystallization of the pale yellow solid product. After 15 h at room temperature, the solid was isolated by filtration and dried to give the desired 3,5-disubstituted-2,4,6-triiodophenol (12.1 g, 17 mmol). Yield 34.3%.During the iodination reaction, the reaction mixture was analyzed by HPLC. In particular, the first analysis was performed 1.5 hours after the start of iodination (the reaction time was chosen based on the literature sources cited), and its results are shown in Fig. 3, and the second analysis was performed after another 2 hours (the total reaction time was 3.5 hours), and its results are shown in Fig. 4. The results show that even after 3.5 hours, the conversion is not complete and a significant amount (13% based on the area on the HPLC chromatogram) of the original substrate is still present. On the other hand, a longer reaction time leads to the formation of a significant amount of impurities, which are decay products, which are easily detected after 3.5 hours of reaction (Fig. 4). This is certainly a factor that adversely affects the reaction yields. However, the low reaction yields can also be attributed to the solubility of 3,5-disubstituted-2,4,6-triiodophenol 2b in an alcohol medium, as confirmed by the analysis of the mother liquor shown in Fig. 5, which interferes with the quantitative isolation of the iodination product.In this regard, the increase in both the reaction yield and the product purity due to the use of an aqueous medium and reaction conditions, expressed in the above results, is evident from a comparison of Figs. 3-5 with Figs. 1 and 2, which show chromatograms (HPLC) of crude reaction solutions (Examples 1 and 6, respectively) obtained using the method of the present invention.

PATENT

https://patents.google.com/patent/KR20200032280A/en

[Scheme 3]

Example One.

Iomeproletic Produce

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) 5g (1 equivalent) and 3.6 g (5 equivalents) of calcium chloride was added to 25 g of methanol together, and dissolved at reflux at room temperature or 70 ° C. for 60 minutes.

After cooling the temperature of the solution to 10 ℃ to 15 ℃ 0.3g (0.62 equivalents) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred for 3 hours at the same temperature until the reaction was completed.

After completion of the reaction, 1 mL of HCl (35%) was added to acidify, 25 mg of 2-butanol was added, stirred at a temperature of 70 to 80 ° C. for 2 hours, cooled, filtered and washed with 2-butanol to obtain an iomeprole crude product.

The above prepared omeprolol was added to a mixture of 25 mL of methanol and 10 mL of water, heated to 50 ° C. to dissolve, put 20 mL of 2-butanol, refluxed at 90 ° C. for 3 hours, cooled to room temperature, and the resulting crystal was filtered.

After washing with 2-butanol and drying under reduced pressure at 90 ° C. for 12 hours, 4.17 g of Iomeprole (HPLC: 99.3%) was obtained.

Example 2.

Preparation of Iomeprole

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) 5g (1 equivalent) and 3.6 g (5 equivalents) of calcium chloride was added to 25 g of methanol together and refluxed at 70 ° C for 30 minutes to dissolve.

After cooling the solution to 0-5 ° C., 0.3 g (0.62 equivalents) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred for 7 hours at the same temperature until the reaction was completed.

After completion of the reaction, 1 mL of HCl (35%) was added to acidify, 30 mL of 2-butanol was added, refluxed at a temperature of 70-80 ° C. for 2 hours, stirred, filtered and washed with 2-butanol to obtain an iomeprole crude product.

After adding the above prepared omeprolol to a mixture of 25 mL of methanol and 10 mL of water, the temperature was raised to 50 ° C. to dissolve, 20 mL of 2-butanol was added, refluxed at 90 ° C. for 3 hours, cooled to room temperature, and the resulting crystal was filtered. .

After washing with 2-butanol and drying under reduced pressure at 90 ° C. for 12 hours, 4.21 g of Iomeprole (HPLC: 99.1%) was obtained.

Comparative example 1 (Inorganic chloride Non-addition )

After adding 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) to 25 g of methanol It was refluxed for 30 minutes.

After the temperature of the turbid solution was cooled to 10 ° C to 15 ° C, 0.3 g (0.62 equivalent) of calcium hydroxide was added and stirred at the same temperature for 1 hour.

2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred at the same temperature for 5 hours.

As a result of reactivity review by HPLC, synthesis of iomeprole progressed 5%, 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6- Triiodoisophthalamide (1b) was found to be 90% or more remaining, so that the reactivity was very low.

Comparative example 2 (Inorganic base Non-addition )

5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6-triiodoisophthalamide (1b) and 3.6 g of calcium chloride are methanol After adding to 25 g, the mixture was refluxed for 30 minutes to dissolve.

After the temperature of the solution was cooled from 10 ° C to 15 ° C, 2.48 g (3 equivalents) of dimethyl sulfate was added to the reaction solution and stirred at the same temperature for 5 hours.

As a result of reactivity review by HPLC, synthesis of iomeprole proceeds 0.5%, 5- (2-hydroxyacetamido) -N, N’-bis (2, 3-dihydroxypropyl) -2, 4, 6- Triiodoisophthalamide (1b) was found to be very low reactivity with more than 99% remaining.

PATENT

https://patents.google.com/patent/CN102363600B/en

.Synthetic route is seen formula 1:

Embodiment

Embodiment 1

5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:

In the there-necked flask that agitator and reflux condensing tube are housed, 76g(0.133mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthalic acid is dissolved in 250mL(2.53mol) in the ethyl acetate, after waiting to stir, add 29mL(0.4mol) sulfur oxychloride, be warming up to 50 ℃ of acyl chloride reaction temperature then, stir and finished reaction in 6 hours.After treating that ethyl acetate and sulfur oxychloride boil off under the decompression, residue boils off solvent and washs through frozen water after adding the 100mL ethyl acetate, dry product 68.9g, yield is that 84.9%(is with 5-methylamino-2,4,6-triiodo m-phthalic acid meter), m.p.167 ~ 169 ℃.

Embodiment 2

5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:

The acyl chloride reaction temperature is 80 ℃, and in 3 hours reaction times, all the other are operated with embodiment 1.

Embodiment 3

5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:

In reaction flask, add 36.6g(0.06mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthaloyl chloride and 80mL N,N-dimethylacetamide, heating in water bath to 50 ℃, after the stirring and dissolving, be cooled to 10 ℃, begin to drip 10.2g(0.09mol) chloroacetyl chloride, dropwising the back heats up 50 ℃, stirred 3 hours, and be cooled to 10 ℃, be added dropwise to the 150mL frozen water.Filter, through the frozen water washing, dry product 38.7g, yield be 94%(with 5-methylamino-2,4,6-triiodo m-phthaloyl chloride meter), m.p.194 ~ 196 ℃.

Embodiment 4

5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:

The chlorine acylation temperature is 90 ℃, and in 1 hour reaction times, all the other are operated with embodiment 3.

Embodiment 5

5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

In reaction flask, add 41.2g(0.06mol under the room temperature) 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride and 80mL N, the N-N,N-DIMETHYLACETAMIDE after the stirring and dissolving, is cooled to 10 ℃, add 16g(0.16mol) triethylamine and 14.6g(0.16mol) 3-amino-1, the 2-propylene glycol is heated to 20 ℃ then, stirs and finishes reaction in 15 hours, be chilled to after-filtration below 10 ℃, after evaporated under reduced pressure, residue is dissolved in the 160mL methyl alcohol with filtrate, adds 200mL water and stirs evenly, leave standstill, with the solid filtering of separating out, the washing, dry product 43.4g, yield is that 91%(is with 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride meter), m.p.204 ~ 207 ℃.

Embodiment 6

5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

The amidate action temperature is 50 ℃, and in 8 hours reaction times, all the other are operated with embodiment 5.

Embodiment 7

5-[N-methyl-glycolamide base]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:

In reaction flask, add 47.7g(0.06mol) 5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide, 250mL water, stir and to add 26g(0.32mol down) sodium acetate, back flow reaction is after 24 hours, the pressure reducing and steaming solvent.The residue dissolve with methanol filters, and filtrate boils off methyl alcohol, and vacuum-drying gets solid, is dissolved in the 150mL water, adds gac 1.8g, and reflux 30min filters.Filtrate is successively respectively by 732 Zeo-karbs and 717 anionite-exchange resin, and pressure reducing and steaming solvent again is after the resistates vacuum-drying, add 180mL ethanol and carry out recrystallization, get white solid 40.1g, HPLC detects purity greater than 99.0%, and yield is that 86%(is with 5-[N-methyl-2-chloracetyl amido]-N, N ‘-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide meter), m.p.〉280 ℃. ¹H-NMR?(DMSO-D ₆)δ（ppm）：2.91(s,4H)，3.21~3.36（m,4H）,?3.41~3.65（m,4H）,?3.85（s,2H）,?3.98（m,2H）,?4.1~?4.5（m,5H）,?8.2~?8.4（d,?2H）； ¹³C-NMR（D ₂O）δ（ppm）33.2，44.7，60.7，64.6，71.2，90.1，99.8，99.9，145.5，150.5，150.6，171.3，171.4，173.9。

PATENT

https://patents.google.com/patent/CN114213273A/en

synthetic route is as follows:

Example 1

The synthesis process of iomeprol with 5-amido-N, N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide as initial material includes successive chloroacetylation, methylation, hydrolysis and hydroxylation to synthesize iomeprol product, and includes the following steps:

the specific process comprises 4 reaction steps:

s1, chloroacetylation (preparation of 5- (2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

12g of 5-amino-N.N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodoisophthalamide was dissolved in 24g N, N-dimethylacetamide and stirred at room temperature. 12g of chloroacetyl chloride were added while controlling the temperature below 60 ℃. After the addition, the temperature is kept between 50 and 60 ℃, the stirring is carried out for 4 hours, and after the reaction is finished, the vacuum concentration is carried out below 65 ℃ until the reaction is dried. 36ml of ethyl acetate and 36ml of a 5% aqueous solution of sodium hydrogencarbonate were added to the concentrate to conduct extraction. The aqueous layer after separation was extracted twice with 10ml of ethyl acetate. The organic solutions thus extracted were mixed, 15ml of 5% saline was added thereto, and the mixture was washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 18.5g of an oily substance.

S2, methylation reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

dissolving 18.5g of the oily substance in the previous step by using 37ml of acetone, cooling to 0 ℃, adding 3.8g of potassium carbonate, keeping the temperature and stirring, dropwise adding 5.8g of dimethyl sulfate while stirring, keeping the temperature and reacting for 8 hours, after the reaction is finished, carrying out vacuum concentration to dryness at 60 ℃, dissolving the concentrated solution in 50ml of ethyl acetate and 50ml of water, and adding 10ml of ethyl acetate into the separated water layer for secondary extraction. The organic solutions thus extracted were mixed, 15ml of 5% saline was added thereto, and the mixture was washed, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 19.3g of an oily substance.

S3, ester hydrolysis reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide):

the above oily substance was dissolved in 20ml of methanol, 6.0g of water was added, 30.0g of 30% aqueous sodium hydroxide solution was added, and the reaction was carried out at 15 ℃ for 4 hours, and after the completion of the reaction, methanol was distilled off under reduced pressure to obtain an aqueous solution containing the objective compound.

S4 hydroxylation reaction (preparation of 5- (N-methyl-2-hydroxyacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide, i.e. iomeprol):

adding 6.0g of sodium acetate into the aqueous solution, heating to reflux for 24 hours, distilling under reduced pressure to remove the solvent, adding methanol into the residue to dissolve, filtering, evaporating the methanol from the filtrate, dissolving the residue in pure water, adding activated carbon, heating to reflux for 30 minutes, filtering, sequentially passing the filtrate through cation resin and anion resin, evaporating to remove the solvent, adding 70ml of ethanol to recrystallize, filtering, drying under reduced pressure at 50 ℃ to obtain 8.5g of white solid, wherein the HPLC purity is 99.2%, and the molar yield is 64%.

Example 2

S1, chloroacetylation (preparation of 5- (2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

500g of 5-amino-N.N’ -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodoisophthalamide was dissolved in 1000g N, N-dimethylacetamide and stirred at room temperature. 500g of chloroacetyl chloride was added while controlling the temperature below 60 ℃. After the addition, the temperature is kept between 50 and 60 ℃, the stirring is carried out for 4 hours, and after the reaction is finished, the vacuum concentration is carried out below 65 ℃ until the reaction is dried. 1500ml of ethyl acetate and 1500ml of 5% aqueous sodium bicarbonate solution were added to the concentrate to extract. The aqueous layer after separation was extracted twice with 480ml of ethyl acetate. The organic solutions thus extracted were mixed, and 650ml of 5% brine was added thereto, followed by washing, and after recovering the organic solution layer, magnesium sulfate was added to remove water, followed by filtration and distillation under reduced pressure to obtain 772.6g of an oil.

S2, methylation reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-bis (2-chloroacetoxy) propyl) -isophthalamide):

dissolving 772.6g of the oily matter in the previous step by 1545ml of acetone, cooling to 0 ℃, adding 158.5g of potassium carbonate, keeping the temperature and stirring, dropwise adding 241.5g of dimethyl sulfate while stirring, keeping the temperature and reacting for 8 hours, after the reaction is finished, vacuum concentrating at 60 ℃ to dryness, dissolving the concentrated solution in 1500ml of ethyl acetate and 1500ml of water, and adding 480ml of ethyl acetate into the separated water layer for secondary extraction. The organic solutions thus extracted were mixed, and then 650ml of 5% saline was added thereto, followed by washing, and after recovering the organic solution layer, magnesium sulfate was added thereto to remove water, followed by filtration and distillation under reduced pressure to obtain 805.7g of an oily substance.

S3, ester hydrolysis reaction (preparation of 5- (N-methyl-2-chloroacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide):

the above oil was dissolved in 800ml of methanol, 250g of water was added, 1250g of a 30% aqueous solution of sodium hydroxide was added, and the reaction was carried out at 15 ℃ for 4 hours, and after the completion of the reaction, methanol was distilled off under reduced pressure to obtain an aqueous solution containing the objective compound.

S4 hydroxylation reaction (preparation of 5- (N-methyl-2-hydroxyacetamido) -2,4, 6-triiodo-N, N’ -bis (2, 3-dihydroxypropyl) -isophthalamide, i.e. iomeprol):

adding 250g of sodium acetate into the aqueous solution, heating to reflux for 24 hours, distilling under reduced pressure to remove the solvent, adding methanol into the residue to dissolve, filtering, evaporating the filtrate to remove the methanol, dissolving the residue in pure water, adding activated carbon, heating to reflux for 60 minutes, filtering, sequentially passing the filtrate through cation resin and anion resin, evaporating to remove the solvent, adding 3000ml of ethanol to recrystallize, filtering, drying under reduced pressure at 50 ℃ to obtain 365.0g of white solid, wherein the HPLC purity is 99.1%, and the molar yield is 66%.

Compared with two synthesis methods in patent EP0026281A1, the synthesis method of iomeprol developed by the invention does not use thionyl chloride, reduces the difficulty of waste gas treatment, does not use acetoxy acetyl chloride, and ensures the process stability. Meanwhile, the used starting material (compound II) is a common intermediate of other contrast agents iohexol and ioversol, so that corresponding supporting construction is reduced.

Therefore, the synthetic route designed by the invention has the advantages of mild reaction conditions, stable quality, high yield, low cost, environmental protection and suitability for industrial production.

The embodiments are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same or similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.

Side effects

It is classified as a water-soluble, nephrotrophic, low osmolar X-ray contrast medium.^[2] Low osmolar non-ionic agents are better tolerated and less likely to cause side effects than the high osmolar ionic agents.^[2]

Society and culture

Iomeprol is not metabolized in the human body but excreted in unchanged form.^{[medical citation needed]} It is decomposed slowly and can therefore accumulate in the environment.^[6]

Legal status

Iomeprol was approved for medical use in the United States in November 2024.^[1]^[4]

Brand names

Iomeprol is sold under the brand name Iomervu.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216017s000,216017s000lbl.pdf
^ Jump up to:^a ^b ^c Rossiter D (2014). South African medicines formulary (11th ed.). Rondebosch, South Africa: Health and Medical Pub. Group .of the South African Medical Association. ISBN 978-1-875098-30-9. OCLC 869772940.
^ Haberfeld H, ed. (2020). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Iomeron 300 mg J/ml-Infusionsflasche.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 29 November 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Pfundstein P, Martin C, Schulz W, Seitz W, Ruth KM, Wille A, et al. (January 2015). “IC-ICP/MS-Analytik”. GIT Labor-Fachzeitschrift (in German): 29–31.
Dooley M, Jarvis B: Iomeprol: a review of its use as a contrast medium. Drugs. 2000 May;59(5):1169-86. doi: 10.2165/00003495-200059050-00013. [Article]
Katayama H, Spinazzi A, Fouillet X, Kirchin MA, Taroni P, Davies A: Iomeprol: current and future profile of a radiocontrast agent. Invest Radiol. 2001 Feb;36(2):87-96. doi: 10.1097/00004424-200102000-00004. [Article]
Rosati G: Clinical pharmacology of iomeprol. Eur J Radiol. 1994 May;18 Suppl 1:S51-60. doi: 10.1016/0720-048x(94)90094-9. [Article]
EMC Summary of Product Characteristics: Iomeron (iomeprol) solution for injection [Link]
FDA Approved Drug Products: IOMERVU (iomeprol) injection, for intra-arterial or intravenous use [Link]
Medsafe NZ: IOMERON® (iomeprol) safety data sheet [Link]

showv t e Contrast media (V08)

Clinical data

Trade names	Iomervu, others
License data	US DailyMed: Iomeprol
Routes of administration	Intravenous, intra-arterial
ATC code	V08AB10 (WHO)
Legal status
Legal status	US: ℞-only^[1]In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism	none
Elimination half-life	109±20 min
Excretion	Kidney
Identifiers
showIUPAC name
CAS Number	78649-41-9
PubChem CID	3731
DrugBank	DB11705
ChemSpider	3600
UNII	17E17JBP8L
KEGG	D01719
ChEBI	CHEBI:31710
CompTox Dashboard (EPA)	DTXSID1049061
Chemical and physical data
Formula	C₁₇H₂₂I₃N₃O₈
Molar mass	777.089 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////////////Iomeprol, Iomervu, FDA 2024, APPROVALS 2024, 78649-41-9, Iomeprolum, Iomeron, Iomeprolo, UNII-17E17JBP8L, E-7337, E 7337, E-7337, E7337, XRAY CONTRAST AGENT

Crinecerfont

April 18, 2025 11:42 am / Leave a comment

Crinecerfont

CAS 752253-39-7

SSR125543

SSR 125543

SSR-125543, WHO 10958, UNII-MFT24BX55I, 06-RORI,NBI-74788

FDA APPROVED 12/13/2024, Crenessity, To treat classic congenital adrenal hyperplasia
Press Release

4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine

WeightAverage: 483.04
Monoisotopic: 482.1594906

Chemical FormulaC₂₇H₂₈ClFN₂OS

CAS No. : 321839-75-2

Molecular Weight	519.50
Formula	C₂₇H₂₉Cl₂FN₂OS

Crinecerfont, sold under the brand name Crenessity, is a medication used for the treatment of congenital adrenal hyperplasia.^[1] It is a corticotropin-releasing factor type 1 receptor (CRF1R) antagonist developed to treat classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD).^[1] It is taken by mouth.^[1]

The most common side effects of crinecerfont in adults include fatigue, dizziness, and arthralgia (joint pain).^[2] For children, the most common side effects include headache, abdominal pain, and fatigue.^[2]

Crinecerfont was approved for medical use in the United States in December 2024.^[2]^[3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

A medication used to reduce the amount of steroid replacement required in patients with a genetic disease that causes, amongst other symptoms, a steroid deficiency.

OriginatorSanofi
DeveloperNeurocrine Biosciences; Sanofi
ClassAmines; Antidepressants; Anxiolytics; Chlorobenzenes; Cyclopropanes; Fluorobenzenes; Halogenated hydrocarbons; Phenyl ethers; Small molecules; Thiazines; Thiazoles
Mechanism of ActionCorticotropin releasing factor receptor 1 antagonists

Orphan Drug StatusYes – Congenital adrenal hyperplasia

MarketedCongenital adrenal hyperplasia
DiscontinuedMajor depressive disorder; Post-traumatic stress disorders

20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In adolescents, In children) in USA (PO)

20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In adolescents, In children, In the elderly, In adults) in USA (PO)
20 Dec 2024Launched for Congenital adrenal hyperplasia (Adjunctive treatment, In the elderly, In adults) in USA (PO)

SYN

https://patents.google.com/patent/US12128033

Example processes and certain intermediates of the present invention are shown in Scheme I to Scheme VII below.

A representative Coupling-Step of 2-cyclopropylacetic acid (Compound

1A) with N,O-dimethylhydroxylamine or a salt thereof in the presence of a coupling-step reagent (e.g., 1,1′-carbonyldiimidazole), a coupling-step base (e.g., triethylamine), and a coupling-step solvent (e.g., dichloromethane) to prepare 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

2A) is provided below in Scheme I.

A representative Reacting-Step between 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

2A) with an organomagnesium reagent of 4-bromo-2-fluoro-1-methylbenzene in the presence of a reacting-step solvent (e.g., tetrahydrofuran (THF)) to prepare 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

3A) is provided below in Scheme II.

A representative Condensing-Step of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

3A) with a Compound of Formula (Ic) or a salt thereof, in the presence of a condensing-step acid (e.g., p-toluenesulfonic acid) and a condensing-step solvent (e.g., toluene) to prepare a Compound of Formula (Ie) is provided below in Scheme III.

- wherein:
- R^1c, R^2c, and R^3care each independently selected from: H, C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, and halogen.

A representative Reducing-Step of a Compound of Formula (Ie) in the presence of a reducing-catalyst (e.g., sponge nickel and Pd/Cu—C), hydrogen, and a reducing-step solvent (e.g., ethanol) to prepare a Compound of Formula (Ig) is provided below in Scheme IV.

- wherein:
- R^1c, R^2c, and R^3care each independently selected from: H, C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, and halogen.

A representative Deprotecting-Step of a Compound of Formula (Ig), or a salt thereof, in the presence of a deprotecting-catalyst (e.g., Pd), hydrogen, and a deprotecting-step solvent (e.g., ethanol) to prepare (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound

6A) or a salt thereof is provided below in Scheme V.

- wherein:
- R^1c, R^2c, and R^3care each independently selected from: H, C₁-C₆alkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, and halogen.

A representative Cyclizing-Step of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound

6A) or a salt thereof, with 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound

8A) or a tautomeric form thereof, in the presence of a cyclizing-step solvent (e.g., n-heptane) to prepare (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound

9A) or a salt thereof is provided below in Scheme VI.

A representative Alkylating-Step of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound

9A) or a salt thereof, with a Compound of Formula (Ii), wherein LG is suitable leaving group (e.g., Br), in the presence of an alkylating-step solvent (e.g., methyl tert-butyl ether (MTBE), toluene, and mixtures thereof), a phase-transfer catalyst (e.g., tetra-n-butylammonium bromide (TBAB)), an alkylating-step base (e.g., potassium hydroxide), and water to prepare 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1) or a pharmaceutically acceptable salt thereof is provided below in Scheme VII.

One aspect of the present invention includes every combination of one or more process steps and intermediates related thereto used in the preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), and/or pharmaceutically acceptable salts, and crystalline forms thereof, such as those processes exemplified by Schemes I, II, III, IV, V, VI, VII, and VII (supra) and Compounds contained therein.

Compound

8A was previously described in International Publication Number WO2010/125414 by Sanofi-Aventis.Example 1: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1), See FIG. 5 for a general synthetic scheme Step1A: Preparation of 2-Cyclopropyl-N-methoxy-N-methylacetamide (Compound 2A)

A suspension of 1,1′-carbonyldiimidazole (CDI, 152.6 kg, 1.01 eq.) in DCM (682 kg, 513 L, 7.3 w/w relative to 2-cyclopropylacetic acid) was treated with a solution of 2-cyclopropylacetic acid (Compound

1A, 93.6 kg, 1 eq.) in DCM (248 kg, 186 L, 2.65 w/w) over at least 1 h, keeping the temperature ≤25° C. and compensating for significant effervescence. The resulting mixture was stirred for 15 min at 22° C. and then N,O-dimethylhydroxylamine-HCl (93.6 kg, 1.03 eq.) was added in portions, keeping the temperature ≤30° C. Subsequently, triethylamine (46.4 kg, 0.49 eq.) was added to the stirring mixture at 20-25° C. The resulting mixture was stirred at 22° C. at least 1 h. The mixture was washed once with KHSO₄solution (0.24 M, 357.1 kg, 0.09 eq.), once with KHSO₄solution (0.40 M, 365.4 kg, 0.15 eq.), once with KHSO₄solution (0.80 M, 384.5 kg, 0.30 eq.), and once with NaHCO₃solution (0.60 M, 393.1 kg, 0.24 eq.). Residual DCM was removed by two put-and-takes of THF (166.6 kg, 1.78 w/w) and vacuum distillation (50-60° C., to minimum volume/until distillation stops) to provide Compound

2A. THF (333.2 kg. 3.56 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (131.5 kg, 98.2% corrected). ¹H-NMR (400 MHz, DMSO-d₆) δ (ppm) −0.01-0.03 (m, 2H), 0.32-0.36 (m, 2H), 0.81-0.90 (br m, 1H), 2.18 (d, J=6.80 Hz, 2H), 2.97 (s, 3H), 3.53 (s, 3H). ESI-MS: 144.0 [M+H]⁺.Step 1B: Preparation of 2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound 3A)

Mg (turnings, 28.6 kg, 1.37 eq.) were suspended in THF (244.7 kg, 2.0 w/w) and DIBAL-H (1 M in n-heptane, 18.9 kg, 0.03 eq.) was added dropwise at 30° C. The resulting mixture was stirred at 30° C. for at least 10 min and then 4-bromo-2-fluoro-1-methylbenzene (neat, 21.1 kg, 0.13 eq.) was added over at least 30 min at 30-50° C. Subsequently, the mixture was treated with a solution of 4-bromo-2-fluoro-1-methylbenzene (191.6 kg, 1.18 eq.) in THF (414.5 kg, 3.37 w/w) at 30-50° C. over 3 h or less. The mixture was stirred at 30° C. for at least 1 h. The mixture was cooled to 12-18° C. and subsequently treated with 2-cyclopropyl-N-methoxy-N-methylacetamide (Compound

2A, 123.0 kg, 1 eq., 25.9% w/w solution in THF) over at least 1 h at 15-25° C. The resulting mixture was stirred at 20-25° C. for at least 1 h. The stirring mixture was then treated with aqueous HCl (3 M, 10.3% w/w, 668.9 kg, 2.24 eq.) at 10-25° C. and the resulting mixture was stirred at least 2 h until no Mg turnings were observed (check pH 3.0-3.5). The layers were separated, and the aqueous layer discarded. The organic layer was distilled at 55-65° C. and 400 mbar until distillation halts. Heptane (290.3 kg, 2.36 w/w) was added. The layers were separated, and the organic layer was washed once with NaHCO₃solution (0.63 M, 211.6 kg, 0.15 eq.) and once with NaCl solution (2.57 M, 213.0 kg, 0.55 eq.). The residual solvents were removed by vacuum distillation at 58-62° C. until distillation stops and then one put-and-take of toluene (275.5 kg, 2.24 w/w) at 107-117° C. until distillation stops. Toluene (275.5 kg, 2.24 w/w) was added and the yield was determined by correcting for the LOD and GC-FID purity of the sample (150.7 kg, 91.3% corrected). ¹H NMR (400 MHz, DMSO-d₆) β (ppm) 0.07-0.21 (m, 2H), 0.40-0.54 (m, 2H), 1.02 (ttt, J=8.16, 8.16, 6.68, 6.68, 4.86, 4.86 Hz, 1H), 2.30 (d, J=1.77 Hz, 3H), 2.91 (d, J=6.57 Hz, 2H), 7.44 (t, J=7.83 Hz, 1H), 7.57-7.78 (m, 2H). ESI-MS: 193.1 [M+H]⁺.Step 1C: Preparation of (S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)-N-(1-phenylethyl)ethan-1-imine (Compound 4A)

A mixture of 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one (Compound

3A, 150.7 kg, 1 eq., as a 27.6% w/w solution in toluene), (S)-(−)-1-phenylethylamine (112.9 kg, 1.19 eq.), and p-toluenesulfonic acid (7.4 kg, 0.05 eq.) was heated to reflux at 110-120° C. for 23-25 h in a reactor set up in a Dean-Stark configuration. The solvent was then removed at 125-135° C. under atmospheric pressure until distillation halts and a portion of toluene (275 kg, 2.24 w/w) was added to afford a suspension. The suspension was heated to reflux at 110-120° C. for 23-25 h. The mixture was cooled to 22° C. and washed twice with aqueous NH₄Cl (10%, 301.2 kg, 0.72 eq.) and once with aqueous NaHCO₃(5%, 301.2 kg, 0.23 eq., check pH 8-9). The solvent was removed at 125-135° C. and atmospheric pressure to a target volume of 256 L, the mixture was filtered over CELITE®, and the cake was washed with toluene (25 kg). The resulting mixture containing Compound 4A was used directly in the next step without further isolation. The yield was determined by correcting for the LOD and GC-FID purity of the sample (208.4 kg, 90.0% corrected). EL-MS: 294.1 [M−H]*, 190.1 [M-C₆H₅CH(CH₃)]+, 105.1 [C₆H₅CH(CH₃)]+.Step 1D: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)-N—((S)-1-phenylethyl)ethan-1-amine (Compound 5A) as the Hydrochloride Salt

Sponge nickel catalyst (144 kg, 0.70 w/w, shipped as a 50% w/w suspension in water) was added to a hydrogenation reactor, equipped with a dip tube capable of removing material from the top of the mass inside, minimizing the amount of water introduced. The supernatant was discarded, ethanol (329.3 kg, 1.58 w/w, anhydrous) was added, the suspension was stirred and then allowed to settle. This process was repeated four more times and the supernatant is checked; ≤1% H₂O w/w (Karl Fisher (KF)). Compound 4A (208.4 kg, 1 eq., as a 62.6% solution in toluene) was added to the mixture in the hydrogenation reactor. Ethanol (389.4 kg, 1.86 w/w) was used to rinse the addition flask into the hydrogenation reactor. The hydrogenation reactor was pressurized/depressurized twice with nitrogen (2 bar), twice with hydrogen (5 bar), and then pressurized with hydrogen (9.8-10.2 bar). The resulting mixture was heated to 33-37° C. and stirred for 17-19 h. The system was depressurized/pressurized three times with nitrogen (1 bar). The suspension was filtered and washed three times with ethanol (total amount, 493.8 kg, 2.37 w/w). The filtrate was combined with HCl (concentrated, 83.4 kg, 1.07 eq.) and the resulting mixture stirred 25-35 min at 20-24° C. The mixture was concentrated by distillation at 78-80° C. and atmospheric pressure to remove water with a distillate target volume of 1167 L (5.6 L/kg based on imine Compound 4A) and the KF of the solution checked (≤1.5% H₂O w/w). The mixture was stirred at 48-52° C. for 55-65 min, then 68-72° C. for 55-65 min, then cooled to 20-24° C. at a rate of 12° C./h and stirred for 25-35 min, then cooled to 0-4° C. at a rate of 10° C./h and stirred for 55-65 min. The suspension was filtered, the cake was washed twice with precooled ethanol (total amount, 329.2 kg, 1.58 w/w, 0° C.), and the collected solid was dried at 40° C. to afford Compound

5A as the HCl salt (156.5 kg, 66.4% uncorrected). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) −0.33–0.06 (m, 2H), 0.11-0.31 (m, 3H), 1.57 (d, J=6.57 Hz, 3H), 1.95 (br t, J=7.07 Hz, 2H), 2.26 (d, J=1.26 Hz, 3H), 3.68 (br d, J=7.83 Hz, 1H), 3.92 (br t, J=6.44 Hz, 1H), 6.98 (dd, J=7.71, 1.14 Hz, 1H), 7.28-7.36 (m, 2H), 7.37-7.50 (m, 5H). EST-MS: 298.2 m/z [M+H]+.Step 1E: Preparation of (S)-2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-amine (Compound 6A) as the Hydrochloride Salt

Compound

5A (HCl salt, 156.5 kg, 1.00 eq.) and Pd/C (7.8 kg, 10% Pd basis) were added to an inerted hydrogenation reactor. The reactor was then pressurized/depressurized twice with nitrogen (2 bar) and then methanol (494.5 kg, 3.16 w/w) was added. The reactor was depressurized/pressurized three times with nitrogen (2 bar) then three times with hydrogen (5 bar), pressurized with hydrogen (9.8-10.2 bar), heated to 58-62° C. and stirred for 7-9 h. The reaction mixture was cooled to 20-24° C. The reactor was depressurized/pressurized three times with nitrogen (1 bar) and the suspension was filtered and washed three times with methanol (total amount, 492.9 kg, 3.15 w/w). The solution was concentrated at 63-67° C. and atmospheric pressure to a distillate target volume of 1408 L (9.0 L/kg Compound

6A), n-Heptane (1173.8 kg, 7.5 w/w) was added and the resulting mixture was heated to reflux at 65-80° C. and atmospheric pressure in Dean-Stark configuration to remove methanol. The suspension was cooled to 31-35° C. and filtered, the cake washed with n-heptane (147.1 kg, 0.94 w/w), and the solid dried at 40° C. to provide Compound

6A as the HCl salt (101.0 kg, 93.8% uncorrected, 99.6% ee). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) −0.12-0.14 (m, 2H), 0.26-0.42 (m, 2H), 0.44-0.55 (m, 1H), 1.70-1.83 (m, 2H), 2.23 (d, J=1.52 Hz, 3H), 4.24 (t, J=7.33 Hz, 1H), 7.22-7.29 (m, 1H), 7.29-7.36 (m, 1H), 7.40 (dd, J=10.99, 1.39 Hz, 1H). ESI-MS: 194.2 [M+H]⁺, 177.0 [M-NH₂]⁺.Step 1F: Preparation of (S)-4-(2-chloro-4-methoxy-5-methylphenyl)-N-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)-5-methylthiazol-2-amine (Compound 9A)

A mixture of n-heptane (146 kg), water (142 kg), Compound

6A (HCl salt, 57.4 kg), and aqueous sodium hydroxide (30% w/w, 41.0 kg) was stirred together. The layers were partitioned, and the aqueous layer removed. The organic layer was washed with water (170 kg) and the layers partitioned. The organic layer was set aside, n-Heptane (145 kg) and 1-(2-chloro-4-methoxy-5-methylphenyl)-2-thiocyanatopropan-1-one (Compound

8A, 66.1 kg, the preparation of Compound

8A has been previously described in International Publication Number WO2010/125414) were added to the reactor and heated to 85° C. The previously set aside organic layer containing the free base of Compound

6A was added at 84-85° C. to the reactor and rinsed with n-heptane (20 kg). The resulting mixture was stirred for 2 h at 83° C. Subsequently, the solvent was switched to methanol by four put-and-take additions/vacuum distillations of methanol (180 kg) at 55° C. with the target volume being 287 L remaining in the reactor. The suspension was cooled to 5° C. and water (570 kg) was added over 4 h at 5-10° C., with the first 60 kg added very slowly. The suspension was aged 2 h at 5° C. and then isolated by filtration, washed with a mixture of methanol/water (91/115 kg) and then a mixture of methanol/water (134/57 kg). The yellow solid was dried at 25° C. and 1 mbar for 17 h then 40° C. and 1 mbar for 22 h to afford Compound

9A (97.4 kg, 87.5% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm −0.01-0.14 (m, 2H), 0.29-0.42 (m, 2H), 0.61-0.73 (m, 1H), 1.47 (dt, J=13.83, 6.85 Hz, 1H), 1.76 (dt, J=13.89, 7.20 Hz, 1H), 2.00 (s, 3H), 2.11 (s, 3H), 2.19 (d, J=1.01 Hz, 3H), 3.82 (s, 3H), 4.54 (q, J=7.58 Hz, 1H), 7.00 (s, 1H), 7.06 (d, J=0.76 Hz, 1H), 7.08-7.14 (m, 2H), 7.18-7.23 (m, 1H), 7.89 (d, 1=8.08 Hz, 1H). ESI-MS: 445.3 m/z [M+H]⁺.Step 1G: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (279 kg), tetra-n-butylammonium bromide (10.5 kg), and Compound

9A (95.4 kg) were heated at 60° C. external temperature for 30 min and then cooled to 0° C. Aqueous potassium hydroxide (52.4% w/w, 364 kg) and propargyl bromide (39.4 kg as an 80% w/w solution in toluene, 1.19 eq.) were added at 0-5° C. The propargyl bromide additional funnel was washed with MTBE (25 kg) and the biphasic mixture was aged 14.5 h at 4-6° C. with vigorous stirring. Subsequently, water (191 kg) was added and the aqueous layer was discharged at 20° C. The organic layer was washed twice with water (382 kg) and once with aqueous acetic acid (5.26% w/w, 190 kg) at 20° C. The mixture is polish filtered, rinsed with ethanol (11 kg) and then the solvent switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (300 kg) at 25-30° C. for the first cycle and then 35-40° C. with the target volume of each cycle being 250 L remaining in the reactor. Ethanol (164 kg) was added and the mixture heated at 60° C. external for 0.5 h before it was cooled to 25° C. in 1 h and seeded with authentic Form I (free base) of Compound 1 (0.340 kg) which can be prepared as described below in Example 2 and Example 3. The suspension was aged for 5 h, cooled to 0° C. in 2 h, aged 12 h, filtered, and washed twice with ethanol (24 kg each) pre-cooled to 0° C. The white solid was dried at 40° C. and 1 mbar for 19 h to yield 80.15 kg of Compound 1 (77.2% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.14 (qt, J=8.59, 4.42 Hz, 2H), 0.29-0.48 (m, 2H), 0.61-0.82 (m, 1H), 1.89 (dt, J=14.08, 6.98 Hz, 1H), 2.07 (br d, J=7.83 Hz, 1H), 2.10 (s, 3H), 2.14 (s, 3H), 2.20 (d, J=1.01 Hz, 3H), 3.11 (t, J=2.27 Hz, 1H), 3.83 (s, 3H), 3.94-4.22 (m, 2H), 5.26 (t, J=7.58 Hz, 1H), 7.05 (s, 1H), 7.10-7.36 (m, 4H). ESI-MS: 483.2 m/z [M+H]⁺.Example 2: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (2 mL), tetra-n-butylammonium bromide (110 mg), and Compound

9A (1.003 g) at 0° C. was treated with aqueous potassium hydroxide (52.4% w/w, 1.80 mL, 2.73 g) and propargyl bromide (405 mg as an 80% w/w solution in toluene) maintaining the temperature at 0-5° C. The resulting biphasic mixture was aged 23 h at 4-6° C. Subsequently, water (2 mL) and MTBE (2 mL) were added and the aqueous layer was discharged. The organic layer was washed twice with water (4 mL) and once with aqueous acetic acid (5% w/w, 2 mL) at 20° C. Ethanol (4 mL) was added and then the solvent was switched to ethanol by 3 put-and-take additions/vacuum distillations of ethanol (6 mL) at 35-40° C. with the target volume of each cycle being 2 mL remaining in the vessel, except for the third cycle where the mixture was concentrated to dryness. Ethanol (4 mL) was added to the vessel and the mixture heated at 60° C. (external) for 0.5 h before it was cooled to 20° C. in 1 h and aged 18 h. The resulting suspension was cooled to 0° C., aged 6 h, filtered, and washed twice with ethanol (2 mL each) pre-cooled to 0° C. to afford a solid. The solid was dried at 40° C. under vacuum to afford Compound 1 (506 mg, 46% yield) as Form I. The ¹H NMR and ESI-MS data matches that as described above in Example 1, Step 1G.Example 3: Preparation of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-1(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1)

A mixture of MTBE (40 mL), tetra-n-butylammonium bromide (1.1 g), and Compound

9A (10.0 g) was heated to 45° C., aged for 10 min, then cooled to 0° C. The solution was treated with aqueous potassium hydroxide (52.4% w/w, 38.2 g) and propargyl bromide (3.36 g as an 80% w/w solution in toluene) maintaining the temperature at 0-5° C. The resulting biphasic mixture stirred vigorously for 16 h at 4-6° C. Subsequently, water (20 mL) was added and the aqueous layer was discharged. The organic layer was washed twice with water (40 mL) and once with aqueous acetic acid (5.2% w/w, 20 mL) at 20° C. The solvent was switched to ethanol by 4 put-and-take additions/vacuum distillations of ethanol (15 mL) at 35-40° C. with the target volume of each cycle being 15 mL remaining in the vessel. The solution was weighed to approximate the amount of ethanol remaining, and ethanol (26 mL) was added to the vessel to bring the total amount of ethanol to 40 mL. The solution was cooled to 4° C. and stirred for 45 min to afford a suspension. The suspension was heated to 38° C. in 15 min, aged 10 min, then cooled to 20° C. over 14 h. The suspension was cooled to 0° C., aged 1.5 h, filtered, and the solids washed twice with ethanol (7.5 mL each) pre-cooled to 0° C. The solid was dried at 40° C. under vacuum to afford Compound 1 (8.27 g, 76% yield) as Form I. The ¹H NMR and ESL-MS data matches that as described above in Example 1, Step 1G.

The crystalline free base Compound

1, Form I was characterized by X-ray powder diffraction (XRPD) (FIG. 1

, Table 2) and DSC (FIG. 2

). The DSC indicated the crystalline Compound

1, Form I has an onset of melt (temperature) at about 83.7° C. (76.6 J/g). The Thermogravimetric Analysis (TGA) (FIG. 2

) of the crystalline free base exhibited substantially no weight loss (about 0.2%) from room temperature to ˜125° C. indicating Form I for the free base of Compound

1 is anhydrous.

Medical uses

Crinecerfont is indicated as adjunctive treatment to glucocorticoid replacement to control androgens in people four years of age and older with classic congenital adrenal hyperplasia.^[1]^[2]

Adverse effects

The US Food and Drug Administration prescription label for crinecerfont has a warning for acute adrenal insufficiency or adrenal crisis.^[2]

History

Crinecerfont’s approval is based on two randomized, double-blind, placebo-controlled trials in 182 adults and 103 children with classic congenital adrenal hyperplasia.^[2] In the first trial, 122 adults received crinecerfont twice daily and 60 received placebo twice daily for 24 weeks.^[2] After the first four weeks of the trial, the glucocorticoid dose was reduced to replacement levels, then adjusted based on levels of androstenedione, an androgen hormone.^[2] The primary measure of efficacy was the change from baseline in the total glucocorticoid daily dose while maintaining androstenedione control at the end of the trial.^[2] The group that received crinecerfont reduced their daily glucocorticoid dose by 27% while maintaining control of androstenedione levels, compared to a 10% daily glucocorticoid dose reduction in the group that received placebo.^[2]

In the second trial, 69 children received crinecerfont twice daily and 34 received placebo twice daily for 28 weeks.^[2] The primary measure of efficacy was the change from baseline in serum androstenedione at week four.^[2] The group that received crinecerfont experienced a statistically significant reduction from baseline in serum androstenedione, compared to an average increase from baseline in the placebo group.^[2] At the end of the trial, children assigned to crinecerfont were able to reduce their daily glucocorticoid dose by 18% while maintaining control of androstenedione levels compared to an almost 6% daily glucocorticoid dose increase in children assigned to placebo.^[2]

The US Food and Drug Administration (FDA) granted the application for crinecerfont fast track, breakthrough therapy, orphan drug, and priority review designations.^[2] The FDA granted the approval of Crenessity to Neurocrine Biosciences, Inc.^[2]

Society and culture

Legal status

Crinecerfont was approved for medical use in the United States in December 2024.^[1]^[2]^[5]

Names

Crinecerfont is the international nonproprietary name.^[6]

Crinecerfont is sold under the brand name Crenessity.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Crenessity- crinecerfont; capsule Crenessity- crinecerfont solution”. DailyMed. 1 December 2024. Retrieved 25 January 2025.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “FDA Approves New Treatment for Congenital Adrenal Hyperplasia”. U.S. Food and Drug Administration (FDA) (Press release). 1 October 2024. Retrieved 16 December 2024. This article incorporates text from this source, which is in the public domain.
^ “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ “Neurocrine Biosciences Announces FDA Approval of Crenessity (crinecerfont), a First-in-Class Treatment for Children and Adults With Classic Congenital Adrenal Hyperplasia” (Press release). Neurocrine Biosciences. 13 December 2024. Retrieved 16 December 2024 – via PR Newswire.
^ World Health Organization (2019). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 82”. WHO Drug Information. 33 (3). hdl:10665/330879.

External links

“Crinecerfont (Code C174708)”. NCI Thesaurus.
Clinical trial number NCT03525886 for “Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NBI-74788 in Adults With Congenital Adrenal Hyperplasia” at ClinicalTrials.gov

Clinical data

Trade names	Crenessity
Other names	SSR-125543, NBI-74788
AHFS/Drugs.com	Crenessity
License data	US DailyMed: Crinecerfont
Routes of administration	By mouth
Drug class	Corticotropin-releasing factor type 1 receptor antagonist
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	752253-39-7
PubChem CID	5282340
DrugBank	DB18518
ChemSpider	4445507
UNII	MFT24BX55I
KEGG	D12366
ChEBI	CHEBI:34969
ChEMBL	ChEMBL291657
CompTox Dashboard (EPA)	DTXSID10996687
Chemical and physical data
Formula	C₂₇H₂₈ClFN₂OS
Molar mass	483.04 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

Prete A, Auchus RJ, Ross RJ: Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2021 Nov 30;186(1):R1-R14. doi: 10.1530/EJE-21-0794. [Article]
Yogi A, Kashimada K: Current and future perspectives on clinical management of classic 21-hydroxylase deficiency. Endocr J. 2023 Oct 30;70(10):945-957. doi: 10.1507/endocrj.EJ23-0075. Epub 2023 Jun 29. [Article]
FDA Approved Drug Products: Crenessity (crinecerfont) capsules/solution for oral administration (December 2024) [Link]
FDA News Release: FDA Approves New Treatment for Congenital Adrenal Hyperplasia [Link]

///////Crinecerfont, Crenessity, FDA 2024, APPROVALS 2024, 752253-39-7, SSR125543, SSR 125543, SSR-125543, WHO 10958, 06-RORI, NBI-74788, ORPHAN DRUG

Bezisterim, HE 3286; NE-3107

April 16, 2025 10:37 am / Leave a comment

Bezisterim, HE 3286; NE-3107

CAS 1001100-69-1

(1R,3aS,3bR,4R,7S,9aR,9bS,11aS)-1-ethynyl-9a,11a-dimethyl-1H,2H,3H,3aH,3bH,4H,6H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthrene-1,4,7-triol

(3β,7β,17α)-Pregn-5-en-20-yne-3,7,17-triol
17α-Ethynyl-5-androstene-3β,7β,17β-triol
17α-Ethynyl-Δ⁵-androstene-3β,7β,17β-triol
17α-Ethynylandrost-5-ene-3β,7β,17β-triol
3β,7β,17β-Trihydroxy-17α-ethynylandrost-5-ene
Bezisterim
HE 3286
NE 3107
Triolex

(3S,7R,8R,9S,10R,13S,14S,17R)-17-ethynyl-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-3,7,17-triol

Formula	C₂₁H₃₀O₃
Molar mass	330.468 g·mol⁻¹

17alpha-pregn-5-en-20-yne-3beta,7beta,17-triol

Q27286562
(3beta,7beta,17alpha)-Pregn-5-en-20-yne-3,7,17-triol
17.ALPHA.-ETHYNYL-5-ANDROSTENE-3.BETA.,7.BETA.,17.BETA.-TRIOL
PREGN-5-EN-20-YNE-3,7,17-TRIOL, (3.BETA.,7.BETA.,17.ALPHA.)-

Bezisterim (developmental code names NE3107, HE3286) is a synthetic analogue of androstenetriol that is believed to have anti-inflammatory and insulin-sensitizing effects in the brain.^[1] The compound crosses the blood–brain barrier and does not activate any neurotransmitter receptors.^[2] It has been tested as a treatment for Alzheimer’s disease,^[3][4][5][6] Parkinson’s disease,^[1] and traumatic brain injury.^[7] The drug is under development for a variety of conditions and its highest developmental phase is phase 3 for Alzheimer’s disease.^[1]

Originator Hollis-Eden Pharmaceuticals
Developer BioVie; Harbor Therapeutics; National Institutes of Health (USA); NeurMedix
Class Anti-inflammatories; Antidementias; Antiepileptic drugs; Antifibrotics; Antiglaucomas; Antihyperglycaemics; Antimigraines; Antineoplastics; Antiparkinsonians; Antirheumatics; Hormones; Insulin sensitisers; Nootropics; Obesity therapies; Small molecules
Mechanism of Action Adiponectin stimulants; Interleukin 23 inhibitors; Interleukin 6 inhibitors; Mitogen-activated protein kinase 1 inhibitors; Mitogen-activated protein kinase 3 inhibitors; NF-kappa B inhibitors; Tumour necrosis factor inhibitors

Cystic fibrosis

Phase III Alzheimer’s disease
Phase II Parkinson’s disease; Traumatic brain injuries
Preclinical Multiple myeloma; Prostate cancer
No development reported Drug-induced dyskinesia
Discontinued Amyotrophic lateral sclerosis; Cognition disorders; Cystic fibrosis; Epilepsy; Glaucoma; Huntington’s disease; Migraine; Myositis; Optic neuritis; Rheumatoid arthritis; Type 1 diabetes mellitus; Type 2 diabetes mellitus; Ulcerative colitis; Uveitis

28 Feb 2025BioVie plans the phase II ADdRESs-LC trial for Post-acute COVID-19 syndrome in USA (PO, Capsule), in February 2025 (NCT06847191)

18 Feb 2025Phase-II clinical trials in Parkinson’s disease (Early-stage disease, In the elderly) in USA (PO) (NCT06757010)
03 Jan 2025BioVie plans a phase II SUNRISE-PD trial for Parkinsons disease (Early stage disease) in February 2025 (PO) (NCT06757010)

SCHEME

US20100227841

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43352763&_cid=P11-M9JSD6-84971-1

17α-Ethynylandrost-5-ene-3β,7β,17β-triol was prepared as follows

Synthesis of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one: A mixture of 14.87 Kg of androst-5-en-17β-one-3β,7β-diol, 23.8 Kg 1,1,1,3,3,3-hexamethyldisilazane (HMDS) and 0.7 Kg saccharin catalyst in 100 L acetonitrile was heated to reflux for 8 hours with stirring under a nitrogen atmosphere. Liberated ammonia was purged under slight vacuum. The reaction volume was then reduced by distillation to collect 30 L of distillate (about 2 h). The reaction volume was further reduced to half of the original reaction volume by distillation under reduced pressure (700 mmHg), which requires about 2 h of heating at 50° C. The resulting uniform thick slurry was cooled to 5° C. (requires about 3 h), with additional acetonitrile added to maintain a minimum mixing volume, and held at that temperature for 1. The precipitated product was collected by filtration and dried at 45-50° C. under vacuum (29 mmHg) to a loss on drying (LOD) of not more than 1% (requires 20 h) to provide 16 Kg (81% yield) of the title compound (95% purity).

Synthesis of 17α-ethynyl-5-androstene-3β,7β,17β-triol: To 11.02 Kg TMS-acetylene in 56.5 L tetrahydrofuran (THF) at −27° C. under a nitrogen atmosphere was added 8.51 L 10M n-BuLi. The n-butyl lithium was added very slowly to maintain a temperature at −7 to −27° C. (about 2 h) and the resulting reaction was stirred 10 min. at approximately 0° C. to produce TMS-lithium-acetylide. To the TMS-lithium-acetylide solution was added a solution of 25.41 Kg of 313,713-bis-(trimethylsiloxy)-5-androsten-17-one in 95.3 L THF filtered through a 25 μM filter while allowing the reaction temperature to rise to 20-25° C.

After addition was completed, the reaction temperature was increased to 40-45° C. To quench the reactor contents, 31.8 L of methanol was added over a period of about 1 h followed by 3.81 Kg KOH in 18.4 L of water giving a final reactor temperature of 50° C. Liberated acetylene is purged under slight vacuum. The reactor contents were then concentrated by distillation at 80° C. for 1 h then under vacuum (175 mmHg) at about 70° C. (with an initial temperature of 25° C. to avoid bumping) to half of the original pot volume. The residue was cooled to about 10° C. and 35.0 Kg of deionized water was added, followed by 16.4 Kg 12N HCl while maintaining a pot temperature of about 10° C. and giving a final pH of 1. Additional 26.0 kg deionized water was added and the resulting mixture was stirred at about 5° C. for 1 h. The resulting slurry was filtered and washed with 75/25 mixture of methanol/water (16.9 L methanol, 5.6 L water). The collected solids were dried under vacuum (28 in Hg) at 45° C. for 12 h for a loss on drying of no more than 0.5% to provide 9.6 Kg of the title compound (83% yield).

Preparation of 17α-ethynylandrost-5-ene-3β,7β,17β-triol by this method using starting material that is substituted at the 7-position yields a product with essentially no by-products that are unsubstituted at the 7-position, eliminating any need to remove such potential impurities.

US20100222315 https://patentscope.wipo.int/search/en/detail.jsf?docId=US43344622&_cid=P11-M9JSIE-88638-1

WO2009149392

PATENT’

WO2009149392

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009149392&_cid=P11-M9JSL7-90448-1

49] Example 7. Synthesis of 3β-acetoxy-androst-5-ene-17,17-ethylenedioxy: A 300L reactor was charged with 36 kg of triethylorthoformate, 20 kg of 3β-acetoxy-5-androsten-17-one, 12.6 kg of ethylene glycol and 400 g of p-toluenesulfonic acid. The mixture was heated to reflux under nitrogen until the reaction was complete (about 2-3 hours). The mixture was then cooled to 60 ⁰C and 16 kg of anhydrous ethanol and 400 ml of pyridine were added. The resulting solution was transferred to a container and refrigerated overnight. The solids that formed were filtered and washed with 80 kg of 50% ethanol and dried at 40-50 ⁰C to afford 18.5-21.0 kg (81.5-92.5%) of the title compound. [50] Example 8. Synthesis of 3β-acetoxy-androst-5-en-7-one-17,17-ethylenedioxy: A 500 L reactor was charged with 200 kg ethyl acetate and 25 kg of 3β-acetoxy-androst-5-en-17,17-ethylenedioxy. The mixture was stirred for 30 minutes whereupon 55 kg of 70% t-butyl peroxide and 9 kg of sodium bicarbonate were added. The reaction mixture was then cooled to 0 ⁰C and 116 kg of 13% sodium perchlorate (aq.) was added over 10 hours so that a reaction temperature below 5 ⁰C and pH between 7.5 and 8.5 were maintained. After the reaction was complete, the organic layer was separated and the aqueous phase was extracted with ethyl acetate (35 kg x 2). The combined organic phase was combined with a solution 33 kg of sodium sulfite in 167 kg of water, and the resulting mixture was stirred at 40 ⁰C for 3 hours. The organic phase was washed with 50 kg of brine and concentrated to 55-60 kg whereupon 50 kg of methanol was added. After refrigeration overnight, a white solid was formed that was filtered and washed with 10 kg of methanol, and dried at 40-50 ⁰C to yield 7.1-7.8 kg (27.4-30.1%) of the title compound.

[51] Example 9. Synthesis of 3β-acetoxy-androst-5-ene-17,17-ethylenedioxy-7β-ol. A 500 L reactor was charged with 48 kg of THF, 10 kg of 3β-acetoxy-androst-5-en-7-one-17,17-ethylenedioxy and a solution of 9.6 kg CeCI₃-7H₂O in 95 kg methanol. This mixture was cooled to 0 ⁰C whereupon 2.0 kg of NaBH₄ was added in batches over 3 hours in order to maintain the temperature below 5 ⁰C. After stirring for 30 more minutes, 28 kg of acetone was added slowly in order to maintain the temperature below 5 ⁰C, with stirring continued for another 30 minutes. To the mixture was added 240 kg water with stirring continued for 1 hour. The organic solvents were removed under vacuum and the residue was extracted with ethyl acetate (100 kg + 50 kg). The combined organic phase was washed with brine. Solvent was then removed to provide 8.6-8.9 kg (85.1-88.1 %) of the title compound. [52] Example 10. Synthesis of 3β-acetoxy-androst-5-en-17-one-7β-ol: A 500 L reactor was charged with 315 kg of acetone and 18 kg of 3β-acetoxy-androst-5-en-17,17-ethylenedioxy-7β-ol. The mixture was cooled to 5 ⁰C and 2.34 kg of p-toluenesulfonic acid was added slowly to maintain the temperature below 10 ⁰C. After stirring the mixture at 8-15 ⁰C for 36-48 hours, 3.0 kg of sodium bicarbonate was added with stirring continued for 1 hour. Acetone was removed under vacuum, and to the residue was added 100 kg of water. The mixture was placed in a refrigerator overnight to give a white precipitate which was filtered to provide 33 kg (wet) of the title compound.

[53] Example 11. Synthesis of androst-5-en-17-one-3β,7β-diol: A 500 L reactor was charged 230 kg methanol, 33 kg (wet) 3β-acetoxy-7β-hydroxy-5-androsten-17-one, 108 kg water and 15 kg NaaCOβ. The mixture was heated to reflux for 3 hours. Methanol was removed under vacuum whereupon 250 kg of water was added to the residue. The mixture was put in refrigerator overnight to give a precipitate. The solids were collected by filtration, then washed with water and dried at 40-50 ⁰C to yield 9.5-10.5 kg (67.9-75.0%) of the title compound as a white solid.

[54] Example 12. Purification of androst-5-en-17-one-3β,7β-diol: A 500 L reactor was charged with 20 kg crude 3β, 7β-dihydroxyandrost-5-en-17-one and 200 kg methanol and heated until all the solid dissolved. The solution was filtered while hot and after the filtrate cooled a white crystalline solid formed. The solids were collected by filtration, washed with small amount of methanol and dried at 40-50 ⁰C. The solid was then refluxed in 50 kg of ethyl acetate for 20 minutes. After cooling the solid was filtered and dried at 40-50 ⁰C under vacuum to provide 15.2 kg (76%) of purified title compound.

[55] Example 13. Synthesis of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one: A mixture of 14.87 Kg of androst-5-en-17-one-3β,7β-diol, 23.8 Kg HMDS and 0.7 Kg saccharin catalyst in 100 L acetonitrile was heated to reflux for 8 hours with stirring under a nitrogen atmosphere. Liberated ammonia was purged under slight vacuum. The reaction volume was then reduced by distillation to collect 3OL of distillate (requires about 2 h). The reaction volume was further reduced to half of the original reaction volume by distillation under reduced pressure (700 mmHg), which requires about 2h of heating at 50 ⁰C. The resulting uniform thick slurry is cooled to 5 ⁰C (requires about 3 h), with additional acetonitrile added to maintain a minimum mixing volume, and held at that temperature for 1. The precipitated product was collected by filtration and dried at 45-50 ⁰C under vacuum (29 mmHg) to a loss on drying (LOD) of not more than 1 % (requires 20 h) to provide 16 Kg (81 % yield) of the title compound (95% purity). [56] Example 14. Synthesis of 17α-ethynyl-5-androstene-3β,7β,17β-triol: To 11.02 Kg TMS-acetylene in 56.5 L tetrahydrofuran (THF) at -27 ⁰C under a nitrogen atmosphere was added 8.51 L 10M n-BuLi. The n-butyl lithium was added very slowly to maintain a temperature at -7 to -27 ⁰C (requires about 2 h) and the resulting reaction was stirred 10 min. at approximately 0°C to produce TMS-lithium-acetylide. To the TMS-lithium-acetylide solution was added a solution of 25.41 Kg of 3β,7β-bis-(trimethylsiloxy)-5-androsten-17-one in 95.3 L THF filtered through a 25 μm filter while allowing the reaction temperature to rise to 20-25 ⁰C. After addition was completed, the reaction temperature was increased to 40-45 ⁰C. To quench the reactor contents, 31.8 L of methanol was added over a period of about 1 h followed by 3.81 Kg KOH in 18.4 L of water giving a final reactor temperature of 50 ⁰C. Liberated acetylene is purged under slight vacuum. The reactor contents were then concentrated by distillation at 80 ⁰C for 1 h then under vacuum (175 mmHg) at about 70 ⁰C (with an initial temperature of 25 ⁰C to avoid bumping) to half of the original pot volume. The residue was cooled to about 10 ⁰C and 35.0 Kg of deionized water was added, followed by 16.4 Kg 12N HCI while maintaining a pot temperature of about 10 ⁰C and giving a final pH of 1. Additional 26.0 kg deionized water was added and the resulting mixture was stirred at about 5 ⁰C for 1 h. The resulting slurry was filtered and washed with 75/25 mixture of methanol/water (16.9 L methanol, 5.6 L water). The collected solids were dried under vacuum (28 in Hg) at 45 ⁰C for 12h for a loss on drying of no more than 0.5% to provide 9.6 Kg of the title compound (83% yield).

[57] Example 15. Recrystallization of 17α-ethynyl-5-androstene-3β,7β,17β-triol: Crude 9.6 Kg 17α-ethynyl-5-androstene-3β,7β,17β-triol prepared in

Example 14 was dissolved in refluxing 50/50 methanol/water (4.2 Kg methanol and 5.4 Kg water). To the solution was added 33.4 Kg methanol followed by 37.6 Kg of THF. The mixture was heated to reflux and stirring was continued until all solids have dissolved, whereupon 99.8 Kg of deionized water was added while maintaining a reactor temperature of 60-75 ⁰C. The mixture was cooled to 0-5 ⁰C over a period of 2 h and maintain at that temperature for 1 h while stirring was continued. The solids were recovered by filtration, washed with 9.6 Kg cold 50/50 methanol water and dried under vacuum (28 in Hg) at 50 ⁰C for 8 h to provide 8.2 Kg of 17α-ethynyl-5-androstene-3β,7β,17β-triol. This first recrystallization is used to remove trace colored impurities from the initial product. A second recrystallization was conducted by heating the solid from the first recrystallization in ~10:1 methanohwater (145.8 Kg methanol and 18.2 Kg of water) to 80°C until all the solids have dissolved. The solution at 55-60 ⁰C was filtered through a 25 μm filter to remove particulate impurities, whereupon 2.5 Kg of methanol at 55-60 ⁰C (used to rinse the reactor) was added. Vacuum distillation at 125 mmHg at 70 ⁰C was conducted until 0.9 to 1.2 times the volume of methanol that was added to the reactor was collected as distillate with water added as necessary to permit stirring (about 120-160 Kg water added). Final reaction volume was 200-225 L. The reactor mixture was cooled to 0-5 ⁰C and maintained at that temperature for 1 h. The resulting slurry was filtered and the filter cake rinsed with 10 Kg deionized water and dried under vacuum (28 in Hg) at 50 ⁰C for 12 h to a residual water content of less than 0.5%. This isolation procedure was used to reduce the THF content in the final product. The yield was 8.0 Kg of recrystallized title compound (83% yield).

[59] Example 16. Synthesis of 3β-acetoxy-androst-5-en-7-on-17-oxime: 3β-Acetoxy-androst-5-en-7,17-dione (45 g, 130 mmol) was dissolved in 800 ml_ methanol, 200 ml_ dichloromethane and 14.5g Et₃N (144 mmol). To the solution at RT was added a solution of 10 g of hydroxylamine hydrochloride dissolved in 200 ml_ methanol. After stirring overnight, 200 ml_ of water was added followed by removal of volatile organics by evaporation under reduced pressure. To the resulting residue was added an additional 1 L of water to give a while solid that was filtered and washed well with water. Obtained was 45 g of crude title oxime in 95% purity by ¹H-NMR, which was used in the next step without further purification.

[60] Example 17. Synthesis of 3β-acetoxy-androst-5-en-17-oxime-7β-ol: To a solution of 44 g of 3β-acetoxy-androst-5-en-7-on-17-oxime (100 mol%) in 800 ml_ methanol and 200 ml_ tetrahydrofuran was added 50 g of cerium chloride heptahydrate (110 mol%) in 20 ml_ of methanol. The resulting mixture was stirred until the solids were completely dissolved. To the solution cooled to about -5 ⁰C was added 7 g sodium borohydride over 30 min. After stirring an additional 1.5 h at -5 ⁰C, the reaction mixture was quenched with acetone (100 mL) and then allowed to warm to room temperature over a 30 min. period. The quenched reaction mixture was concentrated under vacuum to remove volatile organics. To the residue was added 800 mL of water followed by extraction with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, then concentrated to provide 42 g of the title compound as a white foam, which was used in the next step without further purification.. [61] Example 18. 3β-acetoxy-androst-5-en-17-one-7β-ol: To a solution of 42 g of 3β-acetoxy-androst-5-en-17-oxime-7β-ol (100 mol%) in 200 mL of ethanol was added 100 mL of water followed by 80 g (400 mol%) of sodium dithionite. The reaction was heated at 55 ⁰C and stirred 16 h. After cooling, the reaction was concentrated under reduced pressure. The residue was diluted with 100 mL of water, and the resulting solid was collected by filtration and redissolved in 1 L dichloromethane. To the DCM solution was added 1 g activated carbon. After stirring overnight the mixture was filtered, and the resulting filtrate was washed with water, dried and concentrated to provide 25 g of crude product. Recrystallization from ethyl acetate gave 22g of the title compound. [62] Example 19. Estrogen receptor binding assay: A suitable example system is an estrogen receptor- kit manufactured by PanVera for ERβ, which contains recombinant estrogen receptor β ligand, FLUORMONE™ ES2 (ES2), a fluorescently labeled estrogen ligand, and appropriate buffer. The system was used in a fluorescence polarization competition assay in which a test article, such as a preparation of Compound 1 or a positive control displaces ES2 from its binding site. When bound to ERβ, ES2 tumbles slowly and has a high fluorescence polarization value. Unbound ES2 tumbles quickly and displays a low fluorescence polarization value. The change in polarization value in the presence of test compound then determines relative binding affinity of that test compound for ERβ as expressed by its IC_50, which is the concentration of test compound that results in half-maximum shift in polarization. From IC₅₀, K_/ was calculated using the Cheng-Prusoff equation [Biochem. Pharmacol. 22: 3099-3108, (1973)]: K, = IC₅₀Z(I + D/K_d) where D is the concentration of ES2 and K_d is the dissociation constant for binding of ES2 to ERβ (K_d = 4 ± 2 nM).

[63] The competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0712, Rev. 10/03). Assay reagents used were bacculovirus expressed, full length human ERβ 4.5 pmol/μL in 50 mM Bis-Tris Propane (pH = 9), 400 mM KCI, 2 mM DTT, 1 mM EDTA, 10% glycerol, ES2 400 nM in methanol and E2 screening buffer consisting of 100 mM potassium phosphate (pH = 7.4), 100 μg/mL BGG, 0.02% NaN₃. The ES2-ERβ complex was formed with 20 μL 20 nM ERβ (0.020 pmol/μL) and 20 μl_ 2 nM ES2 (0.002 pmol/μL). Positive control (estrogen) solution was prepared using 20 μL of a 1.0 mM stock solution in DMSO and 80 μL DMSO. In a first dilution, 50 μL of this solution is added to 50 μL of DMSO, which is followed by dilutions in 2-fold increments, to provide for a 14 point dilution curve. In a second dilution, to 4 μL of each DMSO solution from the first dilution is added 400 μL of ES2 screening buffer. To 20 μL of test compound, serially diluted in the manner described immediately above, in a 384 well black flat bottom microtiter plate, was added 20 μL of the ES2-ERβ complex (0.5% final DMSO concentration) followed by incubation in the dark at 20-30 ⁰C for 1-4 h. Test compound was treated similarly except the starting concentration was 10 mM. Fluorescence polarization values are obtained using 485 nm excitation and 530 nm emission interference filters. Binding assay for ERa was conducted as for ERβ except bacculovirus expressed, full length human 2.8 pmol/μL ERa was used as reagent with the ERα-ES2 complex formed from 20 μL 30 nM (0.030 pmol/μL) and 20 μL 2 nM ES2 (0.002 pmol/μL). [64] Example 20. AR, GR and PR receptor binding assays. The AR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0844, Rev. 05/02) in the manner described for ERβ with the following exceptions. Reagents used were recombinant rat androgen receptor ligand binding domain tagged with His and GST [AR-LBD (His-GST)] 0.38 pmol/μL in buffer containing protein stabilizing agents and glycerol (pH = 7.5), 200 nM FLUORMONE™ AL Green, which is a fluorescently labeled androgen ligand, in 20 mM Tris, 90% methanol and AR screening buffer containing stabilizing agents and glycerol (pH = 7.5) with 2 μL of 1 mM DTT added per mL screening buffer (AR screening buffer 2 mM in added DTT) was used as the reagents. The AL Green-AR complex was formed with 20 μL 50 nM AR (0.050 pmol/μL) and 20 μL 2 nM AL Green (0.002 pmol/μL). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 20 ± 10 nM. [65] The PR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0503, Rev. 06/03) in the manner described for ERβ with the following exceptions. Reagents used were recombinant human progesterone receptor ligand binding domain tagged with GST [PR-LBD (GST)] 3.6 pmol/μL in 50 mM Tris (pH = 8.0), 500 mM KCI, 1 M urea, 5 mM DTT, 1 mM EDTA and 50% glycerol, 400 nM FLUORMONE™ PL Green, which is a fluorescently labeled progesterone ligand, in 20 mM Tris 90% methanol (pH = 6.8) and PR screening buffer containing protein stabilizing agents and glycerol (pH = 7.4) with 4 μL of 1 mM DTT added per mL screening buffer (PR screening buffer 4 mM in added DTT). The PL Green-PR complex was formed with 20 μL 80 nM PR (0.080 pmol/μL) and 20 μL 4 nM PL Green (0.004 pmol/μL). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 40 nM.

[66] The GR competition assay was conducted according to the manufacturer’s protocol (Lit. No. L0304, Rev. 12/01) in the manner described for ERβ with the following exceptions. Reagents used were recombinant full length human glucocorticoid receptor 0.240 pmol/μL in 10 mM phosphate buffer (pH = 7.4), 200 mM Na₂MoO₄, 0.1 mM EDTA, 5 mM DTT and 10% glycerol, 200 nM FLUORMONE™ GS1 , which is a fluorescently labeled glucocorticoid ligand, in 75% methanol, and GR screening buffer containing 100 mM potassium phosphate (pH = 7.4), 200 mM Na₂MoO_4, 1 mM EDTA, 20% DMSO with 5 μL of 1 mM DTT per mL screening buffer added (GR screening buffer 5 mM in added DTT), 1 mM GR stabilizing peptide, which is a co-activator related peptide [see Chang, CY. MoI. Cell Biol. 19: 8226-36 (1999)] in 10 mM phosphate buffer (pH = 7.4) and 1 M DTT in water were used as the reagents. To 2.5 mL of the GR screening buffer is added 2.5 mL GR stabilizing peptide solution and 125 μL of 1 M DTT to form the GR stabilizing peptide-glucocorticoid receptor complex. Order of addition to the microtiter plate was 20 μL test compound in 1 % DMSO, 10 μL of 16 nM GR (0.016 pmol/μL) and finally 10 μL of 4 nM GS1 , followed by incubation in the dark at 20-30 ⁰C for 4 h (total experiment time should not exceed 7 h). K, was calculated using, for the dissociation constant for binding of the fluorophore to receptor, K_d = 0.3 ± 0.1 nM.

[67] Example 21. Impurity profiling of 17α-ethynyl-5-androstene-3β,7β,17β- triol (Compound 1) preparations.

[68] Process A: HPLC conditions for Impurity profiling of Compound 1 preparations form Process B are give in Table 1.

[69]

Table 1. HPLC Conditions for Impurity Profiling of Compound 1 Preparations form Process A

PATENT

Hollis-Eden Pharmaceuticals, Inc. WO2008039566

Zhejiang Xianju Junye Pharmaceutical Co., Ltd.; Jiangxi Junye Biopharmaceutical Co., Ltd.CN114478672

Harbor BioSciences, Inc.US20100227841

Harbor BioSciences, Inc. US20100222315 A1

Hollis-Eden Pharmaceuticals, Inc. US20100075937

Neurmedix Inc. US20080153792 A1

Hollis-Eden Pharmaceuticals, Inc.; Harbor Therapeutics, Inc. US20080146532 A1

Harbor Therapeutics, Inc.; Neurmedix, Inc. US20160045516 A1

Harbor Therapeutics, Inc. US8354396 B2

Hollis-Eden Pharmaceuticals, Inc. WO2009149392

Clinical data

Other names	NE3107; NE-3107; HE3286; HE-3286; 17α-Ethynyl-5-androstene-3β,7β,17β-triol;
Legal status
Legal status	Investigational
Identifiers
showIUPAC name
CAS Number	1001100-69-1
PubChem CID	16739648
DrugBank	DB05212
ChemSpider	20571043
UNII	PH8858757I
KEGG	D12932
ChEMBL	ChEMBL4297284
CompTox Dashboard (EPA)	DTXSID501267252
Chemical and physical data
Formula	C₂₁H₃₀O₃
Molar mass	330.468 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

References

^ Jump up to:^a ^b ^c “Bezisterim”. AdisInsight. 5 September 2024. Retrieved 26 September 2024.
^ Reading, Chris L; Ahlem, Clarence N; Parameswaran, Narayanan (December 2021). “Rationale for an anti-inflammatory insulin sensitizer in a phase 3 Alzheimer’s disease trial”. Alzheimer’s & Dementia. 17 (S9). doi:10.1002/alz.057438.
^ Stoiljkovic, Milan; Horvath, Tamas L.; Hajós, Mihály (July 2021). “Therapy for Alzheimer’s disease: Missing targets and functional markers?”. Ageing Research Reviews. 68: 101318. doi:10.1016/j.arr.2021.101318. PMC 8131215. PMID 33711510.
^ Balzano, Tiziano; Esteban-García, Noelia; Blesa, Javier (2 January 2023). “Neuroinflammation, immune response and α-synuclein pathology: how animal models are helping us to connect dots”. Expert Opinion on Drug Discovery. 18 (1): 13–23. doi:10.1080/17460441.2023.2160440. PMID 36538833. S2CID 254959175.
^ Liu, Ping; Wang, Yunyun; Sun, Yan; Peng, Guoping (April 2022). “Neuroinflammation as a Potential Therapeutic Target in Alzheimer’s Disease”. Clinical Interventions in Aging. 17: 665–674. doi:10.2147/CIA.S357558. PMC 9064449. PMID 35520949.
^ Xi, Yilong; Chen, Yun; Jin, Yi; Han, Guochen; Song, Mingjie; Song, Tingting; Shi, Yang; Tao, Ling; Huang, Zewei; Zhou, Jianping; Ding, Yang; Zhang, Huaqing (May 2022). “Versatile nanomaterials for Alzheimer’s disease: Pathogenesis inspired disease-modifying therapy”. Journal of Controlled Release. 345: 38–61. doi:10.1016/j.jconrel.2022.02.034. PMID 35257810. S2CID 247285338.
^ “U.S. Clinical Trial: Neurological Associates of West Los Angeles Listed a New Clinical Trial to Study Insulin-sensitizing NE3107 in Improving Sleep and Fatigue in Subjects With Traumatic Brain Injury.” Contify Life Science News, 1 Aug. 2023, p. NA. Gale OneFile: Health and Medicine, link.gale.com/apps/doc/A759542006/HRCA?u=anon~bb46c85&sid=sitemap&xid=0c315c7e. Accessed 14 Dec. 2023.

/////Bezisterim, HE 3286, NE 3107, Triolex, NE3107, NE-3107, HE3286, HE-3286, PHASE 2

Ensartinib

April 16, 2025 2:53 am / Leave a comment

Ensartinib

X396, X 396

1370651-20-9
C26H27Cl2FN6O3,
561.4 g/mol
SMA5ZS5B22

6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-N-[4-[(3R,5S)-3,5-dimethylpiperazine-1-carbonyl]phenyl]pyridazine-3-carboxamide

FDA 12/18/2024, Ensacove, To treat non-small cell lung cancer

Ensartinib, sold under the brand name Ensacove, is an anti-cancer medication used for the treatment of non-small cell lung cancer.^[1] Ensartinib is an Anaplastic lymphoma kinase (ALK) inhibitor used as the salt ensartinib hydrochloride.^[1] It is taken by mouth.^[1]

The most common adverse reactions include rash, musculoskeletal pain, constipation, cough, pruritis, nausea, edema, pyrexia, and fatigue.^[2]

Ensartinib was approved for medical use in the United States in December 2024.^[1]^[2]^[3]^[4]

PATENT

US9126947, 18

https://patentscope.wipo.int/search/en/detail.jsf?docId=US90227390&_cid=P11-M9JBTT-36001-1

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1R)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (B)

Step 1: To a solution of A5 (219 g, 1.05 mol) in 1,2-dichloroethane (3500 mL) was added Boc-D-Pro (141 g, 0.65 mol) followed by EDCI (163 g, 0.85 mol) and DMAP (21.57 g, 0.18 mol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (3500 mL) was added and separated, the water phase was extracted with DCM(1500 mL×3), dried over MgSO ₄, concentrated and purified by column chromatography to (PE:EA=30:1) to give B1 (55.96 g, yield: 51.1%)

Step 2: To a solution of B1 (59.96 g, 268 mmol) in THF (1200 mL) was added 60% NaH (10.71 g, 268 mmol) at 0° C., the resulting mixture was stirred at that temperature for 30 min, was then added A3 (55.82 g, 268 mmol) quickly. The resulting mixture was heated under reflux overnight and evaporated. The residue was purified by column chromatography (PE:EA=4:1) to provide the advanced intermediate B2 (33.95 g, 37.7%). 1H-NMR (300 MHz, CDCl ₃): δ=1.87 (d, 3H), 5.08 (s, 2H), 6.03-6.09 (m, 1H), 6.42 (s, 1H), 7.14 (t, 1H), 7.35 (dd, 1H). LC-MS [M+H] ⁺: 336.0.

Step 3: To a solution of B2 (33.95 g, 101 mmol) in DMF (400 mL) was added BOC ₂O (39.59 g, 182 mmol) and DMAP (2.46 g, 20.2 mmol). The mixture was stirred at r.t. overnight and evaporated. The residue was purified by column chromatography (PE:EA=10:1) and the residue was treated with PE:EA=10:1 to afford B3 (46.9 g, 86.7%).

Step 4: Sodium acetate (14.34 g, 175 mmol) was added to a solution of B3 (46.9 g, 87.4 mmol) in ethanol/DMF [(5:1) (480 mL)]. The mixture was degassed, then added Pd(dppf)Cl ₂.CH ₂Cl ₂(7.14 g, 8.74 mmol). The resulting mixture was heated at CO atmosphere at 90° C. overnight, then evaporated. The residue was purified by column chromatography (PE:EA=4:1) to afford B4 (47.1 g, 94.0%). 1H-NMR (300 MHz, CDCl ₃): δ=1.38 (s, 18H), 1.46 (t, 3H), 1.88 (d, 3H), 4.45-4.53 (m, 2H), 6.18 (q, 1H), 7.13 (t, 1H), 7.34 (dd, 1H), 7.57 (s, 1H). LC-MS [M+H] ⁺: 574.0.

Step 5: To the solution of B4 (47.1 g, 82.1 mmol) in THF (400 mL) was added 1N LiOH aq. (98.5 mL). The resulting mixture was stirred at r.t. over weekend, then acidified by 2N HCl to pH=5, extracted with ethyl acetate (400 mL×3). The combined organic phase was dried over Na ₂SO ₄, filtrated and concentrated to give B (45.94 g, ˜100%).

Synthesis of 6-[bis(tert-butoxycarbonyl)amino]-5-[(1S)-1-(2,6-dichloro-3-fluoro-phenyl)ethoxy]pyridazine-3-carboxylic acid (C)

Step 1: To a solution of A5 (41.8 g, 200 mmol) in 1,2-dichloroethane (800 mL) was added Boc-L-Pro (26.9 g, 125 mmol) followed by EDCI (31.1 g, 163 mmol) and DMAP (4.12 g, 33.8 mmol) at 0° C. The resulting mixture was stirred at r.t. overnight and then water (350 mL) was added and separated, the water phase was extracted with DCM(150 mL×3), dried over MgSO ₄, concentrated and purified by column chromatography to (PE:EA=30:1) to give C1 (13.72 g, yield: 65.6%).

Step 2: The procedure from C1 to C was similar to that of B1 to B (9.46 g, yield: 26.4% from C1).

Synthesis of {5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-aminopyridazin-3-yl}-N-{4-[(4-methylpiperazinyl)carbonyl]phenyl}carboxamide

Step 1: The mixture of B (10.92 g, 20.0 mmol)), HATU (9.12 g, 24.0 mmol) and DIEA (3.87 g, 30.0 mmol) in DMF (100 mL) was stirred at room temperature for 0.5 h, then was added 1a (5.26 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 0.5 h and evaporated. The residue was purified by column chromatography (EA:MeOH=5:1) to provide 1b (12.43 g, 83.2%).

Step 2: 1b (12.43 g, 16.7 mmol) was dissolved in a mixture of DCM (90 mL) and TFA (30 mL), stirred at r.t. for 2 hours and evaporated. The residue was adjusted by sat. Na ₂CO ₃to pH=8 and extracted with DCM (150 mL×5). The combined organic phase was dried over MgSO ₄and concentrated. The residue was triturated with methanol and filtered, then the solid was dissolved in DCM and a solution of HCl in Et ₂O was added, the mixture was stirred at r.t. overnight, then concentrated and dried over oil pump to afford 1 (8.31 g, 80.5%). 1H-NMR (300 MHz, DMSO-d ₆): δ=1.84 (d, 3H), 2.76 (d, 3H), 3.02-3.10 (m, 2H), 3.37-3.53 (m, 5H), 3.40-4.26 (m, 1H), 6.27 (q, 1H), 7.11 (s, 1H), 7.42-7.51 (m, 3H), 7.58-7.62 (m, 1H), 7.86-7.88 (m, 2H). LC-MS [M+H] ⁺:547.2.

Medical uses

Ensartinib is indicated for the treatment of adults with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer who have not previously received an ALK-inhibitor.^[1]^[2]

History

Efficacy was evaluated in eXALT3 (NCT02767804), an open-label, randomized, active-controlled, multicenter trial in 290 participants with locally advanced or metastatic ALK-positive non-small cell lung cancer who had not previously received an ALK-targeted therapy.^[2] Participants were randomized 1:1 to receive ensartinib or crizotinib.^[2]

Society and culture

Legal status

Ensartinib was approved for medical use in the United States in December 2024.^[2]^[3]^[5]

Name

Ensartinib is the international nonproprietary name.^[6]

Ensartinib is sold under the brand name Ensacove.^[1]^[2]^[3]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Ensacove (ensartinib) capsules, for oral use” (PDF). Xcovery Holdings, Inc. U.S. Food and Drug Administration. December 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g “FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer”. U.S. Food and Drug Administration (FDA). 18 December 2024. Retrieved 20 December 2024. This article incorporates text from this source, which is in the public domain.
^ Jump up to:^a ^b ^c “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ “FDA Approval of Ensartinib for ALK-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)” (Press release). Xcovery Holdings. 19 December 2024. Retrieved 20 December 2024 – via Business Wire.
^ World Health Organization (2017). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 77”. WHO Drug Information. 31 (1). hdl:10665/330984.

External links

“Ensartinib (Code C102754)”. NCI Thesaurus.
Clinical trial number NCT02767804 for “eXalt3: Study Comparing X-396 (Ensartinib) to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients” at ClinicalTrials.gov

Horn L, Infante JR, Reckamp KL, Blumenschein GR, Leal TA, Waqar SN, Gitlitz BJ, Sanborn RE, Whisenant JG, Du L, Neal JW, Gockerman JP, Dukart G, Harrow K, Liang C, Gibbons JJ, Holzhausen A, Lovly CM, Wakelee HA: Ensartinib (X-396) in ALK-Positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study. Clin Cancer Res. 2018 Jun 15;24(12):2771-2779. doi: 10.1158/1078-0432.CCR-17-2398. Epub 2018 Mar 21. [Article]
FDA Approved Drug Products: ENSACOVETM (ensartinib) capsules, for oral use (Dec 2024) [Link]
NCI Formulary: Ensartinib (X-396) [Link]

Clinical data

Trade names	Ensacove
Other names	X-396
License data	US DailyMed: Ensartinib
Routes of administration	By mouth
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1370651-20-9
PubChem CID	56960363
DrugBank	DB14860
ChemSpider	58828042
UNII	SMA5ZS5B22
KEGG	D11346
ChEMBL	ChEMBL4113131
ECHA InfoCard	100.306.918
Chemical and physical data
Formula	C₂₆H₂₇Cl₂FN₆O₃
Molar mass	561.44 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

\/////////Ensartinib, FDA 2024, APPROVALS 2024, Ensacove, X396, X 396, GLXC-15836, BCP26265, EX-A2941, NSC793150, s8230

Bexicaserin

April 15, 2025 2:55 am / Leave a comment

Bexicaserin

CAS 2035818-24-5

Formula	C₁₅H₁₉F₂N₃O
Molar mass	295.334 g·mol⁻¹

LP352; LP-352; AN352; AN-352

(3R)-N-(2,2-difluoroethyl)-3-methyl-1,10-diazatricyclo[6.4.1.0^4,13]trideca-4,6,8(13)-triene-5-carboxamide

Bexicaserin is under investigation in clinical trial NCT05626634 (Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy).

PATENT

Arena Pharmaceuticals, Inc.WO2023172685

Arena Pharmaceuticals, Inc., WO2016176177

https://patents.google.com/patent/WO2016176177A1/en

Example 1: Syntheses of Compounds of Table A Example 1.1: Preparation of N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 1)

Step A: Preparation of methyl 3-formyl-lH-indole-4-carboxylate

2M solution of oxalyl dichloride in dichloromethane (DCM) (1.712 ml, 3.425 mmol) was added to DCM (15 mL) cooled down in an ice-water bath. N,N-dimethylformamide (0.250 g, 3.425 mmol) was added dropwise under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. Then methyl lH-indole-4-carboxylate (0.5 g, 2.854 mmol) in DCM (10 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed. THF (15 mL) and 20% aqueous ammonium acetate were added. The reaction mixture was stirred under reflux (-70 °C) for 30 min. The reaction mixture was then extracted with ethyl acetate. The combined organics (organic phases) were concentrated; the residue was purified by silica gel column chromatography with 90% ethyl acetate/hexanes to give the title compound (551 mg, 95.0 %) as white solid. LCMS m/z = 204.2 [M+H]⁺; Ή NMR (400 MHz, CDC1₃) δ ppm 4.00 (s, 3H), 7.34 (t, / = 7.8 Hz, 1H), 7.63 (dd, / = 8.0 and 1.0 Hz, 1H), 7.87 (dd, / = 7.5 and 1.0 Hz, 1H), 8.10 (d, / = 3.2 Hz, 1H), 9.08 (br s, 1H), 10.53 (s, 1H).

Step B: Preparation of methyl 3-methyl-lH-indole-4-carboxylate

To a stirred solution of methyl 3-formyl-lH-indole-4-carboxylate (551 mg, 2.712 mmol) in DMF (8 mL) was added 4-methylbenzenesulfonohydrazide (0.657 g, 3.525 mmol) followed by p- toluenesulfonic acid monohydrate (77.37 mg, 0.407 mmol) and tetramethylene sulfone (sulfolane, 8 mL). The reaction mixture was stirred at 100 °C for 1 h, cooled to room temperature. Sodium cyanoborohydride (0.682 g, 10.85 mmol) was added portionwise. Then the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled down, diluted with water, and extracted with 50% ethyl acetate in hexanes. The organics were concentrated; the residue was purified by silica gel column chromatography with 20% ethyl acetate hexanes to give the title compound (355 mg, 69.2 %) as off- white solid. LCMS m/z = 190.4 [M+H]⁺; Ή NMR (400 MHz, CDC1₃) δ ppm 2.41 (d, / = 1.0 Hz, 3H), 3.96 (s, 3H), 7.07-7.10 (m, 1H), 7.18 (t, / = 7.8 Hz, 1H), 7.50 (dd, / = 8.0 and 1.0 Hz, 1H), 7.64 (dd, J = 7.5 and 1.0 Hz, 1H), 8.12 (bs, 1H).

Step C: Preparation of methyl 3-methylindoline-4-carboxylate

To a solution of methyl 3-methyl-lH-indole-4-carboxylate (1.253 g, 6.622 mmol) in TFA (trifluoroacetic acid) (4.06 mL) in an ice-water bath was added triethylsilane (4.231 ml, 26.49 mmol) drop wise under N₂. The reaction mixture was warmed to room temperature and stirred overnight. The mixture was concentrated and added water. After adjusting pH to 8 with saturated aqueous NaHC0₃ solution, the mixture was extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography with 25% ethyl acetate/hexanes (column prewashed with 0.1% Et₃N/hexanes) to give the title compound (1.013 g, 80.0 %) as orange-red oil. LCMS m/z = 192.2 [M+H]⁺; Ή NMR (400 MHz, CDC1₃) δ ppm 1.25 (d, J = 6.9 Hz, 3H), 3.25 (dd, J = 8.6 and 1.7 Hz, 1H), 3.68 (t, / = 8.5 Hz, 1H), 3.83-3.92 (m, 1H), 3.90 (s, 3H), 6.78 (dd, / = 7.8 and 1.0 Hz, 1H), 7.07 (t, / = 7.8 Hz, 1H), 7.34 (dd, / = 7.8 and 1.0 Hz, 1H).

Step D: Preparation of 2-tert-butyl 8-methyl 7-methyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-hi]indole-2,8(lH)-dicarboxylate

A mixture of methyl 3-methylindoline-4-carboxylate (1.013 g, 5.297 mmol) and 2- bromoethanamine hydrobromide (1.302 g, 6.357 mmol) was heated at 115 °C overnight. The residue was dissolved in methanol and purified by preparative HPLC (5-60% CH₃CN/H₂0 with 0.1% TFA over 30 min). The combined fractions were then concentrated to give methyl l-(2-aminoethyl)-3- methylindoline-4-carboxylate. LCMS m/z = 235.4 [M+H]⁺; Ή NMR (400 MHz, CDC1₃) δ ppm 1.24 (d, / = 7.0 Hz, 3H), 2.92-3.00 (m, 3H), 3.25 (dd, / = 8.5 and 1.7 Hz, 1H), 3.30-3.40 (m, 2H), 3.80-3.90 (m, 1H), 3.88 (s, 3H), 6.64 (d, / = 7.7 Hz, 1H), 7.11 (t, / = 7.8 Hz, 1H), 7.27 (dd, / = 7.9 and 0.8 Hz, 1H).

Methyl l-(2-aminoethyl)-3-methylindoline-4-carboxylate obtained above was dissolved in methanol (10 mL), 37% formaldehyde in water (1.183 ml, 15.89 mmol) was added, followed by TFA (1.217 ml, 15.89 mmol). The reaction mixture was heated at 80 °C for lh and concentrated. The residue was dissolved in THF (8 mL), and added saturated aqueous NaHC0₃ (8 mL) solution and di-tert-butyl dicarbonate (0.776 ml, 5.297 mmol). The reaction mixture was stirred at room temperature overnight, diluted with water, and extracted with ethyl acetate. The combined organics were concentrated. The residue was purified by silica gel column chromatography with 25% ethyl acetate/hexanes to give the title compound (1.212 g, 66.0 %) as colorless oil. LCMS m/z = 347.2 [M+H]⁺; Ή NMR (400 MHz, CDC1₃) δ ppm rotamers 1.20 (d, / = 6.9 Hz, 3H), 1.35-1.45 (br, 9H), 2.80-2.95 (m, 1H), 3.08-3.18 (m,lH), 3.24-3.35 (m, 2H), 3.35-3.45 (m, 1H), 3.85-3.95 (m, 1H), 3.86 (s, 3H), 3.97-4.08 (m, 2H), 4.62-4.88 (m, 1H), 6.91-7.06 (m, 1H), 7.36 (d, J = 8.0 Hz, 1H).

Step E: Preparation of 2-(tert-butoxycarbonyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-hi]indole-8-carboxylic acid

To a solution of 2-tert-butyl 8-methyl 7-methyl-3,4,6,7-tetrahydro-[l,4]diazepino[6,7,l- hi]indole-2,8(lH)-dicarboxylate (1.212 g, 3.499 mmol) in dioxane (10 mL) was added a 1M solution of lithium hydroxide in water (13.99 ml, 13.99 mmol). The reaction mixture was stirred at 80 °C for 2 h. Organic solvent was evaporated. The residue was diluted with water, adjusted pH to 3-4 with aqueous 5% citric acid. The off-white precipitate was collected and dried to give the title compound (1.116 g, 96.0 %) as off-white solid. LCMS m/z = 333.4 [M+H]⁺.

Step F: Preparation of N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-hi]indole-8-carboxamide

To the solution of 2-(tert-butoxycarbonyl)-7-methyl- 1,2, 3,4,6, 7-hexahydro- [l,4]diazepino[6,7,l-hi]indole-8-carboxylic acid (25 mg, 75.21 μιηοΐ), HATU (42.87 mg, 0.113 mmol) and triethylamine (20.97 μί, 0.150 mmol) in DMF (2 mL) was added 2,2-difluoroethanamine (9.146 mg, 0.113 mmol). The reaction was stirred at room temperature overnight. The mixture was purified by semi preparative HPLC (15-85% CH₃CN/H₂0 with 0.1% TFA over 30 min). The combined fractions were lyophilized to give tert-butyl 8-((2,2-difluoroethyl)carbamoyl)-7-methyl-3,4,6,7-tetrahydro- [l,4]diazepino[6,7,l-hi]indole-2(lH)-carboxylate, which was dissolved in dioxane (0.5 mL). A solution of 4M HC1 in dioxane (0.5 mL) was added. The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was purified by semi preparative HPLC (5-60% CH₃CN/H₂0 with 0.1% TFA over 30 min). The combined fractions were lyophilized to give the title compound as TFA salt (17 mg, 55.2 %). LCMS m z = 296.2 [M+H]⁺; Ή NMR (400 MHz, CD₃OD) δ ppm 1.18 (d, / = 6.9 Hz, 3H), 3.10-3.20 (m, 1H), 3.26-3.40 (m, 2H), 3.40-3.64 (m, 3H), 3.65-3.85 (m, 3H), 4.21 (d, / = 14.9 Hz, 1H), 4.40 (d, J = 14.9 Hz, 1H), 6.00 (tt, J = 56.0 and 3.9 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 7.12 (d, / = 7.9 Hz, 1H).

Example 1.2: Preparation of (S)- N-(2,2-difluoroethyl)-7-methyl-l,2,3,4,6,7-hexahydro- [l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 2) and (R)- N-(2,2-difluoroethyl)-7- methyl-l,2,3,4,6,7-hexahydro-[l,4]diazepino[6,7,l-hi]indole-8-carboxamide (Compound 3)

Enantiomers of N-(2,2-difluoroethyl)-7-methyl- 1,2,3, 4,6, 7-hexahydro-[l, 4]diazepino[6,7,l-hi]indole-8- carboxamide were obtained by chiral HPLC separation using following conditions. Column: Chiralpak IC column 250 x 20 mm (L x I.D.)

Flow: 12 mL/min

Eluent: 12 % ethanol/8 % mTBE/80 % hexanes with 0.1 % Et₃N

Detector: UV 254 nm

Retention time: 1^st eluting enantiomer 22.0 min, 2^nd eluting enantiomer 23.5 min

After separation, both enantiomers were further purified by semi preparative HPLC (5-60%

CH₃CN/H₂0 with 0.1% TFA (trifluoroacetic acid) over 30 min). The combined fractions were lyophilized to give the title compounds as the TFA salt.

SCHEME

Bexicaserin (INNTooltip International Nonproprietary Name; developmental code names LP352 and AN352) is a selective serotonin 5-HT_2C receptor agonist which is under development for the treatment of seizures in developmental disabilities such as Dravet syndrome and Lennox-Gastaut syndrome.^[1]^[3]^[2] It is taken by mouth.^[2]^[1]

The drug is highly selective for the serotonin 5-HT_2C receptor, with negligible affinity for the serotonin 5-HT_2A and 5-HT_2B receptors.^[2] Because it does not activate the serotonin 5-HT_2B receptor, bexicaserin is not expected to pose a risk of cardiac valvulopathy, unlike the existing agent fenfluramine.^[2]

As of October 2024, bexicaserin is in phase 3 clinical trials for treatment of developmental disabilities.^[1]^[3] It is being developed by Longboard Pharmaceuticals.^[1]^[3]

The activation of 5HT2c receptors has been shown to reduce epileptic seizure activity by inhibiting CaV3 calcium channels which mediate the T-type calcium current.^[4] CaV3 calcium channels facilitate high frequency burst firing in princible neurons of the subiculum. This firing pattern is upregulated following status epilepticus, with these hyperactive neurons often serving as the initiation point for seizures.^[5]^[6]^[7]

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Bexicaserin – Longboard Pharmaceuticals”. AdisInsight. 16 October 2024. Retrieved 29 October 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f Dell’isola GB, Verrotti A, Sciaccaluga M, Roberti R, Parnetti L, Russo E, et al. (June 2024). “Evaluating bexicaserin for the treatment of developmental epileptic encephalopathies”. Expert Opinion on Pharmacotherapy. 25 (9): 1121–1130. doi:10.1080/14656566.2024.2373350. PMID 38916481.
^ Jump up to:^a ^b ^c “Delving into the Latest Updates on Bexicaserin with Synapse”. Synapse. 28 October 2024. Retrieved 29 October 2024.
^ Petersen AV, Jensen CS, Crépel V, Falkerslev M, Perrier JF (2017). “Serotonin Regulates the Firing of Principal Cells of the Subiculum by Inhibiting a T-type Ca2+ Current”. Frontiers in Cellular Neuroscience. 11: 60. doi:10.3389/fncel.2017.00060. PMC 5339341. PMID 28326015.
^ Menendez de la Prida L, Gal B (June 2004). “Synaptic contributions to focal and widespread spatiotemporal dynamics in the isolated rat subiculum in vitro”. The Journal of Neuroscience. 24 (24): 5525–36. doi:10.1523/JNEUROSCI.0309-04.2004. PMC 6729319. PMID 15201325.
^ Su H, Sochivko D, Becker A, Chen J, Jiang Y, Yaari Y, et al. (May 2002). “Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus”. The Journal of Neuroscience. 22 (9): 3645–55. doi:10.1523/JNEUROSCI.22-09-03645.2002. PMC 6758371. PMID 11978840.
^ Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R. On the origin of interictal activity in human temporal lobe epilepsy in vitro. Science. 2002 Nov 15;298(5597):1418-21. doi: 10.1126/science.1076510. PMID 12434059.

Clinical data

Other names	LP352; LP-352; AN352; AN-352
Routes of administration	Oral^[1]
Drug class	Serotonin 5-HT_2C receptor agonist^[1]^[2]
Pharmacokinetic data
Elimination half-life	5–7 hours^[2]
Identifiers
showIUPAC name
CAS Number	2035818-24-5
PubChem CID	122662787
DrugBank	DB18885
ChemSpider	129309383
UNII	R8XR1D6SCB
KEGG	D13035
ChEMBL	ChEMBL5314507
Chemical and physical data
Formula	C₁₅H₁₉F₂N₃O
Molar mass	295.334 g·mol⁻¹
3D model (JSmol)	Interactive image
showSMILES
showInChI

////Bexicaserin, PHASE 2, LP 352, LP-352, AN 352, AN-352

Olezarsen

April 14, 2025 2:47 am / Leave a comment

Olezarsen

Olezarsen is an ASO directed inhibitor of Apolipoprotein C-III (apoC-III) mRNA, conjugated to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes.

TRYNGOLZA contains olezarsen sodium as the active ingredient. Olezarsen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of olezarsen sodium is C 296H 419N 71O 154P 20S 19Na 20and the molecular weight is 9124.48 daltons. The chemical name of olezarsen sodium is DNA, d(P-thio) ([2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)] rG-[2′- O-(2-methoxyethyl)] m5rC-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] m5rU-[2′- O-(2-methoxyethyl)] rA-[2′- O-(2-methoxyethyl)]m5rU), 5′-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20).

Olezarsen

FDA APPROVED 12/19/2024, Tryngolza, To treat familial chylomicronemia syndrome
Drug Trials Snapshot

Synonyms

AKCEA-APOCIII-LRX
ALL-P-AMBO-5′-O-(((6-(5-((TRIS(3-(6-(2-ACETAMIDO-2-DEOXY-.BETA.-D-GALACTOPYRANOSYLOXY)HEXYLAMINO)-3-OXOPROPOXYMETHYL))METHYL)AMINO-5-OXOPENTANAMIDO)HEXYL))PHOSPHO)-2′-O-(2-METHOXYETHYL)-P-THIOADENYLYL-(3′-O->5′-O)-2′-O-(2-METHOXYETHYL)-P-THIOGUANYLYL-(3
DNA, D(P-THIO)((2′-O-(2-METHOXYETHYL))RA-(2′-O-(2-METHOXYETHYL))RG-(2′-O-(2-METHOXYETHYL))M5RC-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-M5C-T-T-G-T-M5C-M5C-A-G-M5C-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETHYL))M5RU-(2′-O-(2-METHOXYETH
IONIS-APOCIII-LRX
ISIS-APOCIII-LRX

External IDs

ISIS-678354

Olezarsen, sold under the brand name Tryngolza, is a medication used in the treatment of familial chylomicronemia syndrome.^[1]^[2] It is given by injection under the skin.^[1]

Olezarsen was approved for medical use in the United States in December 2024.^[1]^[3] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[4]

PATENT

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9127276	No	2015-09-08	2034-05-01
US9181549	No	2015-11-10	2034-05-01
US9593333	No	2014-02-14	2034-02-14
US9157082	No	2012-04-27	2032-04-27
US9163239	No	2014-05-01	2034-05-01

Medical uses

Olezarsen is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome.^[1]

Pharmacology

Olezarsen is an apolipoprotein C-III-directed antisense oligonucleotide.^[1] By binding to apolipoprotein C-III mRNA, it causes its degradation, which in turn increases clearance of plasma triglycerides and very low-density lipoprotein (VLDL).^[5]

Adverse effects

In a 66-patient trial, olezarsen was demonstrated to cause following side effects:^[5]^[6]

injection site reactions
hypersensitivity reactions (due to immunogenic potential of the medication)
arthralgia
thrombocytopenia
hyperglycemia
elevation of liver enzymes

History

The US Food and Drug Administration (FDA) granted the application of olezarsen orphan drug designation in February 2024.^[7] In August 2024, European Medicines Agency also granted olezarsen this designation.^[8]

Society and culture

Legal status

Olezarsen was approved for medical use in the United States in December 2024.^[3]^[9]

Names

Olezarsen is the international nonproprietary name.^[10]

Olezarsen is sold under the brand name Tryngolza.^[1]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g “Tryngolza- olezarsen sodium injection, solution”. DailyMed. 19 December 2024. Retrieved 25 January 2025.

^ Spagnuolo, Catherine M; Hegele, Robert A (2023). “Recent advances in treating hypertriglyceridemia in patients at high risk of cardiovascular disease with apolipoprotein C-III inhibitors”. Expert Opinion on Pharmacotherapy. 24 (9): 1013–1020. doi:10.1080/14656566.2023.2206015. PMID 37114828.
^ Jump up to:^a ^b “Novel Drug Approvals for 2024”. U.S. Food and Drug Administration (FDA). 1 October 2024. Retrieved 20 December 2024.
^ New Drug Therapy Approvals 2024 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2025. Archived from the original on 21 January 2025. Retrieved 21 January 2025.
^ Jump up to:^a ^b Stroes, Erik S.G.; Alexander, Veronica J.; Karwatowska-Prokopczuk, Ewa; Hegele, Robert A.; Arca, Marcello; Ballantyne, Christie M.; et al. (16 May 2024). “Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome”. New England Journal of Medicine. 390 (19): 1781–1792. doi:10.1056/NEJMoa2400201. ISSN 0028-4793.
^ Ionis Pharmaceuticals, Inc. (11 December 2024). A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA-APOCIII-LRx Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS) (Report). clinicaltrials.gov.
^ “Olezarsen Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Retrieved 20 December 2024.
^ “EU/3/24/2973 – orphan designation for treatment of familial chylomicronaemia syndrome | European Medicines Agency (EMA)”. http://www.ema.europa.eu. 21 August 2024. Retrieved 22 February 2025.
^ “Tryngolza (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet” (Press release). Ionis Pharmaceuticals. 19 December 2024. Retrieved 20 December 2024 – via PR Newswire.
^ World Health Organization (2022). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 87”. WHO Drug Information. 36 (1). hdl:10665/352794.

External links

“Olezarsen (Code C180652)”. NCI Thesaurus.

Clinical trial number NCT04568434 for “A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial Chylomicronemia Syndrome (FCS) (BALANCE)” at ClinicalTrials.gov

Tardif JC, Karwatowska-Prokopczuk E, Amour ES, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Hurh E, Bartlett VJ, Kingsbury J, Figueroa AL, Alexander VJ, Tami J, Witztum JL, Geary RS, O’Dea LSL, Tsimikas S, Gaudet D: Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk. Eur Heart J. 2022 Apr 6;43(14):1401-1412. doi: 10.1093/eurheartj/ehab820. [Article]
Karwatowska-Prokopczuk E, Tardif JC, Gaudet D, Ballantyne CM, Shapiro MD, Moriarty PM, Baum SJ, Amour ES, Alexander VJ, Xia S, Otvos JD, Witztum JL, Tsimikas S: Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia. J Clin Lipidol. 2022 Sep-Oct;16(5):617-625. doi: 10.1016/j.jacl.2022.06.005. Epub 2022 Jun 23. [Article]
Hooper AJ, Bell DA, Burnett JR: Olezarsen, a liver-directed APOC3 ASO therapy for hypertriglyceridemia. Expert Opin Pharmacother. 2024 Oct;25(14):1861-1866. doi: 10.1080/14656566.2024.2408369. Epub 2024 Sep 26. [Article]
Bergmark BA, Marston NA, Prohaska TA, Alexander VJ, Zimerman A, Moura FA, Murphy SA, Goodrich EL, Zhang S, Gaudet D, Karwatowska-Prokopczuk E, Tsimikas S, Giugliano RP, Sabatine MS: Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk. N Engl J Med. 2024 May 16;390(19):1770-1780. doi: 10.1056/NEJMoa2402309. Epub 2024 Apr 7. [Article]
FDA News: FDA approves drug to reduce triglycerides in adult patients with familial chylomicronemia syndrome [Link]
FDA Approved Drug Products: TRYNGOLZA (olezarsen) injection, for subcutaneous use [Link]

Clinical data

Trade names	Tryngolza
Other names	IONIS-APOCIII-LRX
License data	US DailyMed: Olezarsen
Routes of administration	Subcutaneous
Drug class	Antisense oligonucleotide
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
showIUPAC name
CAS Number	2097587-83-0 2298451-31-5
DrugBank	DB18728
UNII	S3RS2SA30L NSY2BY6PSB
KEGG	D13023

////Olezarsen, FDA 2024, APPROVALS 2025, Tryngolza, ISIS-678354, ISIS 678354, familial chylomicronemia syndrome

Fitusiran

April 12, 2025 5:51 am / Leave a comment

Fitusiran
1711.0 g/mol, C₇₈H₁₃₉N₁₁O₃₀

FDA APPROVED 3/28/2025, Qfitlia, To prevent or reduce the frequency of bleeding episodes in hemophilia A or B
Press Release

CAS 1499251-18-1
EX-A12034
DA-53206
N-[1,3-Bis[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]-2-[[3-[3-[5-[(2R,3R,4R,5R,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxypentanoylamino]propylamino]-3-oxopropoxy]methyl]propan-2-yl]-12-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-12-oxododecanamide

Fitusiran Sodium

43 Sodium salt of duplex of [(2S,4R)-1-{1-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]-16,16-bis({3-[(3-{5-[(2-acetamido-2-deoxy-β-D-galactopyranosyl)oxy]pentanamido}propyl)amino]-3-oxopropoxy}methyl)-5,11,18-trioxo-14-oxa-6,10,17-triazanonacosan-29-oyl}-4-hydroxypyrrolidin-2-yl]methyl hydrogen all–P–ambo-2′-deoxy-2′-fluoro-P-thioguanylyl-(3’→5′)-2′-O-methyl-P-thioguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methylcytidylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoro-3′-adenylate and all–P–ambo-2′-O-methyl-P-thiouridylyl-(3’→5′)-2′-deoxy-2′-fluoro-P-thiouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroguanylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methylguanylyl-(3’→5′)-2′-deoxy-2′-fluorouridylyl-(3’→5′)-2′-O-methyluridylyl-(3’→5′)-2′-deoxy-2′-fluoroadenylyl-(3’→5′)-2′-O-methyladenylyl-(3’→5′)-2′-deoxy-2′-fluorocytidylyl-(3’→5′)-2′-O-methyl-P-thiocytidylyl-(3’→5′)-2′-O-methyl-P-thioadenylyl-(3’→5′)-2′-O-methylguanosine

C₅₂₀H₆₃₆F₂₁N₁₇₅Na₄₃O₃₀₉P₄₃S₆ : 17193.39
[1609016-97-8]

Fitusiran, sold under the brand name Qfitlia, is a medication used for the treatment of hemophilia.^[1] It is an antithrombin-directed small interfering ribonucleic acid.^[1] It is given by subcutaneous injection.^[1] Fitusiran reduces the amount of a protein called antithrombin.^[2]

The most common side effects include viral infection, common cold symptoms (nasopharyngitis) and bacterial infection.^[2]

Fitusiran was approved for medical use in the United States in March 2025.^[2]

PATENT

https://patents.google.com/patent/WO2023240199A2/en

Medical uses

Fitusiran is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in people aged twelve years of age and older with hemophilia A or hemophilia B, with or without factor VIII or IX inhibitors (neutralizing antibodies).^[1]^[2]

Adverse effects

The US Food and Drug Administration prescription label for fitusiran contains a boxed warning for thrombotic events (blood clotting) and gallbladder disease (with some recipients requiring gallbladder removal).^[2] The label also has a warning about liver toxicity and the need to monitor liver blood tests at baseline and then monthly for at least six months after initiating treatment with fitusiran or after a dose increase of fitusiran.^[2]

History

The efficacy and safety of fitusiran were assessed in two multicenter, randomized clinical trials which enrolled a total of 177 adult and pediatric male participants with either hemophilia A or hemophilia B.^[2] In one study, participants had inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with medicines known as “bypassing agents” for bleeding.^[2] In the second study, participants did not have inhibitory antibodies to coagulation factor VIII or coagulation factor IX and previously received on-demand treatment with clotting factor concentrates.^[2] In the two randomized trials, participants received either a fixed dose of fitusiran monthly or their usual on-demand treatment (bypassing agents or clotting factor concentrates) as needed for nine months.^[2] The fixed dose of fitusiran is not approved because it led to excessive clotting in some participants.^[2]

The US Food and Drug Administration (FDA) granted the application for fitusiran orphan drug and fast track designations. The FDA granted the approval of Qfitlia to Sanofi.

Society and culture

Legal status

Fitusiran was approved for medical use in the United States in March 2025.^[2]^[3]

Names

Fitusiran is the international nonproprietary name.^[4]

Fitusiran is sold under the brand name Qfitlia.^[1]^[2]

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Qfitlia- fitusiran injection, solution”. DailyMed. 26 March 2025. Retrieved 2 April 2025.

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “FDA Approves Novel Treatment for Hemophilia A or B, with or without Factor Inhibitors”. U.S. Food and Drug Administration. 28 March 2025. Retrieved 29 March 2025. This article incorporates text from this source, which is in the public domain.
^ “Qfitlia approved as the first therapy in the US to treat hemophilia A or B with or without inhibitors”. Sanofi (Press release). 28 March 2025. Retrieved 29 March 2025.
^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information. 30 (1). hdl:10665/331046.

External links

Clinical trial number NCT03417102 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors (ATLAS-INH)” at ClinicalTrials.gov
Clinical trial number NCT03417245 for “A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors” at ClinicalTrials.gov
Clinical trial number NCT03754790 for “Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX (ATLAS-OLE)” at ClinicalTrials.gov

Clinical data
Trade names	Qfitlia
Other names	ALN-AT3SC
License data	US DailyMed: Fitusiran
Routes of administration	Subcutaneous
Drug class	Anthithrombin production inhibitor
ATC code	None
Legal status
Legal status	US: ℞-only^[1]
Identifiers
CAS Number	1499251–18–1
DrugBank	DB15002
UNII	SV9W47ZLE1
KEGG	D11810
Chemical and physical data
Formula	C₅₂₀H₆₃₆F₂₁N₁₇₅Na₄₃O₃₀₉P₄₃S₆
Molar mass	17193.48 g·mol⁻¹

////////Fitusiran, Qfitlia, FDA 2025, APPROVALS 2025, EX-A12034, DA-53206

Tibremciclib

April 11, 2025 8:47 am / Leave a comment

Tibremciclib

cas 2397678-18-9, GTPL12881

CRB7BT5JDQ

518.6 g/mol, C₂₈H₃₂F₂N₈

N-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-[(1R)-6-fluoro-1-methyl-1,2,3,4-tetrahydropyrido[1,2-a]benzimidazol-8-yl]pyrimidin-2-amine

Tibremciclib is a CDK4 inhibitor with antineoplastic activity^[1].

Originator Betta Pharmaceuticals Co Ltd
Class Antineoplastics; Small molecules
Mechanism of Action Cyclin-dependent kinase 4 inhibitors; Cyclin-dependent kinase 6 inhibitors

Phase III Breast cancer; Solid tumours

13 Sep 2024 Efficacy and adverse event data from a phase III trial in Breast cancer presented at the 49th European Society for Medical Oncology Congress 2024 (ESMO-2024)

30 Jun 2023Phase-III clinical trials in Breast cancer (Metastatic disease, Late-stage disease, Combination therapy, Second-line therapy or greater) in China (PO) (NCT05433480)
02 Jun 2023Efficacy, adverse events and PK data from a phase I trial in Solid tumours presented at the 59th Annual Meeting of the American Society of Clinical Oncology (ASCO-2023)

Cyclin-dependent kinases (CDKs) are a class of serine / threonine protein kinases that participate in the regulation of the cell cycle, transcription initiation, and control of certain specific metabolic cascades. Different CDKs and cyclins form CDK-cyclin complexes. If the CDK activity is dysregulated, it will directly or indirectly cause uncontrolled cell proliferation, genomic instability (increased DNA mutation, chromosome deletion, etc.) and chromosomal instability (change in chromosome number). )Wait.

The CDKs family has identified more than 20 subtypes. CDK1, CDK2, CDK4, and CDK6 are involved in cell cycle regulation; CDK7, CDK8, CDK9, and CDK11 are involved in transcription regulation; and other kinases include CDK3 and CDK5. Among them, CDK4 / 6 (cyclin-dependent kinases 4 and 6) is a key factor in regulating the cell cycle. Cancer-related cell cycle mutations mainly exist in the G1 and G1 / S phase transformation. CDK4 / 6 binds to CyclinD A complex with kinase activity is formed and phosphorylation of the tumor suppressor gene Rb product pRb releases the bound transcription factor E2F to initiate transcription of genes related to the S phase, prompting cells to pass the checkpoint and transfer from the G1 phase to the S phase. The specific activation of CDK4 / 6 is closely related to the proliferation of some tumors. About 80% of human tumors have abnormalities in the cyclin D-CDK4 / 6-INK4-Rb pathway. CDK4 / 6 inhibitors block the cell cycle in the G1 phase, thereby inhibiting tumor proliferation.

The development of drugs targeting CDK4 / 6 kinases is a significant area. The advantages of anti-tumor targets are: (1) Most proliferating cells rely on CDK2 or CDK4 / 6 to proliferate, but CDK4 / 6 inhibitors do not show Cytotoxicity of “pan-CDK inhibitors”, such as bone marrow suppression and intestinal response; (2) Preclinical experiments show that if the level of cyclin D or the inactivation of P16INK4a can increase the sensitivity of cells to drugs, due to tumors Compared with normal cells, cells have the above phenomenon, so the targeting of drugs is increased to a certain extent.

PCT International Application PCT / CN2017 / 117950 describes a class of benzimidazole derivatives that are used as CDK4 / 6 protein kinase inhibitors, and most of these compounds effectively inhibit CDK4 and CDK6. Because there are still unmet needs in the treatment options for kinase-mediated diseases, here we further screen the salt forms and crystal forms of benzimidazole derivatives to meet the medical needs of patients.

SCHEME

SIDE CHAIN

SIDE CHAIN

MAIN

Patent

Betta Pharmaceuticals Co., Ltd., WO2019242719

https://patents.google.com/patent/WO2019242719A1/en

Synthesis of 1-A1-01 (Step 1)

In a 50L reactor, add 20L of dichloromethane (DCM), 1-A1-S1 (300g), and triethylamine (390g). While stirring, lower the temperature to below -5 ° C, and add benzyl chloroformate / Cbz- Cl (570 g) was added dropwise for 5 hours, and the temperature was naturally raised to room temperature. TLC (ethyl acetate: n-hexane = 1: 3) was monitored until the reaction was completed. Water (1.5 L) was added, and concentrated hydrochloric acid (80 mL) was slowly added dropwise to control the pH to 1-2. The solution was allowed to stand and separate. The organic phase was washed with 15 L of water, dried over anhydrous sodium sulfate for 0.5 hours, filtered to remove the desiccant, and collected the filtrate. And concentrated to obtain 730 g of light yellow oily liquid, which is crude 1-A1-01, yield 95.4%

Synthesis of 1-A1-02 (Step 2)

720mL of DCM, N, N-dimethylsulfoxide (90g) was added to a 20L reaction flask, protected by nitrogen, and the temperature was lowered below -65 ° C under stirring, and oxalyl chloride (106g) was added dropwise. The addition was completed in 2 hours. Stir for 20 minutes under heat preservation; add 1-A1-01’s dichloromethane solution (143g / 500mL DCM) dropwise. After 40 minutes, the addition is complete and the reaction is held for 15 minutes. Controlled at this temperature, TEA was added dropwise. After the addition was completed for 2 hours, the temperature was naturally raised to -20 ° C. 250 L of water was added to the system. The pH of the system was adjusted to 1-2 with hydrochloric acid. × 2) Washed, dried over anhydrous sodium sulfate, filtered to remove the desiccant, collected the filtrate and concentrated to obtain 432 g of a yellow oily liquid, which is the crude product 1-A1-02, which was directly used in the next reaction.

Synthesis of 1-A1-03 (Step 3)

In a stirred state, 400 mL of tetrahydrofuran (THF) and potassium tert-butoxide (215 g) were sequentially added to a 1 L reaction kettle, the temperature was lowered to 5-15 ° C., and triethyl phosphoryl acetate (430 g) was added dropwise. The dropwise addition was completed in 50 minutes. At a controlled temperature of 15 ° C, a tetrahydrofuran solution of 1-A1-02 (431 g / 100 mL of THF) was added dropwise. After the dropwise addition was completed for 1 hour, TLC (ethyl acetate: n-hexane = 1: 3) was monitored to complete the reaction, and the system was added. Saturated aqueous sodium chloride solution (1.5L), allowed to stand and separate, and collected the tetrahydrofuran phase; the aqueous phase was extracted with dichloromethane (2L), and the organic phases were combined and dried over anhydrous sodium sulfate for 0.5 hours, and the drying agent was removed by filtration. The filtrate was collected and concentrated, and the concentrate was purified by column chromatography to obtain 390 g of a pale yellow oily liquid, which was 1-A1-03 product.

Synthesis of 1-A1-041 (step 4)

In a 5L reactor, an aqueous solution of sodium hydroxide (301 g / 1.5 L of water) was added to a tetrahydrofuran (601 g / 2.3 L of THF) solution of 1-A1-03, and the mixture was heated to reflux for 3-4 hours to stop the reaction. The temperature was lowered to 40-50 ° C, and the layers were left to stand. The organic phase (THF) was collected and concentrated to a large amount of solids; the solids were dissolved by adding water (20L), and the aqueous phase was sequentially treated with methyl tert-butyl ether (2L) and ethyl acetate. Ester (2L), methyl tert-butyl ether (2L) washing; the aqueous phase was adjusted to pH 1-2 with concentrated hydrochloric acid, extracted twice with ethyl acetate (1.5L, 3L), the organic phases were combined, and anhydrous sulfuric acid was used Sodium was dried for 0.5 hours; the desiccant was removed by filtration, and the filtrate was collected and concentrated to a large amount of solids. The solids were added with isopropyl ether (3L) and slurried for 2 hours. The solids were collected by filtration and the solids were rinsed with isopropyl ether (1L). The solid was air-dried at 50 ° C for 3-4 hours to obtain 331 g of a pale yellow solid, which is a 1-A1-041 product with a yield of 52.7%.

Synthesis of 1-051 (step 5)

In a stirred state, 1-A1-041 (600g), methanol (25L), and concentrated sulfuric acid were added to a 50L reactor, and the reaction was heated under reflux for 3-4 hours. After the reaction was completed, the temperature was reduced to room temperature. Dichloromethane (15L) was added to the concentrate, and the pH was adjusted to 9-10 with an aqueous solution of potassium carbonate. The organic phase was collected by stirring, standing, and separating. The organic phase was dried over anhydrous sodium sulfate for 0.5 hours. The desiccant was removed by filtration and the filtrate was collected. And concentrated to obtain 6.37 kg of off-white solid, which is 1-A1-051 product, with a yield of 97.3%.

Synthesis of 1-A1 (step 6)

In a 2L hydrogenation kettle, add 1-A1-051 (500g), methanol (1.8L), and palladium on carbon. The system replaces nitrogen 3 times and hydrogen 3 times in sequence. The system maintains a hydrogen atmosphere, and the temperature is increased to 85 ° C and the pressure is 3.0. The reaction was carried out at Mpa for 3 hours, and the reaction was completed. The temperature was lowered to room temperature, the palladium on carbon was removed by filtration, and the organic phase was collected and concentrated until a large amount of light yellow solid appeared. Isopropyl ether (3L) was added to freeze (-20 ° C) for crystallization, and the solid product was collected by filtration. Ether (500 mL) was rinsed to obtain 234 g of a pale yellow solid, which was a 1-A1 product with a yield of 90.5%.

Synthesis of 1-A2 (Step 7)

In a stirred state, 1-A1 (200g), 4-bromo-2,6-difluoroaniline (410g), and toluene (1.2L) were added to a 50L reactor, and phosphorus oxychloride (413g) was added dropwise to the system. The addition was completed in 1 hour. Triethylamine was added dropwise under an ice bath, and the addition was completed in 1 hour. The temperature was raised to 110 ° C, and the reaction was performed for 1 hour. Reduce the temperature of the system to 2-10 ° C, add 1L of water, adjust the pH = 9-10 with saturated potassium carbonate aqueous solution, extract twice with ethyl acetate (1.5L, 1L), and combine the organic phases with 2L saturated sodium chloride aqueous solution. Wash, dry with anhydrous sodium sulfate for 0.5 hours, remove the desiccant by filtration, collect the filtrate and concentrate to the appearance of a solid product, add isopropyl ether (1L) to beat the solid for 10 minutes, filter, and collect 460 g of a yellow solid as a 1-A2 product.

Synthesis of 1-A3 (step eight)

Under stirring, 1-A2 (450g), N, N-dimethylformamide (2L), and cesium carbonate (700g) were added to the reaction kettle, and the reaction was heated to 110 ° C for 24 hours, and the reaction was detected by TLC. Ethyl acetate (3L) was added to the system, and solid impurities were removed by filtration. The filtrate was washed with a saturated sodium chloride aqueous solution (1L × 5), and the organic phase was dried over anhydrous sodium sulfate for 0.5 hours, concentrated to the appearance of a large amount of solid, Butyl ether (1L × 2) was beaten for 30 minutes, and 382 g of pale yellow solid product was obtained by filtration, that is, 1-A3, and the yield was 90.10%.

Synthesis of 1-01 (step 9)

With stirring, 1-A3 (380 g), pinacol diborate (400 g), potassium acetate (340 g), palladium acetate (6 g), tricyclohexyl phosphorus (7 g), and 1,4-dioxane were sequentially added. The ring was added to the reaction kettle, protected by nitrogen, and heated to 90 ° C for 2 hours. TLC was monitored until the reaction was complete. The temperature was reduced to room temperature, and the filtrate was concentrated to remove a large amount of 1,4-dioxane. The concentrate was purified by n-hexane and dichloromethane column chromatography, and n-hexane (1.2 L) was slurried for 1 hour to obtain 334 g of a gray solid. That is 1-01, and the yield is 70.10%.

Synthesis of 1-02 (step 10)

Under stirring, take 1-01 (128g), 1,4-dioxane (1L), 1-S3 (85g), potassium carbonate (110g), and purified water and add them to a 2L three-necked flask in sequence. [1,1′-Bis (diphenylphosphine) ferrocene] palladium dichloromethane complex (Pd (dppf) Cl ₂ .DCM) was added. The temperature was raised to 60 ° C. After 4 hours of reaction, the reaction was complete. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove most of 1,4-dioxane. Dichloromethane (1.5 L) and purified water (1.1 L) were added, stirred, and allowed to stand and separate. The layers were separated, and water was added. The phases were extracted with dichloromethane (10 L), the organic phases were combined, washed with 0.5% dilute hydrochloric acid (1 L x 2), saturated aqueous sodium chloride solution (1 L), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate (500 g), filtered to remove the drying agent, and the filtrate was concentrated under reduced pressure. Ethyl acetate (0.5 L) was added to the concentrate and the mixture was stirred for 30 minutes to precipitate a solid. After filtration, the obtained solid was rinsed with ethyl acetate (0.5 L) and dried under vacuum at 45 ° C for 3 hours to obtain 120 g of a yellow solid.

Synthesis of 1-03 (step 11)

Under stirring, take 1-02 (100g), 1,4-dioxane (1L), 1-C2 (80g), and cesium carbonate (163g) into a 2L three-necked bottle in sequence, protected by nitrogen, and add palladium acetate ( 2g) and 4,5-bisdiphenylphosphine-9,9-dimethylxanthracene (Xantphos) (4g), heated to 85 ° C. until the reaction was complete. The reaction solution was cooled to room temperature and filtered to obtain a solid product. The solid was rinsed with ethyl acetate, and then added to a mixed system of dichloromethane (1.5 L) and purified water (1.1 L), stirred, allowed to stand, and separated into layers. The aqueous phase was extracted with dichloromethane (700 mL). The organic phases were combined and washed with purified water (700 mL x 2). The organic phase was dried by adding anhydrous sodium sulfate (700 g), filtered to remove the desiccant, and the filtrate was concentrated. Methanol (0.5 L) was added, heated to 55-65 ° C. and stirred for 0.5 hours, lowered to room temperature, and filtered. The solid product was filtered and rinsed with 500 mL of ethyl acetate. The solid was dried under vacuum at 45 ° C for 8 hours to obtain 111.79 g of a pale yellow solid 1-03.

Synthesis of compound II (step twelve)

Under stirring, take 1-03 (500g) and anhydrous methanol (3.8L), add them to a 10L reactor in sequence, and heat to 65 ° C. After the reaction system is clarified for 0.5 hours, add L-tartaric acid in methanol (150.89) dropwise. g of tartaric acid is dissolved in 500mL of anhydrous methanol), and the dropping time is controlled to be 45 to 60 minutes. After the addition is complete, the reaction is kept at 65 ° C for 4 hours. ), Control the dropwise addition time to 30 to 45 minutes. After the dropwise addition is complete, hold the reaction at 65 ° C for 1 hour. Continue to dropwise add L-tartaric acid in methanol (36.55g of tartaric acid dissolved in 250mL of anhydrous methanol) and control the dropwise addition time to 30. To 45 minutes, the dropwise addition was completed. The temperature was kept at 65 ° C for 1.5 hours, and the heating was stopped. The temperature was naturally lowered to 20-30 ° C, filtered, the filter cake was rinsed with methanol (400mL × 2), and dried at 45 ° C under vacuum for 36 hours. 530.64 g of crystalline powder was Compound II, which was identified by X-ray powder diffraction, and showed that the crystal form was Form A of Compound II.

WO2022199656

WO2023131179

[1]. Wang Yiqian, et al. Crystal form of compound useful as CDK4/6 inhibitors for the treatment of cancer. World Intellectual Property Organization, WO2019242719 A1. 2019-12-26.

///Tibremciclib, GTPL12881, BETTA, PHASE 3, CANCER

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