Crisugabalin

Crisugabalin

Cas 2209104-84-5

2-[(1S,2S,3R,6S,8S)-2-(aminomethyl)-2-tricyclo[4.2.1.0^3,8]nonanyl]acetic acid

WeightAverage: 209.289
Monoisotopic: 209.141578856

Chemical FormulaC₁₂H₁₉NO₂

• HSK 16149
• HSK-16149
• HSK16149
• Q3MK7E8686
• PHASE 2

Tricyclo[4.2.1.0^3,8]nonane-2-acetic acid, 2-(aminomethyl)-, (1S,2S,3R,6S,8S)-
(1S,2S,3R,6S,8S)-2-(Aminomethyl)tricyclo[4.2.1.0^3,8]nonane-2-acetic acid

• (1S,2S,3R,6S,8S)-2-(Aminomethyl)tricyclo[4.2.1.03,8]nonane-2-acetic acid
• 2-[(1S,2S,3R,6S,8S)-2-(aminomethyl)-2-tricyclo[4.2.1.03,8]nonanyl]acetic acid
• Tricyclo[4.2.1.03,8]nonane-2-acetic acid, 2-(aminomethyl)-, (1S,2S,3R,6S,8S)-

Crisugabalin (HSK16149) is a selective GABA analog in development for the treatment of chronic pain. It has a wider therapeutic index than pregabalin, which has a similar mechanism of action. In China, it was approved in May 2024 for the treatment of diabetic peripheral neuropathic pain^[1] and approved in July 2024 for the treatment of postherpetic neuralgia.^[2] In the United States, it is in Phase III trials as of 2023.^[3][4] The drug can be administered with or without food.^[5]

Crisugabalin is under investigation in clinical trial NCT06490484 (Efficacy and Safety of HSK16149 Capsule in Chinese Patients With Diabetic Peripheral Neuropathic Pain Who Had an Inadequate Response to Pregabalin).

SCHEME

PATENTS

WO2020029762

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020029762&_cid=P10-MAI1TM-34428-1

Example 1 

[0414]2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-yl)acetate benzenesulfonate (1:1) (Compound 1) 

[0415]

2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1)

[0416]

[0417]

[0418]Step 1: 3-(Cyclohexyl-3-en-1-yl)propanoic acid (1B) 

[0419]

3-(cyclohex-3-en-1-yl)propanoic acid

[0420]

[0421]Anhydrous formic acid (18.82kg, 409.09mol) was pumped into a 100-liter reactor. The temperature was lowered to 10°C. Triethylamine (16.53kg, 163.64mol) was added dropwise to the reaction solution. After addition, it was stirred for 20 minutes. When the internal temperature was 10°C, cycloisopropyl malonate (7.86kg, 54.55mol) was added to the reactor. Then 3-cyclohexene-1-carboxaldehyde (6.00kg, 54.55mol) was added dropwise to the reaction solution at an internal temperature of 40°C. After addition, the temperature was raised to 140-150°C and the reaction was continued until no gas was released. The pH of the reaction solution was adjusted to 1-2 with 6N hydrochloric acid (24.0L). The aqueous phase was extracted with dichloromethane (12L×2), and the organic phases were combined and washed with saturated brine (10L×2). The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 1 hour, filtered, and the filtrate was concentrated and evaporated to dryness to obtain a yellow oil 1B (8.80 kg). 

[0422]

¹H NMR(400MHz,CDCl ₃)δ10.23(s,1H),5.73–5.55(m,2H),2.46–2.30(m,2H),2.09–1.96(m,2H),1.81–1.53(m,6H),1.35–1.17(m,1H)。

[0423]

LCMS m/z＝153.1[M-1]。

[0424]Step 2: 3-(Cyclohexyl-3-en-1-yl)-1-(pyrrolidin-1-yl)propyl-1-one (1C) 

[0425]

3-(cyclohex-3-en-1-yl)-1-(pyrrolidin-1-yl)propan-1-one

[0426]

[0427]Dissolve 1B (11.20kg, 72.727mol) in dichloromethane (60.0L) and pump into a 100L reactor. Add DMF (3.0mL) and drop oxalyl chloride (9.046kg, 71.272mol) into the reaction solution. After addition, stir at room temperature for 2.0 hours. Add tetrahydropyrrole (5.689kg, 79.999mol) and triethylamine (8.814kg, 87.272mol) dropwise into the reactor. Control the internal temperature below 10℃, after addition, stir at room temperature overnight. Cool the reaction solution to 10℃. Add 3N hydrochloric acid (20.0L) dropwise to adjust the pH of the reaction solution to between 1-2. Let stand, separate the liquids, and extract the aqueous phase with dichloromethane (10.0L×1). The organic phases were combined and washed with 5% sodium hydroxide solution (10.0 L x 1) and saturated ammonium chloride solution (20.0 L x 1) in sequence. The organic phase was dried over anhydrous sodium sulfate (2.0 kg) for 30 minutes, filtered, and the filtrate was concentrated to obtain brown liquid 1C (15.00 kg, yield 99.6%). 

[0428]

¹H NMR(400MHz,CDCl ₃)δ5.73–5.56(m,2H),3.43(dd,4H),2.37–2.22(m,2H),2.16–2.01(m,4H),1.90(dt,4H),1.81–1.51(m,6H),1.30–1.15(m,2H)。

[0429]

LCMS m/z＝208.1[M+1]。

[0430]Step 3: Tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-one (1R,3S,6R,8R and 1S,3R,6S,8S racemate) (1D) 

[0431]

tricyclo[4.2.1.0 ^3,8]nonan-2-one(1R,3S,6R,8R and 1S,3R,6S,8S racemate)

[0432]

[0433]Dissolve 1C (5.64kg, 27.22mol) in dichloromethane (40.0L) and pump it into a 100L reactor. Cool to -10°C and add 2,4,6-trimethylpyridine (4.94kg, 40.83mol). Add a dichloromethane solution (16.0L) of trifluoromethanesulfonic anhydride (11.50kg, 40.83mol) dropwise to the reaction solution until complete. Heat and reflux for 12 hours. After the reaction is complete as detected by the central control, add an aqueous solution (23.0L) of sodium hydroxide (3.10kg, 77.5mol) dropwise to the reaction solution and adjust the pH of the reaction solution to between 10-11. Continue to reflux for 5-6 hours. Stand and separate the liquids, extract the aqueous phase with dichloromethane (5.0L×1), and combine the organic phases. Pump the organic phase into the reactor and cool to 10°C. 2.0N hydrochloric acid solution (20.0L) was added dropwise to adjust the pH of the reaction solution to between 1 and 2. The solution was separated by standing, and the organic phase was washed with saturated brine (20L×1), concentrated, and the residue was dissolved with acetone (20.0L), then pumped into a 100L reactor and stirred, and a solution of concentrated sulfuric acid (4.0L) and water (20.0L) was added dropwise, and refluxed for 2 hours after addition. The temperature was lowered to 15°C, saturated brine (20.0L) was added to the reaction solution, and extracted with n-hexane (15.0L×2). The organic phases were combined, washed with saturated brine (20.0L×1), and the organic phase was dried over anhydrous sodium sulfate overnight. After filtration, the filtrate was concentrated under reduced pressure to obtain a yellow solid crude product 1D (3.00kg, yield 81%) with a purity of 50%. 

[0434]1D Further purification steps: 

[0435]Method 1: Anhydrous sodium bisulfite (5.735 kg, 55.147 mol) was dissolved in 66 L of purified water and added to a 100 L reactor. A solution of crude 1D (3.00 kg, 22.059 mol) in ethanol (3.0 L) was added under stirring at room temperature. The mixture was stirred overnight at room temperature and extracted with ethyl acetate (20 L × 2). The aqueous phase was added to the reactor, stirred and cooled to 10°C. A solution of sodium hydroxide (2.250 kg, 56.250 mol) in water (10 L) was added dropwise. The pH was adjusted to 10-12. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with n-hexane (20 L × 2). The organic phases were combined and washed with purified water (20 L × 1). The organic phases were dried with anhydrous sodium sulfate (2 kg) for 1 hour, filtered, and the filtrate was evaporated to dryness to obtain 1D as a colorless crystalline solid (2.7 kg, yield 90%) with a purity of 98.3%. 

[0436]Method 2: Sodium bisulfite (1529g, 14.706mol) was dissolved in 22L water, and a solution of 1D crude product (1000g, 7.353mol) in anhydrous ethanol (1000mL) was added dropwise under stirring, and stirred overnight at room temperature (24 hours). The reaction solution was extracted with dichloromethane (5L×2) to remove impurities, and sulfuric acid solution (prepared with 6.4L concentrated sulfuric acid and 6kg crushed ice) was added dropwise to the aqueous phase, and stirred at room temperature for 5 hours. The reaction solution was extracted with n-hexane (extracted 3-4 times, 4L each time), the organic phases were combined and washed with saturated sodium chloride aqueous solution (5L×2), the organic phases were dried with 1kg anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was evaporated to dryness to obtain 1D, a white solid (900g, yield: 90%), and the purity was determined to be 98.1%. 

[0437]

¹H NMR(400MHz,CDCl ₃)δ3.39(m,1H),3.19(m,1H),2.77(m,1H),2.38(m,1H),2.05(m,1H),1.93(d,1H),1.77(m,1H),1.45(m,4H),1.20(m,1H)。

[0438]

LCMS m/z＝137.1[M+1]。

[0439]Step 4: tert-Butyl 2-(tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-ylidene) acetate (1R,3S,6R,8R and 1S,3R,6S,8S racemate) (1E) 

[0440]

tert-butyl 2-tricyclo[4.2.1.0 ^3,8]nonan-2-ylidene)acetate(1R,3S,6R,8R and 1S,3R,6S,8S racemate)

[0441]

[0442]Potassium tert-butoxide (742.0g, 6.62mol) and tetrahydrofuran (6.20L) were added to a 20L reactor. The temperature was lowered to 5°C, and tert-butyl dimethoxyphosphonoacetate (1480g, 6.62mol, 1.1eq) was added dropwise to the reaction solution. The reaction temperature was controlled at 10°C-15°C, and stirring was continued for 1 hour. Then, a solution of 1D (820.0g, 6.02mol, 1.0eq) in tetrahydrofuran (2.0L) was added dropwise to the reaction solution. The addition was completed within 1 hour, and the temperature was naturally raised to room temperature for reaction for 2 hours. Saturated ammonium chloride solution (2.0L) and purified water (2.0L) were added to the reactor in sequence. After stirring for 20 minutes, the mixture was allowed to stand for stratification, and the aqueous phase was extracted with methyl tert-butyl ether (1.5L×2). The organic phases were combined, washed with saturated brine (2L×2), and dried over anhydrous sodium sulfate. Filtration and concentration afforded 1E as a yellow liquid (1.50 kg). 

[0443]

LCMS m/z＝235.3[M+1]。

[0444]Step 5: tert-Butyl 2-(2-(nitromethyl)tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-yl)acetate (1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate) (1F) 

[0445]

tert-butyl 2-(2-(nitromethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(1R,2R,3S,6R,8R and 1S,2S,3R,6S,8S racemate)

[0446]

[0447]1E (1.40 kg, 5.97 mol, 1.0 eq), nitromethane (1.82 kg, 29.85 mol, 5.0 eq) and dimethyl sulfoxide (9.8 L) were added to a 20 L reactor in sequence. Stir and add cesium carbonate (2.34 kg, 7.16 mol, 1.2 eq) to the reaction solution. After the addition, heat to 80°C-85°C, continue to keep the reaction for 5 hours, then cool to room temperature, add purified water (20.0 L) to the reactor, and extract the aqueous phase with methyl tert-butyl ether (8.0 L × 3). Combine the organic phases, wash with saturated brine (8.0 L × 2), and dry over anhydrous sodium sulfate. Filter and concentrate to obtain a brown liquid 1F (1.62 kg, yield: 92%). 

[0448]

LCMS m/z＝318.1[M+23]。

[0449]Step 6: tert-Butyl 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-yl)acetate (S)-2-acetoxy-2-phenylacetic acid (1H) 

[0450]

tert-butyl2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.03,8]nonan-2-yl)acetate(S)-2-acetoxy-2-phenylacetate

[0451]

[0452]Add 1F (730.0 g, 2.47 mol) and methanol (7.3 L) to a 50 L reactor. Stir, add nickel chloride hexahydrate (118 g, 0.49 mol, 0.2 eq) to the reaction, cool the reaction solution to 5 ° C, add sodium borohydride (374 g, 9.88 mol, 4.0 eq) in batches, keep the reaction system temperature at 20 ° C-30 ° C, and add it in about 3 hours. After the addition, continue to stir and react for 2 hours. Add ice water (16.4 L) to the reactor, and filter the aqueous phase with diatomaceous earth. Extract the filtrate with dichloromethane (3.0 L × 2) and combine the organic phases, wash with saturated brine (4 L × 1), and dry over anhydrous sodium sulfate. Filter, add (S)-(+)-O-acetyl-L-mandelic acid (384 g, 1.97 mol, 0.8 eq) to the filtrate, and stir for 20 minutes after the addition. The organic phase was concentrated by distillation until no solvent was evaporated, and then stirred with isopropanol (5.9 L) for 2 hours, cooled to 5°C and stirred for 1 hour. Filtered, the filter cake was washed with isopropanol (0.4 L × 1), and dried to obtain a white solid product 1H crude product (422 g, yield: 34.96%). The solid was taken and the ee value was determined to be 48.35% after derivatization. 

[0453]First crystallization: Add crude product 1H (420.0 g, 0.92 mol), isopropanol (4.20 L) and water (0.21 L) to the reactor in sequence. Raise the temperature to 82 °C to completely dissolve the solid and keep warm for 0.5 hours. Cool down to 20 °C for crystallization for about 6 hours. When the internal temperature reaches 20 °C, filter and wash the filter cake with isopropanol (0.40 L × 1). Combine the solids and dry them at 60-65 °C for 4 hours to constant weight. Obtain the first crystal of 1H (260 g, yield: 62%). After taking the solid for derivatization, the ee value is 81.25%. 

[0454]Second crystallization: Add the first crystal of 1H (177g, 0.39mol), isopropanol (2.53L) and water (0.126L) to the reactor in sequence. Raise the temperature to 82℃ to completely dissolve the solid and keep warm for 0.5 hours. Cool down to 20℃ for crystallization for about 4.5 hours. When the internal temperature reaches 30℃, filter and wash the filter cake with isopropanol (0.10L×1). Combine the solids and dry them at 60-65℃ for 4 hours to constant weight. Obtain pure white solid 1H (128g, yield: 72%). After taking the solid derivative, the ee value is determined to be 99.73%. 

[0455]

LCMS m/z＝266.3[M+1]。

[0456]Step 7: 2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 

^3,8 ]nonanyl-2-yl)acetic acid benzenesulfonic acid compound (1:1) (Compound 1) 

[0457]

2-((1S,2S,3R,6S,8S)-2-(aminomethyl)tricyclo[4.2.1.0 ^3,8]nonan-2-yl)acetic acid compound with benzenesulfonic acid(1:1)

[0458]

[0459]Add 1H pure product (100.0g, 0.218mol) and purified water (0.8L) to the reactor in sequence and cool to 0-10℃. When the internal temperature reaches 0-10℃, add 1mol/L NaOH (218mL) aqueous solution to the reactor and adjust the pH of the reaction solution to 9-10. Let stand for stratification and extract the aqueous phase with dichloromethane (0.30L×2). Combine the organic phases and wash with 1mol/L NaOH (0.10L×1) solution and saturated brine (0.15L×1) in sequence. Add activated carbon (5.0g) to the organic phase for decolorization and dry with anhydrous sodium sulfate. Filter, concentrate the filtrate, and dissolve the residue in the concentration kettle with acetonitrile (280mL). Prepare a solution of benzenesulfonic acid monohydrate (77.0g, 0.437mol) with purified water (280mL) and add it dropwise to the above acetonitrile solution until complete. The temperature was raised to 80-85°C and kept for 4-6 hours. The reaction solution was cooled to 10-20°C for crystallization for about 4-6 hours. When the internal temperature reached 10-20°C, the solution was filtered and the filter cake was washed with water (30 mL × 1) and acetonitrile (50 mL × 1) in turn. After drying, compound 1 was obtained as a white solid (72 g, yield: 90%). 

[0460]

¹H NMR(400MHz,MeOD)δ7.83(m,2H),7.42(m,3H),3.31(dt,4H),2.86(m,1H),2.55(d,2H),2.48(ddd,1H),2.32(dd,1H),2.15(m,1H),2.04(m,1H),1.77(m,1H),1.62(m,4H),1.45(m,1H),1.28(dt,1H)。

[0461]

LCMS m/z＝210.1[M+1]。

References

^ “Monthly Report: New Drug Approval in China, May 2024”.

1. ^ “海思科苯磺酸克利加巴林胶囊获批新适应症”. PhIRDA. 19 July 2024. Retrieved 26 April 2025.
2. ^ Gou, Xiaoli; Yu, Xiaojuan; Bai, Dongdong; Tan, Bowei; Cao, Pingfeng; Qian, Meilin; Zheng, Xiaoxiao; Chen, Lei; Shi, Zongjun; Li, Yao; Ye, Fei; Liang, Yong; Ni, Jia (March 2021). “Pharmacology and Mechanism of Action of HSK16149, a Selective Ligand of α2δ Subunit of Voltage-Gated Calcium Channel with Analgesic Activity in Animal Models of Chronic Pain”. The Journal of Pharmacology and Experimental Therapeutics. 376 (3): 330–337. doi:10.1124/jpet.120.000315. ISSN 1521-0103. PMID 33293377.
3. ^ Guo, Xiaohui; Zhang, Tingting; Yuan, Geheng; Yukun, LI; Hua Ma, Jian; Hong-Mei, LI (2023). “224-OR: The Efficacy and Safety of HSK 16149 in Chinese with Diabetic Peripheral Neuropathic Pain—A Randomized, Double-Blinded, Placebo and Pregabalin-Controlled Phase II/III Study”. Diabetes. 72. doi:10.2337/db23-224-OR.
4. ^ Wu, Qingqing; Zhu, Huijuan; Song, Rong; Zhang, Mengqi; Li, Fangqiong; Zeng, Weifang; Wang, Wei; Jia, Jingying; Yu, Chen; Liu, Yanmei (June 2023). “Effect of a high-fat and high-calorie food on the pharmacokinetics of a novel, potent GABA analog HSK16149 in healthy subjects”. Pharmacology Research & Perspectives. 11 (3): e01102. doi:10.1002/prp2.1102. PMC 10199234. PMID 37208866.

//////////Crisugabalin, HSK 16149, HSK-16149, HSK16149, Q3MK7E8686, PHASE 2