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RESMETIROM

January 14, 2020 10:20 am / 1 Comment on RESMETIROM

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2D chemical structure of 920509-32-6

RESMETIROM

C₁₇H₁₂Cl₂N₆O₄

435.2 g/mol

MGL-3196

CAS 920509-32-6, Resmetirom, VIA-3196, UNII-RE0V0T1ES0

FDA APPROVED 3/14/2024, To treat noncirrhotic non-alcoholic steatohepatitis with moderate to advanced liver scarring
Press Release

Rezdiffra

Phase III, Non-alcoholic fatty liver disease (NAFLD)

2-[3,5-dichloro-4-[(6-oxo-5-propan-2-yl-1H-pyridazin-3-yl)oxy]phenyl]-3,5-dioxo-1,2,4-triazine-6-carbonitrile

2-(3,5-DICHLORO-4-((5-ISOPROPYL-6-OXO-1,6-DIHYDROPYRIDAZIN-3-YL)OXY)PHENYL)-3,5-DIOXO-2,3,4,5-TETRAHYDRO-(1,2,4)TRIAZINE-6-CARBONITRILE

1,2,4-TRIAZINE-6-CARBONITRILE, 2-(3,5-DICHLORO-4-((1,6-DIHYDRO-5-(1-METHYLETHYL)-6-OXO-3-PYRIDAZINYL)OXY)PHENYL)-2,3,4,5-TETRAHYDRO-3,5-DIOXO-

Madrigal Pharmaceuticals , following the merger between Synta and Madrigal Pharmaceuticals (pre-merger) (following the acquisition of VIA Pharmaceuticals ‘ assets (originally under license from Roche )), is developing resmetirom (MGL-3196, VIA-3196), the lead from oral capsule formulation thyroid hormone receptor (THR) beta agonists, cholesterol and triglyceride modulators, for the use in the treatment of metabolic disorders including hypercholesterolemia and other dyslipidemias, and non-alcoholic steatohepatitis.

MGL-3196 is a first-in-class, orally administered, small-molecule, liver-directed, THR β-selective agonist. Preclinical, toxicology and Phase 1 clinical data suggest MGL-3196 has an attractive, differentiated profile as a potential treatment for non-alcoholic steatohepatitis (NASH) and dyslipidemias. THR-β selectivity also enhances the safety profile of MGL-3196, compared to non-selective agents. MGL-3196 has shown no suppression of the central thyroid axis, no THR-α effects on heart rate or bone, and no elevation of liver enzymes. These characteristics make MGL-3196 among the most promising molecules in development in this therapeutic area. MGL-3196 is in a Phase 2 clinical trial for the treatment of non-alcoholic steatohepatitis (NASH).

PATENT

WO-2020010068

Novel crystalline salt of resmetirom as thyroid hormone receptor agonists useful for treating obesity, hyperlipidemia, hypercholesterolemia and diabetes. Appears to be the first filing from the assignee and the inventors on this compound,

Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen, Physiological reviews, Vol. 81(3): pp. 1097-1126 (2001)). Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior.

[0005] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs or THRs) (M. A. Lazar, Endocrine Reviews, Vol. 14: pp. 348-399 (1993)). TRs belong to the superfamily known as nuclear receptors. TRs form heterodimers with the retinoid receptor that act as ligand-inducible transcription factors. TRs have a ligand binding domain, a DNA binding domain, and an amino terminal domain, and regulate gene expression through interactions with DNA response elements and with various nuclear co-activators and co repressors. The thyroid hormone receptors are derived from two separate genes, a and b. These distinct gene products produce multiple forms of their respective receptors through differential RNA processing. The major thyroid receptor isoforms are aΐ, a2, bΐ, and b2. Thyroid hormone receptors aΐ, bΐ, and b2 bind thyroid hormone. It has been shown that the thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. Recent studies suggest that TIIb 1 plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver. T11b2 plays an important role in the regulation of TSH (thyroid stimulating hormone) (Abel et. al, J. Clin. Invest., Vol 104: pp. 291-300 (1999)). TIIb 1 plays an important role in regulating heart rate (B. Gloss et. al. Endocrinology, Vol. 142: pp. 544-550 (2001); C. Johansson et. al, Am. J. Physiol., Vol. 275: pp. R640-R646 (1998)).

[0006] Efforts have been made to synthesize thyroid hormone analogs which exhibit increased thyroid hormone receptor beta selectivity and/or tissue selective action. Such thyroid hormone mimetics may yield desirable reductions in body weight, lipids, cholesterol, and lipoproteins, with reduced impact on cardiovascular function or normal function of the hypothalamus/pituitary/thyroid axis (see, e.g., Joharapurkar et al, J. Med. Chem, 2012, 55 (12), pp 5649-5675). The development of thyroid hormone analogs which avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones would open new avenues of treatment for patients with metabolic disease such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other disorders and diseases such as liver steatosis and NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, a resistance to thyroid hormone (RTH) syndrome, and related disorders and diseases.

PATENT

WO2018075650

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=38F602DAA4A51CA8DF413F1EDBC87DA4.wapp2nB?docId=WO2018075650&recNum=322&office=&queryString=&prevFilter=%26fq%3DICF_M%3A%22A61K%22&sortOption=Pub+Date+Desc&maxRec=1894357

In one embodiment, the metabolite of Compound A comprises a compound

having the following structure:
(“Ml”).

PATENT

WO 2007009913

PATENT

WO 2014043706

https://patents.google.com/patent/WO2014043706A1/en

Example 3: Preparation of (Z)-ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6- oxo- l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl)carbamate (Int. 8)

A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N₂ inlet/outlet was charged with Int. 7 (75.0 g, 0.239 mol, 1 wt), acetic acid (600 mL, 8 vol), water (150 mL, 2 vol), and concentrated HC1 (71.3 mL, 0.95 vol). The resulting thin slurry was cooled to 6 °C and a solution of NaN0₂ (16.8 g, 0.243 mol, 1.02 equiv) in water (37.5 mL, 0.5 vol) was added over a period of 10 min while maintaining a batch temperature below 10 °C. After an additional 10 min of agitation between 5-10 °C, HPLC analysis showed complete conversion of Int. 7 to the diazonium intermediate. A solution of NaOAc (54.5 g, 0.664 mol, 2.78 equiv) in water (225 mL, 3 vol) was added over a period of 6 min while maintaining a batch temperature below 10 °C. N-cyanoacetylurethane (37.9 g, 0.243 mol, 1.02 equiv) was immediately added, the cooling was removed, and the batch naturally warmed to 8 °C over 35 min. HPLC analysis showed complete consumption of the diazonium intermediate and the reaction was deemed complete. The batch warmed naturally to 21 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (375 mL, 5 vol) twice. The collected orange solid was dried in a 35 °C vacuum oven for 64 h to provide crude Int. 8 (104.8 g, 91%).

A I L, three-neck, round-bottom flask equipped with overhead stirring, a

thermocouple, and N₂ inlet/outlet was charged with crude Int. 8 (104.4 g, 1 wt) and acetic acid (522 mL, 5 vol). The resulting slurry was heated to 50 °C and held at that temperature for 1.5 h. The batch cooled naturally to 25 °C over 2 h and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with water (522 mL, 5 vol) and the cake conditioned under vacuum for 1.75 h. The light orange solid was dried to constant weight in a 40 °C vacuum oven to provide 89.9 g (78% from Int. 7) of the desired product. ¹H NMR (DMSO) was consistent with the assigned structure.

Example 4: Preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)

A 2 L, three-neck, round-bottom flask equipped with overhead stirring, a

thermocouple, N₂ inlet/outlet, and reflux condenser was charged with Int. 8 (89.3 g, 0.185 mol, 1 wt), DMAC (446 mL, 5 vol), and KOAc (20.0 g, 0.204 mol, 1.1 equiv). The mixture was heated to 120 °C and held at that temperature for 2 h. HPLC analysis showed complete conversion to Compound A. The batch temperature was adjusted to 18 °C over 1 h, and acetic acid (22.3 mL, 0.25 vol) was added. The batch temperature was adjusted to 8 °C, and water (714 mL, 8 vol) was added over 1 h; an orange slurry formed. The batch was filtered through Sharkskin filter paper and the cake was allowed to condition overnight under N₂ without vacuum for convenience. A premixed solution of 1 : 1 acetone/water (445 mL, 5 vol) was charged to the flask and added to the cake as a rinse with vacuum applied. After 2 h of conditioning the cake under vacuum, it was transferred to a clean 1 L, three-neck, round- bottom flask equipped with overhead stirring, a thermocouple, and N₂inlet/outlet. Ethanol (357 mL, 4 vol) and acetone (357 mL, 4 vol) were charged and the resulting slurry was heated to 60 °C; dissolution occurred. Water (890 mL, 10 vol) was added over a period of 90 min while maintaining a batch temperature between 55-60 °C. The resulting slurry was allowed to cool to 25 °C and filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with a solution of 1:1 EtOH/water (446 mL, 5 vol). The cake was conditioned overnight under N₂ without vacuum for convenience. The cracks in the cake were smoothed and vacuum applied. The cake was washed with water (179 mL, 2 vol) and dried in a 45 °C vacuum oven to a constant weight of 70.5 g (87%, crude Compound A). HPLC analysis showed a purity of 94.8%.

A 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N₂ inlet/outlet, and reflux condenser was charged with crude Compound A (70.0 g) and MIBK (350 mL, 5 vol). The orange slurry was heated to 50 °C and held at that temperature for 2 h. The batch cooled naturally to 23 °C and was filtered through Sharkskin filter paper. The reactor and cake were washed sequentially with MIBK (35 mL, 0.5 vol) twice. The collected solids were dried in a 45 °C vacuum oven to a constant weight of 58.5 g (84%). This solid was charged to a 500 mL, three-neck, round-bottom flask equipped with overhead stirring, a thermocouple, N₂ inlet/outlet, and reflux condenser. Ethanol (290 mL, 5 vol) was added and the slurry was heated to reflux. After 3.5 h at reflux, XRPD showed the solid was consistent with Form I, and heating was removed. Upon reaching 25 °C, the batch was filtered through filter paper, and the reactor and cake were washed sequentially with EtOH (174 mL, 3 vol). The tan solid Compound A was dried in a 40 °C vacuum oven to a constant weight of 50.4 g (87%, 64% from Int. 8). HPLC analysis showed a purity of 99.1%. ¹H NMR (DMSO) was consistent with the assigned structure.

Example 5: Scaled up preparation of 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile (Compound A)

A larger scale batch of Compound A was synthesized according to the scheme below. The conditions in the scheme below are similar to those described in Examples 1-4 above.

Compound A

Synthesis of 4: A 50 L jacketed glass vessel (purged with N₂) was charged with 3,6- dichloropyridazine (2.00 kg), 4-amino-2,6-dichlorophenol (2.44 kg) and N,N- dimethylacetamide (10.0 L). The batch was vacuum (26 inHg) / nitrogen (1 PSIG) purged 3 times. Cesium carbonate (5.03 kg) was added and the batch temperature was adjusted from 22.3 °C to 65.0 °C over 3.5 hours. The batch was held at 65.0 °C for 20 hours. At this point,

NMR analysis indicated 3.34% 3.6-dichloropyridazine relative to 2. The batch temperature was adjusted to 21.5 °C and ethyl acetate (4.00 L) was added to the batch. The batch was agitated for 10 minutes and then filtered through a 18″ Nutsche filter equipped with polypropylene filter cloth. The filtration took 15 minutes. Ethyl acetate (5.34 L) was charged to the vessel and transferred to the filter as a rinse. The batch was then manually re- suspended in the filter before re-applying vacuum. This process was repeated 2 more times and the filter cake was conditioned for 10 minutes. The filtrate was charged to a 100-L vessel that contained (16.0 L) of a previously prepared 15% sodium chloride in H₂0. The batch was agitated for 5 minutes and then allowed to separate for 35 minutes. The interface was not visible, so the calculated 23 L of the lower aqueous phase was removed. 16.0 L of 15% Sodium chloride in H₂0 was added to the batch. The batch was agitated for 6 minutes and then allowed to separate for 7 minutes. The interface was visible at -19 L and the lower aqueous phase was removed. 17.0 L of 15% Sodium chloride in H₂0 was added to the batch. The batch was agitated for 7 minutes and then allowed to separate for 11 minutes. The lower aqueous phase was removed. The vessel was set up for vacuum distillation and the batch was concentrated from 17.0 L to 8.0 L over 2 hours 20 minutes with the batch temperature kept around 21 °C. Benzoic anhydride (3.19 kg) and acetic acid (18.0 L) were charged to the vessel. The vessel was set up for vacuum distillation and the batch was concentrated from 28.0 L to 12.0 L over 2 days (overnight hold at 20 °C) with the batch temperature kept between 20 and 55 °C. At this point, ^JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.015. Acetic acid (4.0 L) was charged to the batch and the batch was distilled to 12 L. ^JH NMR analysis indicated a mol ratio of acetic acid to ethyl acetate of 1.0:0.0036. Acetic acid (20.0 L) was charged to the batch and the batch temperature was adjusted to 70.0 °C. The batch was sampled for HPLC analysis and 2 was 0.16%. Sodium acetate (2,20 kg) was added to the batch and the batch temperature was adjusted from 72.4 °C to 110.0 °C. After 18.5 hours, HPLC analysis indicated no Int. B detected. The batch temperature was adjusted from 111.3 to 74.7 °C and DI water (30.0 L) was added to the batch over 2 hours. The batch temperature was adjusted to 20 .5 °C and then filtered using a 24″ Haselloy Nutsche filter equipped with polypropylene filter cloth. A previously prepared solution of 1:1 acetic acid in DI H₂0 (10.0 L) was charged to the vessel and agitated for 5 minutes. The wash was transferred to the filter and the batch was then manually re- suspended in the filter before re-applying vacuum. DI H₂0 (10.0 L) was charged to the vessel and then transferred to the filter. The batch was manually re-suspended in the filter before re-applying vacuum. DI H₂0 (10.0 L) was charged directly to the filter and the batch was then manually re-suspended in the filter before re-applying vacuum. The filter cake was allowed to condition for 18 hours to give 14.4 kg of 4. HPLC analysis indicated a purity of 93.7%. This wet cake was carried forward into the purification. A 100 L jacketed glass vessel (purged with N₂) was charged with crude 4 (wet cake 14.42 kg), acetic acid (48.8 L) and the agitator was started. DI H₂0 (1.74 L) was charged. The batch (a slurry) temperature was adjusted from 18.1 to 100.1 °C over 4.25 hours. The batch was held at 100.1 to 106.1 °C for 1 hour and then adjusted to 73.1 °C. DI H₂0 (28.0 L) was added to the batch over 1 hour keeping the batch temperature between 73.1 and 70.3 °C. The batch temperature was adjusted further from 70.3 °C to 25.0 °C overnight. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with polypropylene filter cloth. The filtration took 13 minutes. A solution of DI H₂0 (9.00 L) and acetic acid (11.0 L) was prepared and added to the 100 L vessel. The mixture was agitated for 5 minutes and then transferred to the filter cake. DI H₂0 (20.0 L) was charged to the vessel, agitated for 6 minutes and then transferred to the filter cake. DI H₂0 (20.0 L) was charged to the vessel, agitated for 9 minutes and then transferred to the filter cake. The batch was allowed to condition for 3 days and then transferred to drying trays for vacuum oven drying. After 3 days at 50 °C and 28’7Hg, the batch gave a 74% yield (3.7 kg) of4 as an off-white solid. The ^JH NMR spectrum was consistent with the assigned structure, HPLC analysis indicated a purity of 98.87% and KF analysis indicated 0.14% H₂0. Synthesis of Int. 7: A 100-L jacketed glass vessel (purged with N2) was charged with tetrahydrofuran (44.4 L). The agitator was started (125 RPM) and 4 (3.67 kg) was charged followed by lithium chloride (1.26 kg). The batch temperature was observed to be 26.7 ° C and was an amber solution. Isopropenylmagnesium bromide 1.64 molar solution in 2-methyl THF (21.29 kg) was added over 2 ½ hours keeping the batch between 24.3 and 33.6 °C. The batch was agitated at 24.5 °C for 17 hours at which point HPLC analysis indicated 9% 4. A 2nd 100-L jacketed glass vessel (purged with N2) was charged with 3N hydrogen chloride (18.3 L). The batch was transferred to the vessel containing the 3N HC1 over 25 minutes keeping the batch temperature between 20 and 46 °C. A bi-phasic solution was observed. The quenched batch was transferred back to the 1^st 100-L vessel to quench the small amount of residue left behind. THF (2.00 L) was used as a rinse. The batch temperature was observed to be 40.9 ° C and was agitated at 318 RPM for 45 minutes. The batch temperature was adjusted to 21.8 ° C and the layers were allowed to separate. The separation took 10 minutes. The lower aqueous phase was removed (-26.0 L). A solution of sodium chloride (1.56 kg) in DI water (14.0 L) was prepared and added to the batch. This was agitated at 318 RPM for 10 minutes and agitator was stopped. The separation took 3 minutes. The lower aqueous phase was removed (-16.0 L). The batch was vacuum distilled from 58.0 L to 18.4 L using ~24’7Hg and a jacket temperature of 50 to 55 °C. A solution of potassium hydroxide (2.30 kg) in DI water (20.7 L) was prepared in a 72-L round bottom flask. The vessel was set up for atmospheric distillation using 2 distillation heads and the batch was transferred to the 72-L vessel. THF (0.75 L) was used as a rinse. The batch volume was -41.0 L, the temperature was adjusted to 64.1 °C and distillation started with the aid of a N2 sweep. Heating was continued to drive the batch temperature to 85.4 °C while distilling at which point the 72-L vessel was set up for reflux (batch volume was about 28.0 L at the end of the distillation). The batch was held at 85 °C for 13 hours at which point HPLC analysis indicated 0.3% compound 6A. Heating was stopped and the batch was transferred to a 100-L jacketed glass vessel. Solids were observed. The batch temperature was adjusted from 70.6 °C to 56.7 °C. A previously prepared solution of sodium hydrogen carbonate (2.82 kg) in DI water (35.0 L) was added over 80 minutes keeping the batch temperature between 56.7 and 46.7 °C. The batch pH at the end of the addition was 9.8. The batch was held at

46.7 to 49.0 °C for 40 minutes and then cooled to 25.0 °C. The batch was filtered using a 18″ stainless steel Nutsche filter. DI water (18.4 L) was charged to the vessel and transferred to the filter. The filter cake was manually re-suspended in the filter and then the liquors were removed. This process was repeated once more and the filter cake was 3″ thick. The filter cake was conditioned on the filter for 3 days, was transferred to drying trays and dried in a vacuum oven at 45 °C to provide 2.93 kg Int. 7 (95% yield) with an HPLC purity of 87.6%.

Synthesis of Int. 8: A 100 L jacketed glass vessel (purged with N₂ and plumbed to a caustic scrubber) was charged with acidic acid (13.0 L). Int. 7 (2.85 kg) was charged to the vessel and the agitator was started. N-Cyanoacetylurethane (1.56 kg) and DI water (5.70 L) were charged to the vessel. The batch temperature was adjusted from 17.0 °C to 5.5 °C and a thin slurry was observed. At this point 37% hydrogen chloride (2.70 L) was added over 10 minutes keeping the batch temperature between 4.8 °C and 8.8 °C. A previously prepared solution of sodium nitrite (638 g) in DI water (1.42 L) was added over 26 minutes keeping the batch temperature between 5.8 °C and 8.7 °C. A brown gas was observed in the vessel head space during the addition. HPLC analysis indicated no Int. 7 detected. At this point a previously prepared solution of sodium acetate (2.07 kg) in DI water (8.50 L) was added over 47 minutes keeping the batch temperature between 5.5 °C and 9.5 °C. After the addition, a thin layer of orange residue was observed on the vessel wall just above the level of the batch. The batch temperature was adjusted from 9.4 °C to 24.5 °C and held at 25 °C (+ 5 °C) for 12 hours. The batch was filtered using a 24″ Hastelloy Nutsche filter equipped with tight-weave polypropylene filter cloth. The filtration took 30 minutes. The vessel was rinsed with 14.3 L of a 1 : 1 acidic acid / DI water. The orange residue on the reactor washed away with the rinse. The rinse was transferred to the filter where the batch was manually re-suspended. Vacuum was re-applied to remove the wash. A 2^nd 1 : 1 acidic acid / DI water wash was performed as above and the batch was conditioned on the filter for 26 hours. HPLC analysis of the wet filter cake indicated purity was 90.4%. The batch was dried to a constant weight of 3.97 kg (91% yield) in a vacuum oven at 45 °C and 287Hg. Preparation of Compound A DMAC Solvate

A 100 L, jacketed, glass vessel purged with N₂ was charged with Int. 8 (3.90 kg) and potassium acetate (875 g). N,N-dimethylacetamide (DMAC, 18.3 L) was charged to the vessel and the agitator was started. The batch temperature was adjusted to 115 °C over 2 h. After 2 h at 115 °C, the batch was sampled and HPLC analysis indicated 0.27% Int. 8 remained. The batch temperature was adjusted to 25.0 °C overnight. Acetic acid (975 mL) was added to the batch and the batch was agitated further for 3 h. The batch was transferred to a carboy and the vessel was rinsed clean with 800 mL of DMAC. The batch was transferred back to the 100 L vessel using vacuum through a 10 μιη in-line filter and a DMAC rinse (1.15 L) was used. The filtration was fast at the beginning but slow at the end, plugging up the filter. The batch temperature was adjusted to 11.1 °C and DI water (35.1 L) was added over 2 h 20 min, keeping the batch temperature between 5-15 °C. The batch was held for 1 h and filtered, using an 18″ Nutsche filter equipped with tight-weave

polypropylene cloth. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel, cooled to 10 °C, and transferred to the filter cake. The cake was allowed to condition under N₂ and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg to give 89% yield (3.77 kg) of Compound A DMAC solvate as an orange/tan solid. The ¹H NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated 0.49% H₂0. XRPD indicated the expected form, i.e., Compound A DMAC solvate. Thermogravimetric analysis (TGA) indicated 16% weight loss. HPLC analysis indicated a purity of 93.67%.

Preparation of Crude Compound A

A 100 L, jacketed, glass vessel purged with N₂ was charged with Compound A

DMAC solvate (3.75 kg) and ethanol (15.0 L). The agitator was started and acetone (15.0 L) was added. The batch temperature was adjusted from 10.6 °C to 60.0 °C over 1 h. At this point, the batch was in solution. DI water was added to the batch over 1.5 h, keeping the batch temperature at 60 + 5 °C. The batch was held at 60 + 5 °C for 1 h and cooled to 23.5 °C. An 18″ Nutsche filter equipped with tight-weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 15 h. A 1: 1 ethanol/DI water wash (19.5 L) was charged to the vessel and transferred to the filter cake. The cake was allowed to condition under N₂ and vacuum for 8 h and transferred to drying trays. The batch was dried in a vacuum oven at 45 °C and 28’7Hg for five days to give a 94% yield (2.90 kg) of Compound A as a powdery tan solid. The NMR spectrum is consistent with the assigned structure and Karl Fischer analysis indicated 6.6% H₂0. XRPD indicated the expected form of dihydrate. TGA indicated 6.7% weight loss. HPLC analysis indicated a purity of 96.4% (AUC).

Purification of Crude Compound A

A 50 L, jacketed, glass vessel purged with N₂ was charged with Compound A crude

(2.90 kg) and methyl isobutyl ketone (14.5 L). The agitator was started and the batch temperature was adjusted from 20.2 °C to 50.4 °C over 1.5 h. The batch was held at 50 °C (+ 5 °C) for 1 h and cooled to 20-25 °C. The batch was held at 20-25 °C for 2.5 h. An 18″ Nutsche filter equipped with tight- weave (0.67 CFM) polypropylene cloth was set up and the batch was filtered. The filtration took 20 min. Methyl isobutyl ketone (MIBK, 1.45 L) was charged to the vessel and transferred to the filter cake. The cake was manually resuspended and the liquors were pulled through with vacuum. Methyl isobutyl ketone (2.90 L) was charged to the filter cake and the cake was manually resuspended. The liquors were pulled through with vacuum and the cake was conditioned with vacuum and nitrogen for 15 h. The filter cake dried into a tan, hard 18″ x 1 ½” disc. This was manually broken up and run through coffee grinders to give a 76% yield (2.72 kg) of MGL-3196 MIBK solvate as a tan, powdery solid. No oven drying was necessary. The NMR spectrum was consistent with the assigned structure and Karl Fischer analysis indicated <0.1 % H₂0. XRPD indicated the expected form MIBK solvate. TGA indicated 17.3% weight loss. HPLC analysis indicated a purity of 98.5%.

Example 6: Conversion of Compound A to Form I

Purified Compound A (4802 g) as a 1:1 MIBK solvate which was obtained from Int. 8 as described in Example 5 above was added into a jacketed, 100 L reactor along with 24 liters of ethanol. The resulting slurry was heated to 80 + 5 °C (reflux) over 1 h 25 min; the mixture was stirred at that temperature for 4 h 25 min. Analysis of the filtered solids at 2 h 55 min indicated that the form conversion was complete, with the XRPD spectra conforming to Form I. The mixture was cooled to 20 + 5 °C over 45 min and stirred at that temperature for 15 min. The slurry was filtered and the filter cake was washed twice with prefiltered ethanol (2 x 4.8 L). The wet cake (4.28 kg) was dried under vacuum at 40 + 5 °C for 118 h to afford 3390 g of Compound A form I.

PAPER

Journal of Medicinal Chemistry (2014), 57(10), 3912-3923

https://pubs.acs.org/doi/abs/10.1021/jm4019299

The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor β (THR-β) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor α (THR-α). A pyridazinone series has been identified that is significantly more THR-β selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-β over THR-α in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.

Abstract Image

//////////////RESMETIROM , MGL-3196, VIA-3196, UNII-RE0V0T1ES0, Phase III

CC(C)C1=CC(=NNC1=O)OC2=C(C=C(C=C2Cl)N3C(=O)NC(=O)C(=N3)C#N)Cl

Avapritinib, アバプリチニブ , авапритиниб , أفابريتينيب ,

January 13, 2020 9:38 am / Leave a comment

ChemSpider 2D Image | avapritinib | C26H27FN10

Avapritinib

BLU-285, BLU285

Antineoplastic, Tyrosine kinase inhibitor

アバプリチニブ

авапритиниб [Russian] [INN]

أفابريتينيب [Arabic] [INN]

(1S)-1-(4-fluorophenyl)-1-[2-[4-[6-(1-methylpyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]piperazin-1-yl]pyrimidin-5-yl]ethanamine

(1S)-1-(4-Fluorophenyl)-1-(2-{4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl}-5-pyrimidinyl)ethanamine

10613

1703793-34-3 [RN]

513P80B4YJ

5-Pyrimidinemethanamine, α-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-, (αS)-

(S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine

(αS)-(4-fluorophenyl)-α-methyl-2-[4-[6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-1-piperazinyl]-5-pyrimidinemethanamine

Formula	C26H27FN10
CAS	1703793-34-3
Mol weight	498.558

No.	Drug Name	Active Ingredient	Approval Date	FDA-approved use on approval date*
1.	Ayvakit	avapritinib	1/9/2020	To treat adults with unresectable or metastatic gastrointestinal stromal tumor (GIST)

PRIORITY; Orphan, NDA 212608

Avapritinib, sold under the brand name Ayvakit, is a medication used for the treatment of tumors due to one specific rare mutation: It is specifically intended for adults with unresectable or metastatic ( y) gastrointestinal stromal tumor (GIST) that harbor a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation.^[1]

Common side effects are edema (swelling), nausea, fatigue/asthenia (abnormal physical weakness or lack of energy), cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation (secretion of tears), abdominal pain, constipation, rash. and dizziness.^[1]

Ayvakit is a kinase inhibitor.^[1]

History

The U.S. Food and Drug Administration (FDA) approved avapritinib in January 2020.^[1] The application for avapritinib was granted fast track designation, breakthrough therapy designation, and orphan drug designation.^[1] The FDA granted approval of Ayvakit to Blueprint Medicines Corporation.^[1]

Avapritinib was approved based on the results from the Phase I NAVIGATOR^[2]^[3] clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 subjects with PDGFRA D842V mutation.^[1] Subjects received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity.^[1] The recommended dose was determined to be 300 mg once daily.^[1] The trial measured how many subjects experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).^[1] For subjects harboring a PDGFRA exon 18 mutation, the overall response rate was 84%, with 7% having a complete response and 77% having a partial response.^[1] For the subgroup of subjects with PDGFRA D842V mutations, the overall response rate was 89%, with 8% having a complete response and 82% having a partial response.^[1] While the median duration of response was not reached, 61% of the responding subjects with exon 18 mutations had a response lasting six months or longer (31% of subjects with an ongoing response were followed for less than six months).^[1]

PATENT

WO 2015057873

https://patents.google.com/patent/WO2015057873A1/en

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na₂S0₄, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C₂5H₂₂FN₉0 requires: 483, found: 484 [M + H]⁺.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l- methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5- yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C2₉H₃iFN₁₀OS requires: 586, found: 587 [M + H]⁺.

Step 3: Synthesis of (_lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

(_lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (_lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C₃oH₃₅FN₁₀OS requires: 602, found: 603 [M + H]⁺. Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l- f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1- /] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4- yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C₂₆H₂₇FN₁₀requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]⁺.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin- 1 -yl)pyrimidin- -yl)ethanamine:

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH- pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (_lS^,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4- yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C₂₆H₂₇FN₁₀ requires: 498, found: 499 [M + H]⁺.

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “FDA approves the first targeted therapy to treat a rare mutation in patients with gastrointestinal stromal tumors”. U.S. Food and Drug Administration (FDA) (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020. This article incorporates text from this source, which is in the public domain.
^ “Blueprint Medicines Announces FDA Approval of AYVAKIT (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor”. Blueprint Medicines Corporation (Press release). 9 January 2020. Archived from the original on 11 January 2020. Retrieved 9 January 2020.
^ “Blueprint Medicines Announces Updated NAVIGATOR Trial Results in Patients with Advanced Gastrointestinal Stromal Tumors Supporting Development of Avapritinib Across All Lines of Therapy”. Blueprint Medicines Corporation (Press release). 15 November 2018. Archived from the original on 10 January 2020. Retrieved 9 January 2020.

External links

“Avapritinib”. Drug Information Portal. U.S. National Library of Medicine (NLM).

Avapritinib
Clinical data
Trade names	Ayvakit
Other names	BLU-285, BLU285
License data	US FDA: Ayvakit
Routes of administration	By mouth
Drug class	Antineoplastic agents
ATC code	none
Legal status
Legal status	US: ℞-only
Identifiers
CAS Number	1703793-34-3
PubChem CID	118023034
DrugBank	DB15233
ChemSpider	58828673
UNII	513P80B4YJ
KEGG	D11279
Chemical and physical data
Formula	C₂₆H₂₇FN₁₀
Molar mass	498.570 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] CC(C1=CC=C(C=C1)F)(C2=CN=C(N=C2)N3CCN(CC3)C4=NC=NN5C4=CC(=C5)C6=CN(N=C6)C)N
InChI [hide] InChI=1S/C26H27FN10/c1-26(28,20-3-5-22(27)6-4-20)21-13-29-25(30-14-21)36-9-7-35(8-10-36)24-23-11-18(16-37(23)33-17-31-24)19-12-32-34(2)15-19/h3-6,11-17H,7-10,28H2,1-2H3/t26-/m0/s1 Key:DWYRIWUZIJHQKQ-SANMLTNESA-N

///////Avapritinib, 2020 APPROVALS, PRIORITY, Orphan, BLU-285, BLU285, FDA 2020, Ayvakit, アバプリチニブ , авапритиниб , أفابريتينيب ,

TERIPARATIDE, テリパラチド , терипаратид , تيريباراتيد , 特立帕肽 ,

January 8, 2020 9:31 am / Leave a comment

ChemSpider 2D Image | Teriparatide | C181H291N55O51S2

Teriparatide recombinant human.png

Image result for teriparatide

TERIPARATIDE

テリパラチド;

терипаратид [Russian] [INN]

تيريباراتيد [Arabic] [INN]

特立帕肽 [Chinese] [INN]

PTH 1-34
LY 333334 / LY-333334 / LY333334 / ZT-034

Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe-OH
Type	Peptide

Formula	C181H291N55O51S2
CAS	52232-67-4 99294-94-7 (acetate)
Mol weight	4117.7151

(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-oxobutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]hexanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxypropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-amino-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1,4-dioxobutan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-oxopentanoic acid

SVG Image
IUPAC Condensed	H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH
Sequence	SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF
PLN	H-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF-OH
HELM	PEPTIDE1{S.V.S.E.I.Q.L.M.H.N.L.G.K.H.L.N.S.M.E.R.V.E.W.L.R.K.K.L.Q.D.V.H.N.F}$$$$
IUPAC	L-seryl-L-valyl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparagyl-L-leucyl-glycyl-L-lysyl-L-histidyl-L-leucyl-L-asparagyl-L-seryl-L-methionyl-L-alpha-glutamyl-L-arginyl-L-valyl-L-alpha-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-alpha-aspartyl-L-valyl-L-histidyl-L-asparagyl-L-phenylalanine

L-Phenylalanine, L-seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-

Other Names

L-Seryl-L-valyl-L-seryl-L-α-glutamyl-L-isoleucyl-L-glutaminyl-L-leucyl-L-methionyl-L-histidyl-L-asparaginyl-L-leucylglycyl-L-lysyl-L-histidyl-L-leucyl-L-asparaginyl-L-seryl-L-methionyl-L-α-glutamyl-L-arginyl-L-valyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-arginyl-L-lysyl-L-lysyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-valyl-L-histidyl-L-asparaginyl-L-phenylalanine
(1-34)-Human parathormone
(1-34)-Human parathyroid hormone
1-34-Human PTH
1-34-Parathormone (human)

11: PN: WO0039278 SEQID: 17 unclaimed protein
14: PN: WO0181415 SEQID: 16 claimed protein
15: PN: WO0123521 SEQID: 19 claimed protein
1: PN: EP2905289 SEQID: 1 claimed protein
1: PN: WO0198348 SEQID: 13 claimed protein
1: PN: WO2011071480 SEQID: 14 claimed protein
225: PN: US20090175821 SEQID: 272 claimed protein
22: PN: US6110892 SEQID: 22 unclaimed protein
2: PN: US20100261199 SEQID: 4 claimed protein
31: PN: US20070099831 PAGE: 7 claimed protein
32: PN: WO2008068487 SEQID: 32 claimed protein
5: PN: WO2008033473 SEQID: 4 claimed protein
692: PN: WO2004005342 PAGE: 46 claimed protein
69: PN: US20050009742 PAGE: 20 claimed sequence
7: PN: WO0031137 SEQID: 8 unclaimed protein
7: PN: WO0040611 PAGE: 1 claimed protein
93: PN: WO0069900 SEQID: 272 unclaimed protein
Forsteo
Forteo
HPTH-(1-34)
Human PTH(1-34)
Human parathormone(1-34)
Human parathyroid hormone-(1-34)
LY 333334
Osteotide
Parathar
Parathormone (human)
Teriparatide
ZT 034

Product Ingredients

INGREDIENT	UNII	CAS
Teriparatide acetate	9959P4V12N	99294-94-7

Teriparatide is a form of parathyroid hormone consisting of the first (N-terminus) 34 amino acids, which is the bioactive portion of the hormone. It is an effective anabolic (promoting bone formation) agent^[2] used in the treatment of some forms of osteoporosis.^[3] It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone.

Recombinant teriparatide is sold by Eli Lilly and Company under the brand name Forteo/Forsteo. A synthetic teriparatide from Teva Generics has been authorised for marketing in European territories^[4]. Biosimilar product from Gedeon Richter plc has been authorised in Europe^[5]. On October 4, 2019 the US FDA approved a recombinant teriparatide product, PF708, from Pfenex Inc. PF708 is the first FDA approved proposed therapeutic equivalent candidate to Forteo.

Teriparatide (recombinant human parathyroid hormone) is a potent anabolic agent used in the treatment of osteoporosis. It is manufactured and marketed by Eli Lilly and Company.

Teriparatide is a recombinant form of parathyroid hormone. It is an effective anabolic (i.e., bone growing) agent used in the treatment of some forms of osteoporosis. It is also occasionally used off-label to speed fracture healing. Teriparatide is identical to a portion of human parathyroid hormone (PTH) and intermittent use activates osteoblasts more than osteoclasts, which leads to an overall increase in bone. Teriparatide is sold by Eli Lilly and Company under the brand name Forteo.

Indication

For the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. Also used to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Associated Conditions

Pharmacodynamics

Clinical trials indicate that teriparatide increases predominantly trabecular bone in the lumbar spine and femoral neck; it has less significant effects at cortical sites. The combination of teriparatide with antiresorptive agents is not more effective than teriparatide monotherapy. The most common adverse effects associated with teriparatide include injection-site pain, nausea, headaches, leg cramps, and dizziness. After a maximum of two years of teriparatide therapy, the drug should be discontinued and antiresorptive therapy begun to maintain bone mineral density.

Mechanism of action

Teriparatide is the portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34 of the complete molecule which contains amino acid sequence 1 to 84. Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. Daily injections of teriparatide stimulates new bone formation leading to increased bone mineral density.

Medical uses

Teriparatide has been FDA-approved since 2002.^[6] It is effective in growing bone (e.g., 8% increase in bone density in the spine after one year)^[7] and reducing the risk of fragility fractures.^[6]^[8] When studied, teriparatide only showed bone mineral density (BMD) improvement during the first 18 months of use. Teriparatide should only be used for a period of 2 years maximum. After 2 years, another agent such a bisphosphonate or denosumab should be used in cases of osteoporosis. ^[9]

Teriparatide cuts the risk of hip fracture by more than half but does not reduce the risk of arm or wrist fracture.^[10]

Other

Teriparatide can be used off-label to speed fracture repair and treat fracture nonunions.^[11] It has been reported to have been successfully used to heal fracture nonunions.^[12] Generally, due to HIPAA regulations, it is not publicized when American athletes receive this treatment to improve fracture recovery.^[11] But an Italian football player, Francesco Totti, was given teriparatide after a tibia/fibula fracture, and he unexpectedly recovered in time for the 2006 World Cup.^[11] It has been reported that Mark Mulder used it to recover from a hip fracture Oakland A’s for the 2003 MLB playoffs^[13] and Terrell Owens to recover from an ankle fracture before the 2005 Super Bowl.^[13]

Administration

Teriparatide is administered by injection once a day in the thigh or abdomen.

Contraindications

Teriparatide should not be prescribed for people who are at increased risks for osteosarcoma. This includes those with Paget’s Diseaseof bone or unexplained elevations of serum alkaline phosphate, open epiphysis, or prior radiation therapy involving the skeleton. In the animal studies and in one human case report, it was found to potentially be associated with developing osteosarcoma in test subjects after over 2 years of use. ^[14]

Patients should not start teriparatide until any vitamin D deficiency is corrected. ^[15]

Adverse effects

Adverse effects of teriparatide include headache, nausea, dizziness, and limb pain.^[6] Teriparatide has a theoretical risk of osteosarcoma, which was found in rat studies but not confirmed in humans.^[2] This may be because unlike humans, rat bones grow for their entire life.^[2] The tumors found in the rat studies were located on the end of the bones which grew after the injections began.^[15]After nine years on the market, there were only two cases of osteosarcoma reported.^[7] This risk was considered by the FDA as “extremely rare” (1 in 100,000 people)^[6] and is only slightly more than the incidence in the population over 60 years old (0.4 in 100,000).^[6]

Mechanism of action

Teriparatide is a portion of human parathyroid hormone (PTH), amino acid sequence 1 through 34, of the complete molecule (containing 84 amino acids). Endogenous PTH is the primary regulator of calcium and phosphate metabolism in bone and kidney. PTH increases serum calcium, partially accomplishing this by increasing bone resorption. Thus, chronically elevated PTH will deplete bone stores. However, intermittent exposure to PTH will activate osteoblasts more than osteoclasts. Thus, once-daily injections of teriparatide have a net effect of stimulating new bone formation leading to increased bone mineral density.^[16]^[17]^[18]

Teriparatide is the first FDA approved agent for the treatment of osteoporosis that stimulates new bone formation.^[19]

FDA approval

Teriparatide was approved by the Food and Drug Administration (FDA) on 26 November 2002, for the treatment of osteoporosis in men and postmenopausal women who are at high risk for having a fracture. The drug is also approved to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture.

Combined teriparatide and denosumab

Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture by increasing BMD. However, there is no evidence of fracture rate reduction in patients taking a teriparatide and denosumab combination. Moreover, the combination therapy group showed a significant decrease in their bone formation marker, indicating that denosumab, an antiresorptive agent, might actually counteract the effect of teriparatide, a bone formation anabolic agent, in bone formation. ^[20]

PATENT

KR 2011291

WO 2019077432

CN 109897099

CN 109879955

CN 109879954

CN 108373499

PATENT

WO-2020000555

Process for preparing teriparatide as parathyroid hormone receptor agonist, useful for treating osteoporosis in menopausal women. Appears to be the first filing from the assignee and the inventors on this compound, however, this invention was previously seen as a Chinese national filing published in 12/2013. Daiichi Sankyo , through its subsidiary Asubio Pharma , was developing SUN-E-3001 , a nasally administered recombinant human parathyroid hormone, for the treatment of osteoporosis.

Teriparatide is a 1-34 fragment of human parathyroid hormone, which has the same biological activity as human parathyroid hormone. Hypogonadous osteoporosis and osteoporosis in menopausal women have great market prospects.

The peptide sequence is:

H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-Ser-Met-Glu-Arg-Val-Glu-Trp-Leu- Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH.

Patent US6590081 uses a method of genetic recombination to obtain teriparatide. However, the genetic recombination method has problems such as complicated process, high cost and serious waste.

Patent CN201510005427 uses Wang resin or 2-Cl-CTC resin to synthesize teriparatide one by one from the C-terminus to the N-terminus, which belongs to the conventional solid-phase synthesis method. However, the reaction is incomplete when the method is coupled to the late stage, which makes purification of the final product difficult and the purity is not high.

Patent CN201310403743 is synthesized by one-by-one coupling method. Unlike patent CN201510005427, this patent ester-condenses the free hydroxyl of Ser at the 17-position with the carboxyl group of Asn at the 16-position, and then obtains teriparatide through O → N acyl transfer. Although this method can reduce the difficulty of coupling at subsequent sites by changing the spatial configuration of the target peptide, it still has the problem of many solid-phase coupling steps and difficult purification.

In patent CN201410262511, a pseudoproline dipeptide Fmoc-Asn (Trt) -Ser (ψ ^{Me, Me} Pro) -OH is used instead of the two amino acids at the original 16-17 positions for coupling one by one, and the final cleavage yields teriparatide. This method adopts the method of feeding pseudoproline dipeptide to avoid the generation of oxidative impurities, but it cannot avoid a variety of missing peptides due to the excessively long peptide chain. At the same time, the pseudoproline dipeptide is expensive and difficult to obtain.

Patent CN201511024053 uses multiple di- or tripeptide fragments to replace a single amino acid for coupling, and finally cleavages to obtain teriparatide. This method requires liquid phase synthesis to obtain 11 short peptide fragments, which are complicated in operation and low in production efficiency.

A method for preparing teriparatide includes:

[0016]

Step 1: Coupling 3-Fmoc-4-diaminobenzoic acid with a solid phase carrier, and then sequentially coupling Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc from the C-terminus to the N-terminus according to the peptide sequence -His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met -OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and PG- Ser (tBu) -OH, then benzimidazolone is closed by phenyl p-nitrochloroformate, and finally fragmented by salicylaldehyde and TFA to obtain fragment APG-Ser-Val-Ser-Glu-Ile-Gln-Leu- Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL;

[0017]

Step 2: Coupling Fmoc-Phe-OH with a solid support, and then coupling Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val in sequence from the C-terminus to the N-terminus according to the peptide sequence. -OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf ) -OH, Fmoc-Leu-OH, Fmoc-Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu)- OH, Fmoc-Met-OH and Fmoc-Ser (tBu) -OH, TFA cleavage to obtain fragment B Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp- Val-His-Asn-Phe-OH;

[0018]

Step 3: Coupling Fragment A and Fragment B, and then removing the protecting group of Ser at Fragment A to obtain a crude teriparatide peptide;

[0019]

Step 4: Purifying the teriparatide crude peptide to obtain teriparatide;

[0020]

Step 1 and Step 2 are not in order.

[0021]

Preferably, the solid phase carrier in step 1 is Rink Amide Resin or 2-Cl-CTC Resin.

[0022]

Preferably, the coupling agent in step 1 is HOBt / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0023]

Preferably, the PG of PG-Ser (tBu) -OH in step 1 is a Msz protecting group, a Teoc protecting group, or a Fmoc protecting group.

[0024]

Preferably, the cracking lysing agent in step 1 is a mixed solution of TFA and water.

[0025]

Preferably, the solid phase support in step 2 is Wang Resin.

[0026]

Preferably, the coupling agent in step 2 is HOBt / DIPCDI, HOBt / DMAP / DIPCDI, HOBt / PyBop / DIPEA, HATU / HOAt / DIPEA, HOAt / PyAop / DIPEA, or HBTU / HOBt / DIPEA.

[0027]

Preferably, the lysing lysing agent in step 2 is a mixed solution of TFA and TIS.

[0028]

Preferably, the specific operation of the coupling in step 3 is to dissolve in a pyridine / acetic acid buffer solution for 2-4 hours.

[0029]

Preferably, the specific operation of removing the protecting group of 1-Ser in the fragment A in step 3 is:

[0030]

When the PG of PG-Ser (tBu) -OH in the fragment A is the protecting group of Msz, the coupling of the fragment A and the fragment B is completed by adding TFA / ammonium iodide / dimethylsulfide to remove the protecting group Msz, and the ether precipitates;

[0031]

When the PG of PG-Ser (tBu) -OH in the fragment A is a Teoc protecting group, the fragment A and the fragment B are coupled and tetrabutylammonium fluoride is added to remove the protecting group Teoc;

[0032]

When the PG of PG-Ser (tBu) -OH in the fragment A is a Fmoc protecting group, the fragment A and the fragment B are coupled and diethylamine is added to remove the protecting group Fmoc.

[0033]

The method for preparing teriparatide in the present invention uses fragment condensation to prepare teriparatide. First synthesize the teriparatide peptide sequence 1-16 (fragment A) and the 17-34 peptide sequence (fragment B), and then couple the two fragments to obtain the crude teriparatide peptide. Riparide. The side chain of the fragment in the invention has no protecting group, has good solubility in water, does not have the problem of difficult coupling, simple operation, and high production efficiency. The obtained teriparatide product has high purity and is easy to purify. Experiments show that the crude peptide of teriparatide obtained by the present invention can obtain a purity of 80% and a total yield of 45%. After simple purification, the purity of spermeptide can reach 99.92%, and the single largest impurity is 0.05%. Compared with the prior art, the invention has the characteristics of high product quality, low cost, and suitability for industrial production.

Example 1: Synthesis of fragment one (Msz-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0097]

Weigh 20.0 g (10 mmol) of Rink Amide Resin with a substitution degree of 0.5 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 18.7 g (50 mmol) ) 3-Fmoc-4-diaminobenzoic acid and 8.1 g (60 mmol) of HOBt were dissolved in DMF, 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and added to a solid-phase reaction column, and reacted at room temperature for 2 hours. The solution was removed by DMF Wash 3 times. The 20% piperidine solution was used to remove the Fmoc protecting group (reaction time 5 + 7 minutes), and DMF was washed 6 times.

[0098]

According to the peptide sequence of fragment one, the above steps of amino acid coupling and removal of the Fmoc protecting group are repeated, using the coupling agent HOBt / DIPCDI or HOBt / PyBop / DIPEA or HATU / HOAt / DIPEA or HOAt / PyAop / DIPEA or HBTU / HOBt / DIPEA, coupled Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Gly-OH, Fmoc-Leu- OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Msz-Ser (tBu) -OH.

[0099]

Weigh 10.1 g (50 mmol) of phenyl p-nitrochloroformate in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 12.9 g (100 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Separately weigh 10.6 g (100 mmol) of sodium carbonate and 100 ml of salicylaldehyde in a mixed solution of DCM / THF (1: 3), add to the peptide resin, react at room temperature overnight, filter, and concentrate the filtrate under reduced pressure to dryness. Finally, it was cleaved with TFA / H ₂ O (95: 5) for 2 hours and precipitated with ether to obtain 19.2 g of fragment one.

[0100]

Example 2: Synthesis of fragment two (Teoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0101]

Weigh 16.7 g (10 mmol) of 2-Cl-CTC Resin with a substitution degree of 0.6 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, remove the solution, and weigh 7.48 g (20 mmol) of 3-Fmoc-4-diaminobenzoic acid was dissolved in DMF, 5.2 g (40 mmol) of DIPEA was added under an ice bath, and the solid phase reaction column was added, and the reaction was performed at room temperature for 0 hours, and 6 ml of methanol was added to block the resin for 1 hour. The solution was removed and washed 6 times with DMF.

[0102]

Fmoc-Asn (Trt) -OH, Fmoc-Leu-OH, Fmoc-His (Trt) -OH, Fmoc-Lys (Boc) -OH were sequentially coupled according to the peptide sequence of fragment two according to the method in Example 1. , F moc-Gly-OH, Fmoc-Leu-OH, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Met-OH, Fmoc-Leu-OH, Fmoc-Gln (Trt) -OH, Fmoc-Ile-OH, Fmoc-Glu (OtBu) -OH, Fmoc-Ser (tBu) -OH, Fmoc-Val-OH, and Teoc-Ser (tBu) -OH.

[0103]

Weigh 6.1 g (30 mmol) of phenyl p-nitrochloroformate and dissolve it in dichloromethane, add it to a solid-phase reaction column, and react at room temperature for 1 hour, then add 7.7 g (60 mol) of DIPEA, react for 30 minutes, and remove the solution. Wash with methyl chloride 6 times. Another 6.4 g (60 mmol) of sodium carbonate and 60 ml of salicylaldehyde dissolved in a mixed solution of DCM / THF (1: 1) were added to the peptide resin, reacted at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to dryness. Finally, it was cleaved with TFA / H2O (95: 5) for 2 hours and precipitated with ether to obtain 10.5 g of fragment two.

[0104]

Example 3: Synthesis of fragment three (Fmoc-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-Gly-Lys-His-Leu-Asn-SAL)

[0105]

Fmoc-Ser (tBu) -OH was used for serine at position 1. Other synthetic methods were the same as in Example 1.

[0106]

Example 4: Synthesis of fragment four (Ser-Met-Glu-Arg-Val-Glu-Trp-Leu-Arg-Lys-Lys-Leu-Gln-Asp-Val-His-Asn-Phe-OH)

[0107]

Weigh 62.5 g (50 mmol) of Wang Resin with a degree of substitution of 0.8 mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, and swell the resin with DMF for 3 minutes, then weigh 19.37 g (50 mmol) of Fmoc-Phe- OH, 8.1 g (60 mmol) of HOBt and 6.1 g (5 mmol) of DMAP were dissolved in DMF. 8.2 g (65 mmol) of DIPCDI was added under an ice bath, and the solid phase reaction column was added. The mixture was reacted at room temperature for 2 hours and washed with DMF 6 times. 79.1 g (1000 mmol) of pyridine and 102.1 g (1000 mmol) of acetic anhydride were added to seal the resin for 6 hours, washed with DMF 6 times, and the methanol was shrunk and dried to obtain 71.4 g of Fmoc-Phe-WangResin. .

[0108]

According to the method in Example 1, Fmoc-Asn (Trt) -OH, Fmoc-His (Trt) -OH, Fmoc-Val-OH, Fmoc-Asp (tBu) -OH, Fmoc-Gln (Trt) -OH, Fmoc-Leu-OH, Fmoc-Lys (Boc) -OH, Fmoc-Lys (Boc) -OH, Fmoc-Arg (Pbf) -OH, Fmoc-Leu-OH, Fmoc- Trp (Boc) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Val-OH, Fmoc-Arg (Pbf) -OH, Fmoc-Glu (OtBu) -OH, Fmoc-Met-OH and Fmoc-Ser ( tBu) -OH, the obtained peptide resin was cleaved with TFA / TIS (95: 5) for 2 hours, and the ether was precipitated to obtain 23.2 g of fragment four.

[0109]

Example 5: Synthesis of crude teriparatide

[0110]

19.2 g (10 mmol) of fragment 1 obtained in Example 1 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 2 hours, and concentrated under reduced pressure to Dry, add TFA / ammonium iodide / dimethylsulfide (90: 5: 5) to react for 30 minutes, and diethyl ether precipitates to obtain 37 g of teriparatide crude peptide, purity 80.10%, weight yield 90%. The purity test results are shown in Figure 2 and Table 1.

[0111]

Example 6: Synthesis of crude teriparatide

[0112]

21.9 g (10 mmol) of fragment 2 obtained in Example 2 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), and reacted at room temperature for 3 hours, and then 26.15 g was added. Tetrabutylammonium fluoride (100 mmol) was reacted overnight to obtain the teriparatide crude peptide solution for direct purification. The purity of the crude peptide was 67.97%. The purity test results are shown in Figure 3 and Table 1.

[0113]

Example 7: Synthesis of crude teriparatide

[0114]

21.5 g (10 mmol) of fragment 3 obtained in Example 3 and 23.2 g (10 mmol) of fragment 4 obtained in Example 4 were dissolved in a pyridine / acetic acid buffer solution (1: 1, 10 mM), reacted at room temperature for 4 hours, and concentrated under reduced pressure to Dry, add methanol to dissolve, then add 14.63 g of diethylamine (200 mmol), react at room temperature for 2 hours, and concentrate to dryness under reduced pressure to obtain 45 g of teriparatide crude peptide, purity 63.22%, weight yield 109%. The purity test results are shown in Figure 4 and Table 1.

[0115]

Example 8: Purification of crude teriparatide

[0116]

The crude teriparatide peptide obtained in Example 5 was purified by HPLC with a wavelength of 220 nm, a chromatographic column was a reversed-phase C18 column, a 0.1% TFA solution, and acetonitrile were used as mobile phases. The target fractions were collected, concentrated by rotary evaporation, and lyophilized. 18.5 g of teriparatide spermidine was obtained, with a purity of 99.92%, a single maximum impurity of 0.05%, and a total yield of 45%. The purity test results are shown in Figure 5 and Table 1.

[0117]

The crude teriparatide peptide obtained in Example 6 was purified under the same conditions as described above to obtain 14.8 g of teriparatide spermeptide with a purity of 99.76%, a single maximum impurity of 0.07%, and a total yield of 36%.

[0118]

The crude teriparatide peptide obtained in Example 7 was purified under the same conditions as described above to obtain 14.0 g of teriparatide spermeptide with a purity of 99.73%, a single maximum impurity of 0.06%, and a total yield of 34%.

References

^ http://www.minsa.gob.pa/sites/default/files/alertas/nota_seguridad_teriparatida.pdf
^ Jump up to:^a ^b ^c Riek AE and Towler DA (2011). “The pharmacological management of osteoporosis”. Missouri Medicine. 108 (2): 118–23. PMC 3597219. PMID 21568234.
^ Saag KG, Shane E, Boonen S, et al. (November 2007). “Teriparatide or alendronate in glucocorticoid-induced osteoporosis”. The New England Journal of Medicine. 357 (20): 2028–39. doi:10.1056/NEJMoa071408. PMID 18003959.
^ BfArM (2017-05-08). “PUBLIC ASSESSMENT REPORT – Decentralised Procedure – Teriparatid-ratiopharm 20 µg / 80ml, Solution for injection” (PDF).
^ “Summary of the European public assessment report (EPAR) for Terrosa”. Retrieved 2019-08-14.
^ Jump up to:^a ^b ^c ^d ^e Rizzoli, R.; Reginster, J. Y.; Boonen, S.; Bréart, G. R.; Diez-Perez, A.; Felsenberg, D.; Kaufman, J. M.; Kanis, J. A.; Cooper, C. (2011). “Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis”. Calcified Tissue International. 89 (2): 91–104. doi:10.1007/s00223-011-9499-8. PMC 3135835. PMID 21637997.
^ Jump up to:^a ^b Kawai, M.; Mödder, U. I.; Khosla, S.; Rosen, C. J. (2011). “Emerging therapeutic opportunities for skeletal restoration”. Nature Reviews Drug Discovery. 10 (2): 141–156. doi:10.1038/nrd3299. PMC 3135105. PMID 21283108.
^ Murad, M. H.; Drake, M. T.; Mullan, R. J.; Mauck, K. F.; Stuart, L. M.; Lane, M. A.; Abu Elnour, N. O.; Erwin, P. J.; Hazem, A.; Puhan, M. A.; Li, T.; Montori, V. M. (2012). “Comparative Effectiveness of Drug Treatments to Prevent Fragility Fractures: A Systematic Review and Network Meta-Analysis”. Journal of Clinical Endocrinology & Metabolism. 97(6): 1871–1880. doi:10.1210/jc.2011-3060. PMID 22466336.
^ O’Connor KM. Evaluation and Treatment of Osteoporosis. Med Clin N Am. 2016; 100:807-26
^ Díez-Pérez A, Marin F, Eriksen EF, Kendler DL, Krege JH, Delgado-Rodríguez M (September 2018). “Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis”. Bone. 120: 1–8. doi:10.1016/j.bone.2018.09.020. PMID 30268814.
^ Jump up to:^a ^b ^c Bruce Jancin (2011-12-12). “Accelerating Fracture Healing With Teriparatide”. Internal Medicine News Digital Network. Retrieved 2013-09-20.
^ Giannotti, S.; Bottai, V.; Dell’Osso, G.; Pini, E.; De Paola, G.; Bugelli, G.; Guido, G. (2013). “Current medical treatment strategies concerning fracture healing”. Clinical Cases in Mineral and Bone Metabolism. 10 (2): 116–120. PMC 3796998. PMID 24133528.
^ Jump up to:^a ^b William L. Carroll (2005). “Chapter 1: Defining the Issue”. The Juice: The Real Story of Baseball’s Drug Problems. ISBN 1-56663-668-X. Retrieved 2013-09-23.
^ Harper KD, Krege JH, Marcus R, et al. Osteosarcoma and teriparatide? J Bone Miner Res 2007;22(2):334
^ Jump up to:^a ^b https://www.drugs.com/pro/forteo.html
^ Bauer, E; Aub, JC; Albright, F (1929). “Studies of calcium and phosphorus metabolism: V. Study of the bone trabeculae as a readily available reserve supply of calcium”. J Exp Med. 49 (1): 145–162. doi:10.1084/jem.49.1.145. PMC 2131520. PMID 19869533.
^ Selye, H (1932). “On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol”. Endocrinology. 16 (5): 547–558. doi:10.1210/endo-16-5-547.
^ Dempster, D. W.; Cosman, F.; Parisien, M.; Shen, V.; Lindsay, R. (1993). “Anabolic actions of parathyroid hormone on bone”. Endocrine Reviews. 14 (6): 690–709. doi:10.1210/edrv-14-6-690. PMID 8119233.
^ Fortéo: teriparatide (rDNA origin) injection Archived 2009-12-27 at the Wayback Machine
^ Tsai, Joy N; Uihlein, Alexander V; Lee, Hang; Kumbhani, Ruchit; Siwila-Sackman, Erica; McKay, Elizabeth A; Burnett-Bowie, Sherri-Ann M; Neer, Robert M; Leder, Benjamin Z (2013). “Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: The DATA study randomised trial”. The Lancet. 382 (9886): 1694–1700. doi:10.1016/S0140-6736(13)60856-9. PMC 4010689. PMID 24517156.

External links

Teriparatide
Clinical data

Trade names	Forteo/Forsteo, Teribone^[1]
AHFS/Drugs.com	Monograph
License data	EU EMA: by INN
Pregnancy category	C
Routes of administration	Subcutaneous
ATC code	H05AA02 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	95%
Metabolism	Hepatic (nonspecific proteolysis)
Elimination half-life	Subcutaneous: 1 hour
Excretion	Renal (metabolites)
Identifiers
CAS Number	52232-67-4
PubChem CID	16132393
DrugBank	DB06285
ChemSpider	17289052
UNII	10T9CSU89I
KEGG	D06078
ECHA InfoCard	100.168.733
Chemical and physical data
Formula	C₁₈₁H₂₉₁N₅₅O₅₁S₂
Molar mass	4117.72 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] [H]/N=C(\N)/NCCC[C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2c1cccc2)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN/C(=N/[H])/N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](Cc3cnc[nH]3)C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](Cc4ccccc4)C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc5cnc[nH]5)NC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(=O)N)NC(=O)[C@H](Cc6cnc[nH]6)NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(=O)N)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CO)N

PATENT NUMBER	PEDIATRIC EXTENSION	APPROVED	EXPIRES (ESTIMATED)
CA2314313	No	2005-02-08	2018-12-08
CA2325371	No	2004-08-17	2019-08-19
US6770623	No	2004-08-03	2018-12-08
US6977077	No	2005-12-20	2019-08-19
US7163684	No	2007-01-16	2019-08-19
US7351414	No	2008-04-01	2019-08-19
US7550434	No	2009-06-23	2018-12-08
US7144861	No	2006-12-05	2018-12-08
US7517334	No	2009-04-14	2025-03-25

Showing 1 to 9 of 9 entries

FORTEO (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1- 34), and is also called rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids(the biologically active region) of the 84-amino acid human parathyroid hormone.

Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

FORTEO (teriparatide)Structural Formula Illustration

Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. FORTEO is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate (anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium hydroxide solution 10% may have been added to adjust the product to pH 4.

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

REFERENCES

1: Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ. Teriparatide for osteoporosis: importance of the full course. Osteoporos Int. 2016 Feb 22. [Epub ahead of print] Review. PubMed PMID: 26902094.

2: Im GI, Lee SH. Effect of Teriparatide on Healing of Atypical Femoral Fractures: A Systemic Review. J Bone Metab. 2015 Nov;22(4):183-9. doi: 10.11005/jbm.2015.22.4.183. Epub 2015 Nov 30. Review. PubMed PMID: 26713309; PubMed Central PMCID: PMC4691592.

3: Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: What is the evidence? World J Orthop. 2015 Jul 18;6(6):457-61. doi: 10.5312/wjo.v6.i6.457. eCollection 2015 Jul 18. Review. PubMed PMID: 26191492; PubMed Central PMCID: PMC4501931.

4: Lecoultre J, Stoll D, Chevalley F, Lamy O. [Improvement of fracture healing with teriparatide: series of 22 cases and review of the literature]. Rev Med Suisse. 2015 Mar 18;11(466):663-7. Review. French. PubMed PMID: 25962228.

5: Sugiyama T, Torio T, Sato T, Matsumoto M, Kim YT, Oda H. Improvement of skeletal fragility by teriparatide in adult osteoporosis patients: a novel mechanostat-based hypothesis for bone quality. Front Endocrinol (Lausanne). 2015 Jan 30;6:6. doi: 10.3389/fendo.2015.00006. eCollection 2015. Review. PubMed PMID: 25688232; PubMed Central PMCID: PMC4311704.

6: Wheeler AL, Tien PC, Grunfeld C, Schafer AL. Teriparatide treatment of osteoporosis in an HIV-infected man: a case report and literature review. AIDS. 2015 Jan 14;29(2):245-6. doi: 10.1097/QAD.0000000000000529. Review. PubMed PMID: 25532609; PubMed Central PMCID: PMC4438749.

7: Campbell EJ, Campbell GM, Hanley DA. The effect of parathyroid hormone and teriparatide on fracture healing. Expert Opin Biol Ther. 2015 Jan;15(1):119-29. doi: 10.1517/14712598.2015.977249. Epub 2014 Nov 3. Review. PubMed PMID: 25363308.

8: Yamamoto M, Sugimoto T. [Glucocorticoid and Bone. Beneficial effect of teriparatide on fracture risk as well as bone mineral density in patients with glucocorticoid-induced osteoporosis]. Clin Calcium. 2014 Sep;24(9):1379-85. doi: CliCa140913791385. Review. Japanese. PubMed PMID: 25177011.

9: Chen JF, Yang KH, Zhang ZL, Chang HC, Chen Y, Sowa H, Gürbüz S. A systematic review on the use of daily subcutaneous administration of teriparatide for treatment of patients with osteoporosis at high risk for fracture in Asia. Osteoporos Int. 2015 Jan;26(1):11-28. doi: 10.1007/s00198-014-2838-7. Epub 2014 Aug 20. Review. PubMed PMID: 25138261.

10: Eriksen EF, Keaveny TM, Gallagher ER, Krege JH. Literature review: The effects of teriparatide therapy at the hip in patients with osteoporosis. Bone. 2014 Oct;67:246-56. doi: 10.1016/j.bone.2014.07.014. Epub 2014 Jul 15. Review. PubMed PMID: 25053463.

11: Meier C, Lamy O, Krieg MA, Mellinghoff HU, Felder M, Ferrari S, Rizzoli R. The role of teriparatide in sequential and combination therapy of osteoporosis. Swiss Med Wkly. 2014 Jun 4;144:w13952. doi: 10.4414/smw.2014.13952. eCollection 2014. Review. PubMed PMID: 24896070.

12: Krege JH, Lane NE, Harris JM, Miller PD. PINP as a biological response marker during teriparatide treatment for osteoporosis. Osteoporos Int. 2014 Sep;25(9):2159-71. doi: 10.1007/s00198-014-2646-0. Epub 2014 Mar 6. Review. PubMed PMID: 24599274; PubMed Central PMCID: PMC4134485.

13: Nakano T. [Once-weekly teriparatide treatment on osteoporosis]. Clin Calcium. 2014 Jan;24(1):100-5. doi: CliCa1401100105. Review. Japanese. PubMed PMID: 24369286.

14: Yano S, Sugimoto T. [Daily subcutaneous injection of teriparatide : the progress and current issues]. Clin Calcium. 2014 Jan;24(1):35-43. doi: CliCa14013543. Review. Japanese. PubMed PMID: 24369278.

15: Lewiecki EM, Miller PD, Harris ST, Bauer DC, Davison KS, Dian L, Hanley DA, McClung MR, Yuen CK, Kendler DL. Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis. J Clin Densitom. 2014 Oct-Dec;17(4):490-5. doi: 10.1016/j.jocd.2013.09.018. Epub 2013 Oct 25. Review. PubMed PMID: 24206867.

16: Delivanis DA, Bhargava A, Luthra P. Subungual exostosis in an osteoporotic patient treated with teriparatide. Endocr Pract. 2013 Sep-Oct;19(5):e115-7. doi: 10.4158/EP13040.CR. Review. PubMed PMID: 23757619.

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/////TERIPARATIDE, テリパラチド , терипаратид , تيريباراتيد , 特立帕肽 , PTH 1-34, LY 333334, LY-333334, LY333334, ZT-034, 52232-67-4, PEPTIDES

Coblopasvir

January 7, 2020 8:38 am / Leave a comment

Coblopasvir
CAS: 1312608-46-0
Chemical Formula: C41H50N8O8
Molecular Weight: 782.89

UNII-67XWL3R65W

methyl {(2S)-1-[(2S)-2-(4-{4-[7-(2-[(2S)-1-{(2S)-2- [(methoxycarbonyl)amino]-3-methylbutanoyl}pyrrolidin-2-yl]-1H-imidazol-4-yl)-2H-1,3-benzodioxol-4-yl]phenyl}-1Himidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

Carbamic acid, N-((1S)-1-(((2S)-2-(5-(4-(7-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methyl-1-oxobutyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-1,3-benzodioxol-4-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)-, methyl ester

hepatitis C virus infection

KW-136

Coblopasvir is an antiviral drug candidate.

Coblopasvir dihydrochloride

CAS 1966138-53-3

C41 H50 N8 O8 . 2 Cl H
Molecular Weight	855.806
PHASE 3	Beijing Kawin Technology Share-Holding

Hepatitis C virus (HCV), or hepatitis C virus infection, is a chronic blood-borne infection. Studies have shown that 40% of chronic liver diseases are associated with HCV infection, and an estimated 8,000-10,000 people die each year. HCV-related end-stage liver disease is the most common indication for liver transplantation in adults.

In the past ten years, antiviral therapy for chronic liver disease has developed rapidly, and significant improvement has been seen in the treatment effect. However, even with the combination therapy with pegylated IFN-α plus ribavirin, 40% to 50% of patients fail to treat, that is, they are non-responders or relapsers. These patients do not currently have an effective treatment alternative. Because the risk of HCV-related chronic liver disease is related to the duration of HCV infection, and the risk of cirrhosis increases in patients who have been infected for more than 20 years, chronic liver disease often progresses to advanced stages with cirrhosis, ascites, jaundice, and rupture of varicose veins. , Brain disease, and progressive liver failure, and the risk of liver cancer is also significantly increased.

HCV is a enveloped positive-strand RNA virus of the Flaviviridae family. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) that encodes a single open reading frame (ORF) of approximately 3,000 amino acids. Mostly polyprotein. In infected cells, cellular and viral proteases cleave this polyprotein at multiple sites to produce viral structural and non-structural (NS) proteins. There are two viral proteases that affect the production of mature non-structural proteins (NS2, NS3, NS4, NS4A, NS4B, NS5A, and NS5B). The first viral protease is cleaved at the NS2-NS3 junction of the polyprotein; the second viral protease is A “NS3 protease” that mediates all subsequent cleavage events at a site downstream of the NS3 position relative to the polyprotein (ie, the site between the C-terminus of NS3 and the C-terminus of the polyprotein). The NS3 protease exhibits cis-activity at the NS3-NS4 cleavage site and, conversely, exhibits trans-activity at the remaining NS4A-NS4B, NS4B-NS5A, and NS5A-NS5B sites. The NS4A protein is thought to provide multiple functions, such as acting as a cofactor for the NS3 protease, and may promote membrane localization of NS3 and other viral replicase components. The formation of a complex between NS3 and NS4A may be necessary for NS3-mediated processing events and improves the proteolytic efficiency at all sites recognized by NS3. NS3 protease may also exhibit nucleotide triphosphatase and RNA helicase activity. NS5B is an RNA-dependent RNA polymerase involved in HCV RNA replication. In addition, compounds that inhibit the effects of NS5A in viral replication may be useful for treating HCV.

Beijing Kawin Technology Share-Holding, in collaboration with Beijing Fu Rui Tiancheng Biotechnology and Ginkgo Pharma , is developing coblopasvir as an oral capsule formulation of dihydrochloride salt (KW-136), for treating hepatitis C virus infection. In June 2018, an NDA was filed in China by Beijing Kawin Technology and Sichuan Qingmu Pharmaceutical . In August 2018, the application was granted Priority Review in China . Also, Beijing Kawin is investigating a tablet formulation of coblopasvir dihydrochloride.

PATENT

WO2011075607 , claiming substituted heterocyclic derivatives as HCV replication inhibitors useful for treating HCV infection and liver fibrosis, assigned to Beijing Kawin Technology Share-Holding Co Ltd and InterMune Inc ,

PATENT

CN 108675998

PATENT

WO-2020001089

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020001089&tab=FULLTEXT&_cid=P22-K53D18-32430-1

Novel crystalline and amorphous forms of methyl carbamate compound, particularly coblopasvir dihydrochloride , (designated as Forms H) processes for their preparation, compositions and combinations comprising them are claimed. Also claim is an article or kit comprising a container and a package insert, wherein the container contains coblopasvir dihydrochloride.

Step 7

To a solution of compound 1-IXf (250 mg, 0.31 mmol) in toluene (10.0 mL) was added NH4OAc (4.0 g, 50 mmol) and the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed and the residue was purified by preparative HPLC to give Compound I (43.5 mg, yield 20%) as a white solid. MS (ESI) m / z (M + H) + 783.4.

Example 2 Preparation of a compound of formula II

Compound of formula (I) N-[(2S) -1-[(2S) -2- {4- [7- (4- {2-[(2S) -1-[(2S) -2-[(A Oxycarbonyl) amino] -3-methylbutanoyl] pyrrolidin-2-yl] -1H-imidazol-4-yl} phenyl) -2H-1,3-benzodioxo-4-yl] Preparation of -1H-imidazol-2-yl} pyrrolidin-1-yl] -3-methyl-1-oxobutane-2-yl] carbamate dihydrochloride

At room temperature, a solution of the pure product of structural formula I (800 g, 1.0 eq) and ethyl acetate (8 L) were sequentially added to a 20 L bottle and stirred. A 11.2% HCl / ethyl acetate solution (839 g) was added dropwise to the system, the temperature of the system was controlled at 15 ° C to 25 ° C, and the mixture was stirred for more than 3 hours to stop the reaction. The filter cake was filtered with ethyl acetate (2L). Wash the cake, bake the cake at a controlled temperature of 40-60 ° C, sample and test until the ethyl acetate residue is <0.5%, (about 73 hours of baking), to obtain the compound of formula II, off-white solid powder or granules, 774 g, HPLC Purity: 98.65%, yield: 88.5%, tested XRPD as amorphous.

///////////////Coblopasvir , KW-136, hepatitis C virus infection, CHINA, Beijing Kawin Technology, NDA, Phase III

O=C(OC)N[C@@H](C(C)C)C(N1[C@H](C2=NC(C3=CC=C(C4=C5OCOC5=C(C6=CNC([C@H]7N(C([C@@H](NC(OC)=O)C(C)C)=O)CCC7)=N6)C=C4)C=C3)=CN2)CCC1)=O

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