Meglimin hydrochloride

Imeglimin
hydrochloride

Twymeeg

Formula	C6H13N5. HCl
CAS	775351-61-6 (HCl). , C6H14ClN5 191.66CAS 775351-65-0, FREEFORM 155.20
Mol weight	191.6619

AntidiabeticAPPROVED PMDA JAPAN2021/6/23, イメグリミン塩酸塩

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

DB12509

NCGC00378621-02

HY-14771

Q6003719

UNII-UU226QGU97

UU226QGU97

1,3,5-Triazine-2,4-diamine,1,6-dihydro-N,N,6-trimethyl-,(+)-(9CI)

(4R)-6-N,6-N,4-trimethyl-1,4-dihydro-1,3,5-triazine-2,6-diamine

Imeglimin [INN]

Emd 387008 (R-imeglimin) HCl

EMD-387008

JAPAN

Twymeeg Tablets 500 mg
(Sumitomo Dainippon Pharma Co., Ltd.)

Imeglimin is an experimental drug being developed as an oral anti-diabetic.^[1][2] It is an oxidative phosphoryl

Imeglimin (brand name Twymeeg) is an oral anti-diabetic medication.^[1][2] It was approved for use in Japan in June 2021.^[3]

It is an oxidative phosphorylation blocker that acts to inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion. It is the first approved drug of this class of anti-diabetic medication.

PATENT

https://patents.google.com/patent/WO2012072663A1/enEXAMPLESExample 1 : Synthesis and isolation of (+)-2-amino-3,6-dihydro-4-dimethylamino-6- methyl-l,3,5-triazine hydrochloride by the process according to the invention

Preliminary step: Synthesis of racemic 2-amino-3,6-dihydro-4-dimethylamino- 6-methyl-l,3,5-triazine hydrochloride:

Metformin hydrochloride is suspended in 4 volumes of isobutanol. Acetaldehyde diethylacetal (1.2 eq.) and para-toluenesulfonic acid (PTSA) (0.05 eq) are added and the resulting suspension is heated to reflux until a clear solution is obtained. Then 2 volumes of the solvent are removed via distillation and the resulting suspension is cooled to 20°C. The formed crystals are isolated on a filter dryer and washed with isobutanol (0.55 volumes). Drying is not necessary and the wet product can be directly used for the next step.Acetaldehyde diethylacetal can be replaced with 2,4,6-trimethyl-l,3,5-trioxane (paraldehyde).- Steps 1 and 2: formation of the diastereoisomeric salt and isolation of the desired diastereoisomer

Racemic 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine hydrochloride wet with isobutanol (obtained as crude product from preliminary step without drying) and L-(+)-Tartaric acid (1 eq.) are dissolved in 2.2 volumes of methanol at 20-40°C. The obtained clear solution is filtered and then 1 equivalent of triethylamine (TEA) is added while keeping the temperature below 30°C. The suspension is heated to reflux, stirred at that temperature for 10 minutes and then cooled down to 55°C. The temperature is maintained at 55°C for 2 hours and the suspension is then cooled to 5- 10°C. After additional stirring for 2 hours at 5-10°C the white crystals are isolated on a filter dryer, washed with methanol (2 x 0.5 Vol) and dried under vacuum at 50°C. The yield after drying is typically in the range of 40-45%

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

γ ethanol HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt is suspended in 2 volumes of ethanol and 1.02 equivalents of HCl-gas are added under vacuum (-500 mbar). The suspension is heated to reflux under atmospheric pressure (N₂) and 5% of the solvent is removed via distillation. Subsequent filtration of the clear colourless solution into a second reactor is followed by a cooling crystallization, the temperature is lowered to 2°C. The obtained suspension is stirred at 2°C for 3 hours and afterwards the white crystals are isolated with a horizontal centrifuge. The crystal cake is washed with ethanol and dried under vacuum at 40°C. The typical yield is 50-55% and the mother liquors can be used for the recovery of about 25-30%) of (+)-2-amino- 3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate.Example 2: Modification of the solvent of steps 3 and 4

– Steps 3 and 4: transformation of the isolated diastereoisomer of the tartrate salt into the hydrochloride salt and recovery of the salt

HN^NH _acetone HN^NH(+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt synthesized according to steps 1 and 2 of example 1 is suspended in 1 volume (based on total amount of (+) 2-amino-3,6-dihydro-4-dimethylamino-6-methyl-l,3,5-triazine tartrate salt) of acetone at 20°C. To this suspension 1.01 equivalents of 37% Hydrochloric acid are added. The suspension is heated to reflux under atmospheric pressure (N₂) and water is added until a clear solution is obtained. 1.5 vol of acetone are added at reflux temperature. The compound starts crystallising and the obtained suspension is kept at reflux for 2 hours followed by a cooling crystallization to 0°C. The obtained suspension is stirred at 0°C for 2 hours and the white crystals are isolated by centrifugation. The crystal cake is washed with isopropanol and dried under vacuum at 40°C in a continuous drying oven.

References

1. ^ Vuylsteke V, Chastain LM, Maggu GA, Brown C (September 2015). “Imeglimin: A Potential New Multi-Target Drug for Type 2 Diabetes”. Drugs in R&D. 15 (3): 227–32. doi:10.1007/s40268-015-0099-3. PMC 4561051. PMID 26254210.
2. ^ Dubourg J, Fouqueray P, Thang C, Grouin JM, Ueki K (April 2021). “Efficacy and Safety of Imeglimin Monotherapy Versus Placebo in Japanese Patients With Type 2 Diabetes (TIMES 1): A Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Phase 3 Trial”. Diabetes Care. 44 (4): 952–959. doi:10.2337/dc20-0763. PMID 33574125.
3. ^ Poxel SA (June 23, 2021). “Poxel and Sumitomo Dainippon Pharma Announce the Approval of TWYMEEG® (Imeglimin hydrochloride) for the Treatment of Type 2 Diabetes in Japan” (Press release).

Clinical data
Trade names	Twymeeg
Legal status
Legal status	Rx-only in Japan
Identifiers
showIUPAC name
CAS Number	775351-65-0
PubChem CID	24812808
ChemSpider	26232690
UNII	UU226QGU97
CompTox Dashboard (EPA)	DTXSID50228237
Chemical and physical data
Formula	C6H13N5
Molar mass	155.205 g·mol−1
3D model (JSmol)	Interactive image
showSMILES
showInChI

/////////Imeglimin hydrochloride, Twymeeg, JAPAN 2021, APPROVALS 2021, Antidiabetic, イメグリミン塩酸塩, ATI DIABETES, DIABETES, Imeglimin

CC1N=C(NC(=N1)N(C)C)N.Cl