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CC-90010
CC-90010
C21 H21 N O4 S, 383.46
CAS 1706738-98-8
1(2H)-Isoquinolinone, 4-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-
- 4-[2-(Cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-2-methyl-1(2H)-isoquinolinone
- 4-[2-(Cyclopropylmethoxy)-5-(methanesulfonyl)phenyl]-2-methylisoquinolin-1(2H)-one
- 4-[2-(Cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one
Quanticel Pharmaceuticals Inc, Michael John BennettJuan Manuel BetancortAmogh BoloorStephen W. KaldorJeffrey Alan StaffordJames Marvin Veal
Celgene (now a wholly owned subsidiary of Bristol-Myers Squibb ) , following its acquisition of Quanticel , is developing CC-90010, an oral inhibitor of BET (bromodomain and extraterminal) proteins, for the potential treatment of solid tumors and non-Hodgkin’s lymphoma. In August 2019, a phase I trial for diffuse astrocytoma, grade III anaplastic astrocytoma and recurrent glioblastoma was planned
PATENT
WO2018075796 claiming solid composition comprising a bromodomain inhibitor, preferably 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one in crystalline form A.
PATENT
WO2015058160 (compound 89, page 103).
Example 89: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one
Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one
[00344] A suspension of 4-bromo-2-methylisoquinolin-l-one (100 mg, 0.42 mmol), bis(pinacolato)diboron (214 mg, 0.84 mmol), Pd(dppf)Cl2 (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 mL) under nitrogen was warmed up to 90 °C for 135 minutes. It was then cooled down to room temperature and diluted with ethyl acetate (8 mL). The mixture was washed with aqueous saturated solution of NaHC03 (8 mL) and brine (8 mL). The organic phase was separated, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purifed by normal phase column chromatography (10-90% EtOAc/Hexanes) to give the title compound (44 mg, 37%). 1H NMR (CDC13, 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1 H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1 H), 7.68 (s, 1 H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M+H)+ 286. Step 2: 4-[2-(cyclopropylmethox -5-methylsulfonylphenyl]-2-methylisoquinolin-l-one
[00345] The title compound was prepared in a manner similar to Example 18, step 3, substituting 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene for 4-bromo-2-methylisoquinolin-l(2H)-one and 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one for N-benzyl-2-methoxy-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide. 1H NMR (DMSO-d6, 400 MHz) δ 0.09 (m, 2 H), 0.29 (m, 1H), 0.35 (m, 1H),
0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s, 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J =
8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8,
2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M+H)+ 384.
[00346] Alternatively, 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one can be prepared as described below.
Step 1 : 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)isoquinolin-l-one
[00347] A mixture of 4-bromo-2-methylisoquinolin-l-one (8.0 g, 33.6 mmol),
bis(pinacolato)diboron (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd2(dba)3 (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 mL) was stirred at 60 °C for 12 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (PE : EA = 15 : 1) to give the title compound (6.0 g, 62 %) as a solid.
Step 2: 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-l-one
[00348] The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-l-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl2 (1.4 g, 1.75 mmol) in a dioxane/water (100 mL / 10 mL) mixture were stirred at 60 °C for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA : DCM = 1 : 4).
Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM / MTBE (1 : 1, 50 mL) to give the title compound (4.0 g, 60 %) as a white solid. 1H NMR: (CDC13, 400 MHz) δ 8.51 (dd, Ji = 8.0 Hz, J2 = 0.8 Hz, 1 H), 7.98 (dd, Ji = 8.4 Hz, J2 = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H), 7.53 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.10 (m, 2 H), 3.88 (m, 2 H), 3.66 (s, 3 H), 3.09 (s, 3 H), 1.02-0.98 (m, 1 H), 0.44-0.38 (m, 2 H), 0.11-0.09 (m, 2 H). LCMS: 384.1 (M+H)+
Patent
WO-2020023438
A process for preparing bromodomain inhibitor, particularly 4-[2(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one (having HPLC purity of 99%; compound 1; (hereafter referred to as C-90010)) and its hydrates, solvates, prodrugs and salts comprising the reaction of a substituted 4-(methylsulfonyl)phenol compound with a quinoline derivative, followed by purification is claimed. Also claimed are novel intermediates of CC-90010 and their processes for preparation. Further claimed are novel crystalline form of CC-90010. CC-90010 is known and disclosed to be a bromodomain containing protein inhibitor, useful for treating cancer.
Scheme 10: Synthesis of Compound 1
[0090] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compound 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223g, l.OSmol). Agitation
was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum purged three times with nitrogen. The batch was heated to about 65 to about 75 °C (or any temperature in between and including these two values) and contents stirred for at least about 16 hours until reaction was complete by HPLC analysis. The batch was cooled to about 60 to about 70 °C (or any temperature in between and including these two values), agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at about 60 to about 70°C (or any temperature in between and including these two values). Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at about 60 to about 70°C (or any temperature in between and including these two values). After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at about 60 to about 70°C (or any temperature in between and including these two values). The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to about 60 to about 65°C (or any temperature in between and including these two values) and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at about 60 to about 65°C (or any temperature in between and including these two values). The slurry was cooled to about 15 to about 25°C (or any temperature in between and including these two values) over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at about 40°C with nitrogen purge. Yield: 139g of 1.
[0091] The above procedure for coupling Compound 3 and Compound 2 to produce
Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox et al., Chem. Soc. Rev., 43: 412 (2014). Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used.
Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used.
The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);
Pd(PPh3)2Cb (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.
Table 4: Catalyst screen summary
VI. Purification of Compound 1 fCC-900101 bv crystallization from formic acid and water
[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4
The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1); cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCh(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5);
Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.
Table 4: Catalyst screen summary
VI. Purification of Compound 1 (CC-90010! bv crystallization from formic acid and water
[0092] Described herein are methods of purifying Compound 1 by crystallization from formic acid and water. Also described are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1 and two metastable forms, Form 4
33 -a
and Form 5. Supporting data (XRPD, DSC, photomicroscopy) for all three forms is provided in the examples below.
[0093] The stmcture of Compound 1 (CC-90010) is shown below:
Example 1: Synthesis of Compound 1
[0217] Synthesis of compound 1 was accomplished according to Scheme 1 below. Referring to Scheme 1, synthesis commenced with bromination of starting material 4-(methylsulfonyl)phenol 4, to produce compound 5. Compound 5 was O-alkylated with (bromomethyl)cyclopropane to produce compound 6. Boronate Compound 2 was then formed by borylation of Compound 6 with Pd catalyst and bis(pinacolato)diboron to produce transient Compound 7, which was subsequenctly treated with diethanolamine (DBA) to afford cross-coupling partner Compound 2. Cross-coupling partner Compound 3 was formed in one pot starting from commercially available Compound 8. Compound 8 was N-methylated and brominated to afford Compound 3. Compounds 2 and 3 were cross-coupled (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)) to afford the target compound 1.
Scheme 1: Synthesis of compound 1
1.1: Bromination of 4
[0218] The bromination of Compound 4 to produce Compound 5 itself is simple, however stopping at the mono-brominated Compound 5 was challenging. The bis-brominated Compound 5-a (see Scheme 2 below) is a particularly pernicious impurity as it couples downstream to form a di ffi cult-to-purge impurity.
Scheme 2: Bromination of Compound 4
[0219] The key to high purity with reasonable yield was to exploit the solubility differences of the starting material Compound 4 (46 mg/ml at 20 °C) and the product Compound 5 (8 mg/ml) in CH2CI2. These solubility differences are summarized in Table 3 below.
[0220] This solubility difference is exploited by performing the reaction at a high
concentration to drive Compound 5 out of solution once formed, thereby minimizing its ability to react further with the brominating reagent to form Compound 5-a diBr. The reaction is seeded with Compound 5 to initiate its crystallization.
[0221] In Fig. 22 (Conversion of Compound 4 to Compound 5: Effect of Sulfuric Acid) it can be seen that in the absence of acid the initial reaction to Compound 5 is rapid, however the conversion plateaus at about 30% Compound 5. The main side product was found to be the impurity Compound 5-a diBr (see Fig. 23: Conversion of Compound 5 and Compound 5-a diBr: No H2SO4). Addition of increasing amounts of sulfuric acid leads to a higher conversion to desired Compound 5.
[0222] Fig. 24 (Compound 4 to Compound 5 Reaction Profile: Portion-wise Addition of NBS, Seeding) depicts further reaction control. The portion-wise addition ofNBS after addition of catalytic sulfuric acid minimizes the temperature rise, and the addition of Compound 5 after an initial NBS charge promotes the reactive crystallization of Compound 5. After about 6 to 7 hours of reaction it can be seen that the major product is Compound 5, with only a small (<5%) of the di-brominated impurity formed. In contrast, in a reaction where Compound 4 and all of the NBS were charged followed by the addition of 4 volumes of methylene chloride, a rapid exotherm resulted and undesired Compound 5-a diBr was found to be the major product.
[0223] Thus, the reaction was run under a high concentration in CH2CI2 with a portion-wise solid addition of NBS (to control both availability of the electrophile and the exotherm). An end of reaction slurry sample typically showed not more than 5% of the starting material Compound 4 remaining. After filtration the crude cake was washed with cold CH2CI2 and the OkCk-washed filter cake contained not more than 0.5% by weight dibrominated Compound 5-a. It also contained a large amount of HPLC-silent succinimide.
[0224] The following procedure was carried out: Compound 4 (25g, 145mmol) followed by CH2CI2 (lOOmL) were added to a reaction vessel and agitated. The batch was adjusted to 17 °C to 23 °C. Sulfuric acid was charged (2.7mL, Slmmol) to the batch maintaining 17 °C to 23°C. The batch was stirred at 17 °C to 23 °C for 10 minutes to 20 minutes. The first portion of A-bromosuccimide (NBS) was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The second portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23°C and stirred for at least 30 min. The batch was seeded with
Compound 5 (0.02wt) and stirred for ca. 30 min at 17 °C to 23 °C to induce crystallization.
[0225] The third portion of NBS was charged (6.5g, 36.5 mmol) to the batch at 17 °C to 23 °C and stirred for at least 30 min. NBS (6.5g, 36.5 mmol) was charged to the batch at 17 °C to 23 °C and stirred for at least 30 min. Additional CH2CI2 was charged (50mL) to the batch while maintaining 17 °C to 23 °C to aid in agitation and transfer for filtration. The batch was stirred at 17 °C to 23 °C until complete by HPLC analysis (~20 – 40 h). The product was collected by suction filtration. The filter cake was slurry washed with CH2CI2 (3 x 50mL) at 17 °C to 23 °C (target 20 °C). The filter cake was slurry washed with purified water (3.0vol) at 65 °C to 75 °C for 2 to 3 hours. Then, the filter cake was slurry washed with purified water (3 x 1.0 vol, 3 x 1.0 wt) at 17 °C to 23°C. The wet cake was dried under vacuum with nitrogen bleed at 60 °C. Yield: 27g 5 (74% molar) >97% by weight. ¾ NMR (500 MHz, de-DMSO) 8.01 (1H, d, 4J = 2.1 Hz, RO-Ar meta- H ), 7.76 (1H, dd, J = 8.6 and 4J = 2.1 Hz, RO-Ar meta-H ), 7.14 (1H, d, J = 8.6 Hz, RO-Ar ortho- H), 3.38 (1H, br s, OH), 3.20 (3H, s,
CHJ); MS (ES-) calc. 249/251; found 249/251. Melting point (MP): (DSC) 188 °C.
[0226] The above procedure allowed for the following modifications. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as acetonitrile, tetrahydrofuran, or 2- methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from about 2X vol to about 20 X vol (with respect to Compound 4). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 1.9 equiv. Bromination reagent addition: The brominating reagent can be added all at once, portion wise in about 2 to about 20 portions, or continuously. The addition times can vary from about 0 to about 72 hours. Temperature: Reaction temperatures from about 0 °C to about 40 °C could be used. Acids: Different acids can be envisioned, including benzenesulfonic acid, para-toluenesulfonic acid, triflic acid, hydrobromic acid, and trifluoroacetic acid. Isolation: Instead of directly filtering the product and washing with methylene chloride and water, at the end of reaction an organic solvent capable of dissolving Compound 5 could be charged, followed by an aqueous workup to remove succinimide, and addition of an antisolvent or solvent exchange to an appropriate solvent to crystallize Compound 4. Drying: A temperature range of about 10 to about 60 °C could be used for drying.
[0227] An alternative process to Compound 5 has also been developed. This process is advantageous in that it does not use a chlorinated solvent, and provides additional controls over the formation of the Compound 5-a dibromo impurity. See Oberhauser, T. J Org. Chem 1997, 62, 4504-4506. The process is as follows. Compound 4 (10 g, 58 mmol) and acetonitrile (100 ml) were charged to the reactor and agitated. The batch was cooled to -20 °C. Triflic acid (CF3SO3H or TfOH, 5.5 mL, 62 mmol) was charged while maintaining a batch temperature of -10 to -25 °C. N-bromosuccinimide was charged (NBS, 11.4 g, 64 mmol), stirred at -10 to -25 °C for 30 minutes, then warmed to 20 °C over 3 to 4 hours. Agitation was continued at 15 °C to 25 °C until reaction completion. If the reaction conversion plateaued before completion, the reaction was cooled to -5 to -15 °C, and additional NBS was added, the amount based off of unreacted starting material, followed by warming to 15 °C to 25 °C and reacting until complete.
[0228] After reaction completion, the batch was warmed to 40 °C to 50 °C and concentrated under reduced pressure to 40 mL. The batch was cooled to -5 °C to -15 °C and the resulting product solids were filtered off. The solids were slurry washed three times, each with 20 mL water, for at least 15 minutes. The final cake was dried at 50 °C to 60 °C under reduced pressure to furnish 10 g of 5 containing less than 0.1% MeCN, 0.07% water, and 0.1% triflic acid (TfOH) by weight.
[0229] Alternatives to the above procedure employing MeCN and TfOH are as follows. Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination Reagent Stoichiometry: Different amounts of the brominating reagent can be used, from about 0.8 equiv to about 2 equiv. Drying: A temperature range of about 10 °C to about 60 °C could be used for drying.
[0230] The impurity 5-a is was prepared and characterized as follows. 10 g of Compound 4 and sulfuric acid (35 mol%) were dissolved in MeOH (10 vol). The mixture was set to stir at 20 °C to 25 °C for 5-10 min and 2.0 equivalents of NBS were charged in one portion. The resulting yellow mixture was stirred for three days at 20-25 °C. The batch was concentrated under reduced pressure and the resulting solid was slurried in water at 95-100 °C for 3 hours. After a second overnight slurry in CH2CI2 at room temperature, the batch was filtered and dried to give a white solid 5-a (15.0 g, 78%). ¾ NMR (500 MHz, de-DMSO), 8.05 (2H, s, ArH), 3.40 (1H, br s, HO-Ar), 3.28 (3H, s, CH3); MS (ES‘) calc. 327/329/331; found
327/329/331; MP (DSC): 226 °C (onset 221 °C, 102 J/g); lit. 224-226 °C.
1.2: O-alkylation of 5 to produce 6
[0231] Compound 6 was prepared according to Scheme 7 below.
Scheme 7: O-alkylation of 5 to produce 6
[0232] Compound 5 (100 g, 398 mmol) and methyl ethyl ketone (MEK, 700 mL) were charged to the reaction vessel and agitated. Potassium carbonate (K2CO3, 325 mesh 82.56 g, 597 mmol) was then charged to the stirred reaction vessel at 15 °C to 25 °C.
Bromomethylcyclopropane (64.4 mL, 664 mmol) was charged to the reaction vessel over at least 1 hour, maintaining the temperature between 15 °C to 25 °C. MEK (200 mL) was added into the reactor and the reactor heated to 65 to 75 °C. The contents of the reaction vessel were stirred at 65 to 75°C for approximately 10 hours until reaction was complete by HPLC analysis. Water (3.0 vol, 3.0wt) was charged to the vessel maintaining the temperature at 65 to 75 °C. The batch was stirred at 65 to 75 °C. The phases were allowed to separate at 65°C to 75 °C and the lower aqueous phase was removed. Water (300 mL) was charged to the vessel maintaining the temperature at 65 °C to 75 °C. The batch was agitated for at least 10 minutes at 65 to 75 °C. The phases were allowed to separate at 65 °C to 75 °C and the lower aqueous phase was removed. The water wash was repeated once. The temperature was adjusted to 40 to 50°C. The mixture was concentrated to car. 500 mL under reduced pressure. The mixture was distilled under reduced pressure at up to 50 °C with MEK until the water content was <1.0% w/w. n-heptane (500mL) was charged to the vessel maintaining the temperature at 40 to 50 °C. The mixture was continuously distilled under vacuum with n-heptane (300mL), maintaining a 1L volume in the reaction vessel. Compound 6 seeds (0.0 lwt) were added at 40 to 50 °C. The mixture was continuously distilled under reduced pressure at up to 50 °C with n-heptane (300mL) while maintaining 1L volume in the reactor. The batch was cooled to 15 to 25 °C and aged for 2 hours. The product was collected by suction filtration. The filter cake was washed with a solution of 10% MEK in n-heptane (5vol) at 15 to 25°C. The filter cake was dried under reduced pressure at up to 40 °C under vacuum with nitrogen flow to afford 95g of 6. 1H NMR (500 MHz, de-DMSO) 8.07 (1H, d, 4J = 2.2 Hz, ArH), 7.86 (1H, d, J = 8.7 Hz, meta-ArH), 7.29 (1H, d, J = 8.8 Hz, ortho-AiK),
4.04 (2H, d, J = 6.9 Hz, OCH2CH), 3.21 (3H, s, CH3), 1.31-1.24 (1H, m, OCH), 0.62- 0.58 (2H, m, 2 x CHCHaHb), 0.40-0.37 (2H, m, 2 x CHC¾Hb); MS (ES+) calc. 305/307; found 305/307; MP: (DSC) 93 °C.
[0233] The following modifications of the above reaction, synthesis of 6 from 5, may be employed as well. Solvent: Different solvents could be used, for example acetone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, or 2-methyl tetrahydrofuran. Reaction volume: Reaction volumes of 3 to 30 volumes with respect to 3 could be used. Base: Different inorganic bases, such as cesium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Also, organic bases, such as trimethylamine or diisopropyldiimide could be used. Base particle size: Different particle sizes of potassium carbonate from 325 mesh could be used. Reaction temperature: A lower temperature, such
as 50 °C could be used. A higher temperature, such as about 100 °C could be used. Any temperature above the boiling point of the solvent could be run in a pressure vessel.
Isolation: Different solvent ratios of MEK to n-heptane could be used. Different amounts of residual water can be left. Different amounts of seeds, from 0 to 50% could be used.
Seeding could take place later in the process and/or at a lower temperature. An un-seeded crystallization can be employed. A different isolation temperature, from 0 °C to 50 °C could be used. A different wash could be used, for example a different ratio of MEK to n-heptane. A different antisolvent from n-heptane could be used, such as hexane, pentane, or methyl tert-butyl ether. Alternatively, the batch could be solvent exchanged into a solvent where Compound 3 has a solubility of less than 100 mg/ml and isolated from this system. Drying: A temperature range of 10 to 60 °C could be used for drying.
[0234] Compound 10, shown below may also be formed as a result of O-alkylation of unreacted 4 present in product 5, or alternatively from or via a palladium mediated proteodesbromination or proteodesborylation in subsequent chemistry discussed in Example 1.3 below.
[0235] Preparation of methylsulfonylphenyl(cyclopropylmethyl) ether 10: Compound 4 (0.86 g, 5.0 mmol) and K2CO3 (1.04 g, 7.5 mmol) were slurried in acetone (17 mL, 20 vols). Cyclopropylmethyl bromide (0.73 mL, 7.5 mmol) was added in several small portions over ~1 minute and the reaction mixture heated to 50 °C for 48 hours, then cooled to 25 °C. Water (5.0 mL) was added with stirring and the acetone was evaporated on a rotary evaporator from which a fine white solid formed which was filtered off and returned to a vessel as a damp paste. A 1 : 1 mixture of MeOH/ water (8 mL) was added and heated to 40 °C with stirring. After 1 hour, the white solid was filtered off. Some residual solid was washed out with fresh water that was also rinsed through the cake, which was then isolated and left to air dry over the two days to give a dense white solid 10 (1.00 g, 88%). ¾ NMR (500 MHz, CDCb) 7.85
(2H, d, J = 8.8 Hz, RO-Ar ortho-H), 7.00 (2H, d, J = 8.8 Hz, RO-Ar meta- H), 3.87 (2H, d, J = 7.0 Hz, OCH2CH), 3.02 (3H, s, CHs), 1.34-1.23 (1H, m, OCH2CH), 0.72-0.60 (2H, m, 2 x CHCHflHb), 0.42-0.31 (2H, m, 2 x CHCH^.
1.3: Synthesis and Isolation Coupling Partner Boronic Ester 2
[0236] The final bond forming step to Compound 1 is a Suzuki-Miyaura coupling between Compounds 2 and 3, as shown in Scheme 3 below (Norio, M. and Suzuki, A., Chem. Rev., 95(7), 2457-2483 (1995)). Early studies demonstrated that the boronic ester of the isoquinolinone Compound 3-a had poor physical attributes and solid phase stability (Kaila, N. et al., J. Med Chem., 57: 1299-1322 (2014)). The pinacolatoboronate of the O-alkyl phenol, Compound 7, had acceptable solid phase stability and could be isolated via crystallization.
Scheme 3: Suzuki-Miyaura coupling between 2 and 3
[0237] Process robustness studies for the isolation of Compound 7, however, indicated that Compound 7 has poor solution stability, decomposing primarily to the proteodeborylated compound 10, as shown in Scheme 4 below. This was particularly problematic as the isolation process involved a solvent exchange from 2-MeTHF (2-methyl tetrahydrofuran) to iPrOAc (isopropyl acetate), which is not a fast unit operation on scale.
Scheme 4: Modification of 7
[0238] A search for a more stable boronic ester was undertaken. Early attempts targeted making N-methyliminodiacetic acid (MID A) boronate Compound 2-a (E. Gilis and M. Burke,“Multi step Synthesis of Complex Boronic Acids from Simple MIDA Boronates,” J Am. Chem. Soc., 750(43): 14084-14085 (2008)), however, all attempts resulted in product decomposition. Applicant then turned to a relatively obscure boronate formed by the addition of diethanolamine to Compound 7 (Bonin et al., Tetrahedron Lett., 52: 1132-1135 (2011)). Addition of diethanolamine to a solution of Compound 7 led to rapid ester formation and concomitant crystallization of Compound 2.
[0239] The discovery of boronic ester Compound 2 allowed for a simple, fast, high-yielding, high-purity process comprising the following procedure. Tetrahydrofuran (THF, 1500mL) was charged to a flask containing Compound 6 (100g, 328 mmol), bis(pinacolato)diboron (90.7g, 357 mmol) and cesium acetate (CsOAc, 158g, 822 mmol). The system was vacuum purged three times with nitrogen. Pd(PPh3)2Cl2 (13.8g, 20 mmol) was charged to the reaction and the system was vacuum purged three times with nitrogen. The reaction was then heated to 55 to 65°C.
[0240] The batch was stirred for approximately 8 hours until reaction was complete by HPLC analysis. The batch was cooled to 15 to 25 °C (target 20 °C ) and charged with silica gel (20g) and Ecosorb C-941 (20g). After lh, the mixture was filtered to remove solid. The residual solids were washed twice, each with THF (300mL). The filtrate and washes were combined. In a separate vessel, diethanolamine (34.5mL, 360 mmol) was dissolved in THF (250 mL). The diethanolamine solution in THF (25mL) was then charged to the batch. After 10 minutes, the batch was seeded with 2 (1 g) and aged for 1 to 2 hours. The remaining of the diethanolamine solution in THF was charged to the batch over at least 2 hours and the slurry was stirred for at least 2 hours. The product 2 was collected by suction filtration. The wet cake was washed thrice with THF (200mL). The material was dried under vacuum at 40 °C with nitrogen purge yielding 94.6g of 2.
[0241] The reaction to synthesize Compound 2 from Compound 6 described above may be modified as follows. Solvent: Different solvents from THF could be used, such as 1,4 dioxane or 2-methyltetrahydrofuran. Reaction volume: The reaction volume can be varied from 4 to 50 volumes with respect to compound 2. Catalyst and base: Different palladium catalyst and bases can be used for the borylation. Examples can be found in Chow et al., RSC Adv., 3 : 12518-12539 (2013). Borylation reaction temperature: Reaction temperatures from room temperature (20 °C) to solvent reflux can be used. Carbon/ Silica treatment:
The treatment can be performed without silica gel. The process can be performed without a carbon treatment. Different carbon sources from Ecosorb C-941 can be used. Different amounts of silica, from 0.01X to IX weight equivalents, can be used. Different amounts of Ecosorb C-941, from 0.01X to IX weight equivalents, can be used. Crystallization: A different addition rate of diethanolamine can be used. Different amounts of diethanolamine, from 1.0 to 3.0 molar equivalents can be used. A different cake wash with more or less THF can be used. Different amount of seeds from 0.0001X wt to 50X wt can be used.
Alternatively, the process can be unseeded. Drying: A temperature range of 10 °C to 60 °C could be used for drying.
[0242] The subsequent Suzuki-Miyaura coupling between Compounds 2 and 3 also proceeded well, providing over 20 kg of crude compound 1 with an average molar yield of 80% and LCAP of 99.7%.
1.4: Synthesis of Coupling Partner 3
[0243] Cross-coupling partner 3 was prepared by two different processes corresponding to Schemes 8 and 9 shown below.
Scheme 8: Process A for preparation of 3
[0244] According to Process A, Compound 9 (100g, 628 mmol) was dissolved in acetonitrile (450 mL) at room temperature. In a separate vessel, N-bromosuccinimide (NBS, 112g, 628 mmol) was suspended in acetonitrile (1 L). Compound 9 in acetonitrile was charged to the NBS slurry over at least 45 minutes. The contents of the reaction vessel were warmed to 45 °C to 55 °C and the batch stirred until the reaction was complete by HPLC analysis. The batch was cooled to 35 °C to 45 °C and ensured dissolution. Norit SX plus carbon (lOg) was charged to the mixture and the reaction mixture adjusted to 55 °C to 60 °C. The mixture was stirred at 55 °C to 60 °C for about lh and the mixture filtered at 55 °C to 60 °C to remove solids. The solids were washed with acetonitrile (500mL) at 55 °C to 60 °C. The volume of the combined filtrate was reduced to 900 mL by distilling off acetonitrile under reduced pressure. The batch with Compound 3 (lg) and stirred at 35 °C to 45 °C for at least 60 minutes. The contents of the reaction vessel were cooled to 15 °C to 25 °C over at least 1 hour. Water (2000 mL) was charged to the reaction vessel over at least 90 minutes and the slurry aged for at least 60 minutes. The product was collected by suction filtration. The cake was washed with a premixed 5% solution of acetonitrile in water (300mL). The wet cake was dried under vacuum at 40 °C with nitrogen purge. Yield: 120g of 3.
[0245] The above procedure, Process A for this synthesis of 3, may be practiced with alternative reagents and conditions as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 9). Brominating agents: Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent Stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 °C to 60 °C could be used for drying.
Scheme 9: Process B for preparation of 3
[0246] According to Process B, Compound 3 can be formed starting from 8 via non-isolated compound 9 as follows. Compound 8 (80 g, 55 mmol), cesium carbonate (CS2CO3, 215 g, 66 mmol), and acetonitrile (800 mL) were charged to the reactor. The temperature was adjusted from 15 to 25 °C and iodomethane charged to the reactor (Mel, 86 g, 0.61 mol) while maintaining a batch temperature below 25 °C. The batch was heated to 40 °C and agitated for 10 hours to form Compound 9. The batch was cooled to 25 °C, filtered into a fresh reactor to remove solids, and the solids washed twice with acetonitrile. The combined organic layers were concentrated via atmospheric distillation to about 320 mL.
[0247] In a separate reactor N-bromosuccinimide (NBS, 98.1 g, 0.55 mol) was charged to acetonitrile (800 mL) and agitated. The batch containing Compound 9 was transferred to the NBS solution while maintaining a batch temperature of 15 to 25 °C. The batch was heated to 45 to 55 °C and agitated for at least 4 hours to allow for reaction completion to Compound 3. Upon reaction completion, Norit SX Plus activated carbon (8 g) was charged, and agitated at 45 to 55 °C for one hour. The batch was filtered into a fresh vessel, the Norit SX plus cake was washed with 400 ml of 45 to 55 °C acetonitrile. The acetonitrile layers were combined, cooled to 35 to 45 °C, and distilled under reduced pressure to 720 mL. The batch was adjusted to a temperature of 40 °C, charged with Compound 3 seeds (0.8 g), agitated for one hour, cooled to 15 to 25 °C over at least on hour, then charged with water (1600 mL) over at least two hours. The mixture was agitated for an additional one to two hours, filtered, the cake washed with a premixed 5% solution of acetonitrile in water (240 mL). The wet cake was dried under vacuum at 40°C with nitrogen purge. Yield: 52 g of 3.
[0248] Process B to synthesize Compound 3, described above, may be modified as follows. Solvents: Alternative solvents could be used. Examples include chlorinated solvents, such as methylene chloride, chloroform or 1,2 dichloroethane, and non-chlorinated solvents such as tetrahydrofuran, or 2-methyltetrahydrofuran. Reaction concentration: The reaction concentration can be varied from 2X vol to 40 X vol (with respect to Compound 8).
Alkylating reagent: Alternative methylating reagents to methyl iodide can be used such as dimethylsulfate. Alkylating reagent stoichiometry: 1 to 10 molar equivalents of methyl iodide may be used. Base: Different inorganic bases, such as potassium carbonate or phosphate bases (sodium, potassium, or cesium) could be used. Brominating agents:
Additional brominating reagents include bromine and l,3-dibromo-5,5-dimethylhydantoin. Bromination reagent stoichiometry: Different amounts of the brominating reagent can be used, from 0.8 equiv to 2 equiv. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. Seeding levels from 0.0001% to 50% can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying.
1.5: Cross-coupling of 2 and 3 to Produce Target Compound 1
[0249] 1 is synthesized by Suzuki cross-coupling of 3 and 2 according to Scheme 10 and as described below.
Scheme 10: Synthesis of 1
[0250] Acetonitrile (1.6L) was charged to a mixture of Compound 2 (156.7g, 460 mmol), Compovmd 3 (lOOg, 420 mmol) and potassium phosphate tribasic (223 g, l.OSmol). Agitation was begun and water (400mL) charged to the batch. The system was vacuum purged three times with nitrogen and charged with Pd(PPh3)2Cl2 (2.9g, 4 mmol) and the system vacuum
purged three times with nitrogen. The batch was heated to 65 to 75°C and contents stirred for at least 16 hours until reaction was complete by HPLC analysis. The batch was cooled to 60 to 70°C, agitation halted and the mixture allowed to settle. The bottom aqueous layer was removed. Water (150mL) and acetonitrile (700mL) were charged at 60 to 70°C. Ecosorb C-941 (15g) and Celite (lOg) were charged to the reaction vessel at 60 to 70°C. After lh, the mixture was filtered to remove solids. The solids were washed twice each with 18% water in acetonitrile (500 mL) at 60 to 70°C. The filtrates were combined and concentrated under atmospheric pressure to a final volume of 1.5L. The batch was cooled to 60 to 65°C and seeded with Compound 1 (1 g). After lh, water (500 mL) was charged over at least 1 hour at 60 to 65°C. The slurry was cooled to 15 to 25°C over 4 hours. The product was collected by suction filtration. The wet cake was washed with 45% water in acetonitrile (500mL) twice. The product was dried under vacuum at 40°C with nitrogen purge. Yield: 139g of 1.
[0251] The above procedure for coupling Compound 3 and Compound 2 to produce
Compound 1 may be modified in any of the ways that follow. Reaction solvents: Different reaction solvents from acetonitrile can be used, including tetrahydrofuran, 2-methyl tetrahydrofuran, toluene, and isopropanol. Boronic ester: Different boronic esters from Compound 2 can be used, including pinacolato ester compound 7, and the free boronic acid of Compound 2. Examples of boronic esters can be found in Lennox, Alister, J.J., Lloyd-Jones, Guy C. Chem. Soc. Rev., 2014, 43, 412. Carbon treatment: Different carbon treatments from Ecosorb C-941 could be used. Different amounts of carbon, from 0.01 to 0.5X weight can be used. The carbon can be eliminated. Different amounts of Celite, from 0.01 to 0.5X weight can be used. Crystallization: Different amounts of water, including 5 volumes to 50 volumes can be used. The crystallization can also proceed without the addition of seeds. Different water addition times and final hold times can be used. Different wash procedures can be used. Drying: A temperature range of 10 to 60 °C could be used for drying. Catalysts: Different metal and ligand combination could be used. Examples of metal/ligand combinations can be found in Maluenda, Irene; Navarro, Oscar, Molecules, 2015, 20, 7528. Various catalysts can be including: XPhos-3G (cas# 1445085-55-1);
cataCXium® A Pd 3G (CAS# 1651823-59-4); PdCk(DtBPF) (CAS# 95408-45-0); SPhos 3G (Cas# 1445085-82-4); AmPhos 3G (Cas# 1820817-64-8); PCy3 3G (Cas# 1445086-12-3); Pd PEPPSI IPent Cas#l 158652-41-5); Pd(PPh3)2Cl2 (Cas# 13965-03-2). Examples of
catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.
Table 4: Catalyst screen summary
1.6: Crystallization of 1
[0252] The final isolation of Compound 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH
Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).
catalyst systems that have been demonstrated to afford Compound 1 are listed below in Table 4 using boronic esters 2 or 7 in coupling to 3.
Table 4: Catalyst screen summary
1.6: Crystallization of 1
[0252] The final isolation of Compoxmd 1 requires a polish filtration. For this, the batch must be completely soluble. Unfortunately, Compound 1 has low solubility in almost all
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Class 3 and common Class 2 (e.g. THF, MeCN) solvents (ICH
Harmonized Guideline“Impurities: Guideline for Residual Solvents Q3C(R6)” October 20, 2016). A reasonable solubility was obtained in a warm MeCN-water mix, but this is not an optimal system (requires a heated filtration, MeCN has a residual solvent limit of only 410 ppm). Additional solvents with reasonable solubility (>50 mg/ml) include N-methyl-2- pyrrolidone (NMP) and dimethylacetamide (DMAc); but the development of isolations from these solvents required large volumes and raised residual solvent limit concerns (530 ppm or less for NMT and 1090 ppm or less for DMAc).
[0253] Formic acid is one ICH Class 3 solvent in which Compound 1 is highly soluble, having a solubility greater than 250 mg/ml at 20 °C. The solubility curve of Compound 1 in formic acid-Water is quite steep (see Figure 7), which enables a volumetrically efficient process.
[0254] Initial attempts to recrystallize crude Compound 1 involved dissolving in formic acid, polish filtering, and charging polish filtered water to about 20% supersaturation, followed by seeding with the thermodynamically most stable form (Form 1), followed by slow addition of water to the final solvent ratio, filtration, washing, and drying. Applicant observed that during the initial water charge, if the batch self-seeded it formed a thick slurry. X-ray diffraction (XRD), differential scanning calorimetry (DSC), and photomicroscopy demonstrated that a metastable form was produced. Once seeded with Form 1, the batch converted to the desired form (Form 1) prior to the addition of the remaining water. This process worked well during multiple lab runs, consistently delivering the desired form and purity with about 85% yield.
[0255] Unfortunately, upon scale-up, the batch did not convert to Form 1 after seeding. Additional water was charged and the batch began to convert to the desired form (mix of Form 1 and the metastable form by X-ray powder diffraction (XRPD)). When additional water was charged, the XRPD indicated only the metastable form. After a few hours with no change, Applicant continued the water charge to the final solvent ratio, during which time the batch eventually converted to Form 1. This process is summarized in Figure 8.
[0256] It was subsequently found by closer analysis of the plant and laboratory retains that a new metastable form was formed during scale up, with a similar, but different XRPD pattern. This form (metastable B) could be reproduced in the laboratory, but only when the batch has a high formic acid:water ratio and is seeded with Form 1. Without Form 1 seeds, metastable A is the kinetic form. Both metastable forms converted to Form 1 with additional water and/or upon drying, leading Applicant to believe that the metastable forms are formic acid solvates. These findings are summarized in Figure 9.
[0257] While there is little risk in not being able to control the final form, there is a risk of forming a difficult-to-stir slurry which can lead to processing issues. The crystallization procedure was therefore modified to keep a constant formic acid-water ratio. This was performed by charging 2.4X wt. formic acid and 1.75X wt. water (final solvent composition)
to the crystallizer with 0.03X wt. Form 1 seeds, and performing a simultaneous addition of Compound 1 in 6. IX wt. formic acid and 4.4X wt. water. The batch filtered easily and was washed with formic acid/water, then water, and dried under reduced pressure to yield 8.9 kg of Compound 1 (92% yield) with 99.85% LCAP and N.D. formic acid.
Example 2: Exemplary high throughput experimentation reaction
[0258] The following procedure is an exemplary high throughput experimentation reaction.
[0259] An overview of the reaction is shown below in Scheme 5:
Scheme 5: Reaction conditions tested for cross-coupling reaction of 2 and 3
[0260] Pd catalysts were dosed into the 24-well reactor vial as solutions (100 pL of 0.01 M solution in tetrahydrofuran (THF) or dichloroethane (DCE) depending upon the solubility of the ligand). Plates of these ligands are typically dosed in advance of the reaction, the solvent is removed by evacuation in an evaporative centrifuge and plates are stored in the glovebox. The catalysts screened in the coupling are the following: XPhos, SPhos, CataCXium A, APhos, P(Cy)3, PEPPSI-IPent. For the first five ligands, these were initially screened as the Buchwald Pd G2/G3 precatalysts.
[0261] To the plates was then added a stock solution of Compound 3 (10 pmol) and Compound 2 (12 pmol) dissolved in the following solvents: dimethylformamide (DMF),
tetrahydrofuran (THF), butanol (/r-BuOH), and toluene. The base was then added as a stock solution (30 mmol) in 20 mL of water.
[0262] A heatmap summarizing catalyst performance is shown in Figs. 10A and 10B. High performance liquid chromatography (HPLC) yields for this screening span from <5% up to -85%. Larger circles indicate higher yield. Lighter circles indicate higher cleanliness.
[0263] A similarly designed screening of base and solvent also indicate that a range of alcoholic solvents (methanol, ethanol, propanol, 2-butanol, 2-propanol, and /-amyl alcohol) are also all viable in this coupling chemistry. Bases such as potassium phosphate, potassium carbonate, potassium acetate, and potassium hydroxide were all successful in achieving the coupling. Fig. 10B shows a heatmap with HPLC yields ranging from -50 – 95%. Larger, darker circles indicate higher yield.
[0264] This chemistry from microvial screening has been scaled to a laboratory process. To a 3 -necked jacketed 250 mL flask equipped with overhead stirring, nitrogen inlet, and thermocouple was added Compound 3 (1.0 eq, 4.00 grams), Compound 2 (1.2 eq, 1.71 x wt), potassium carbonate (3.0 eq, 1.74 x wt). The reactor was inerted three times and then degassed 2-propanol (24 x vol.) followed by degassed water (6 x vol) was then added.
Stirring was then initiated at 300 rpms. The reactor was then stirred and blanketed with nitrogen for 1 hour. The catalyst was then added (0.01 eq, 0.028 x wt) and stirring continued (300 rpms) and the reactor was heated into the Tj = 65 °C.
[0265] After 2 hours, with full conversion confirmed analytically, trioctylphosphine (0.1 eq, 0.16 x wt) dosed, and reaction mixture allowed to cool slowly to room temperature hours.
The reaction mixture was then filtered, washed with 2-propanol (4 x vol), 2-propanol: water (4: 1, 4 x vol), and then with water (4 x vol). Note: If 2 is dimer present in cake, an additional ethyl acetate (EtOAc) wash (4 x vol) can be added for purging. The cake was then transferred to a vacuum oven to dry overnight at 40 °C, -40 cm Hg, under nitrogen flow. After transfer to a bottle, 6.03 grams of 1 were isolated, 98.6% assay, 91% overall yield.
Scheme 6: Alternative reagents and solvents for cross-coupling
[0266] Based on the previously delineated results, it was expected that a variety of monodentate (PPI13 [triphenylphosphine], PBu3 [tributylphosphine], etc) and bidentate phosphines (dppf [1,1 ‘-bis(diphenylphosphino)ferrocene], BINAP [2,2 -bis(diphenylphosphino)- 1 , 1 -binaphthyl], Xantphos [4,5-bis(diphenylphosphino)-9,9-dimethylxanthene], dppe [l,2-bis(diphenylphosphino)ethane], etc) ligated to any number of Pd sources (Pd halides, Pd(H) precatalyts, Pd(0) sources) could reasonably be employed to arrive at the Compound 1 crude material. A range of organic solvents ranging from non-polar (heptane, benzene), protic (alcohols), polar aprotic (dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile) as well as a variety of esters and ketones (acetone, 2-butanone, ethylacetate) should also serve as effective solvents for this reactivity. Finally, inorganic bases of varying strength (phosphates, carbonates, acetates, etc) along with organic variants such as triethylamine, l,8-diazabicyclo(5.4.0)undec-7-ene, and others in a wide pKa range are viable as stoichiometric basic additives.
Example 3: Exemplary Compound 5 process
[0267] The purpose of this example was to describe an exemplary process for making Compound 5.
[0268] Charge 4 (lOg, 58mmol) and acetonitrile (lOOmL) to a reaction vessel and start the stirrer. Adjust the batch to -18 °C to -22 °C (target -20 °C). Charge triflic acid (5.5mL, 62mmol) to the batch maintaining -10 °C to -25 °C (target -20 °C). Stir the batch at -10 °C to -25 °C (target -20 °C) for 10 to 20 minutes. Charge NBS (11.38g, 64mmol) to the batch at -10 °C to -25 °C (target -20 °C) and stir for ca. 30 min at -10 °C to -25 °C (target -20 °C). Warm the batch to 20 °C over 3-4 hours (reaction will occur when internal temp is between 5 °C and 15 °C). Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and sample for reaction completion.
[0269] If Compound 4 relative to Compound 5 is more than 5%:
[0270] Cool the bath to -5 °C to -15 °C (target -10 °C) (cooling below 0 °C to ensure selectivity). Charge NBS to the batch according to the follow formula: Mass of NBS = (% Compound 4 x lOg). Warm the batch to 20 °C over 1-2 hours. Stir the batch at 15 °C to 25 °C (target 20 °C) for approximately 1 hour and check reaction for completion. Proceed to next line.
[0271] If Compound 4 relative to Compound 5 is less than 5%:
[0272] Warm the batch to 40 °C to 50 °C (target 48 °C). Concentrate the batch under reduced pressure to a final volume of ~40mL. Cool the batch to -15 °C to -5 °C (target -10 °C) and stir for ca. lh. Filter the batch by suction filtration. Slurry wash the filter cake with purified water (3 x 20mL) at 15 °C to 25 °C (target 20 °C) for 10 to 15 minutes each wash. Remove a sample of the filter cake for analysis by ¾ NMR. Continue washing cake until the residual succimide is below 1.0%mol% relative to 5. Dry the filter cake at up to 60°C under vacuum and nitrogen purge. Analyse the 5 by HPLC analysis (97%w/w to 99%w/w). Expected yield: 60-85% theory (90-110% w/w).
Example 4: Purification of Compound 1 (CC-90010) by crystallization from formic acid and water.
[0273] This example describes a method for the purification of Compound 1 by
crystallization from formic acid and water. Also detailed are methods for obtaining three different polymorphs of Compound 1, including the most stable form, Form 1.
[0274] Figure 11 shows XH NMR of Compound 1 (CC-90010). Solvent: d6DMSO; and Figure 12 shows microscopy of Compound 1 (CC-90010) Form I. Figure 13 shows XRPD of Compound 1 (CC-90010) Form I, with peak information detailed in Table 6:
PATENT
US 20190008852
WO 2018081475
US 20180042914
WO 2016172618
WO 2015058160
/////////CC-90010, solid tumors , non-Hodgkin’s lymphoma, PHASE 1, CANCER, QUANTICEL
CS(=O)(=O)c4cc(C1=CN(C)C(=O)c2ccccc12)c(OCC3CC3)cc4
Delgocitinib
Delgocitinib
デルゴシチニブ
3-[(3S,4R)-3-methyl-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,7-diazaspiro[3.4]octan-1-yl]-3-oxopropanenitrile
1,6-Diazaspiro(3.4)octane-1-propanenitrile, 3-methyl-beta-oxo-6-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)-, (3S,4R)-
3-((3S,4R)-3-methyl-6-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)-1,6-diazaspiro(3.4)octan-1-yl)-3-oxopropanenitrile
| Formula |
C16H18N6O
|
|---|---|
| CAS |
1263774-59-9
|
| Mol weight |
310.3537
|
Approved, Japan 2020, Corectim, 2020/1/23, atopic dermatitis, Japan Tobacco (JT)
Torii
7/23/2025 fda approved, Anzupgo
| To treat moderate-to-severe chronic hand eczema when topical corticosteroids are not advisable or produce an inadequate response |
UNII-9L0Q8KK220, JTE-052, LP-0133, ROH-201, 9L0Q8KK220, LEO 124249A, LEO 124249, HY-109053
CS-0031558, D11046, GTPL9619, JTE-052A, JTE052
Delgocitinib, also known as LEO-124249 and JTE052, is a potent and selective JAK inhibitor. JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation.
Delgocitinib is a JAK inhibitor first approved in Japan for the treatment of atopic dermatitis in patients 16 years of age or older. Japan Tobacco is conducting phase III clinical trials for the treatment of atopic dermatitis in pediatric patients. Leo is developing the drug in phase II clinical trials for the treatment of inflammatory skin diseases, such as atopic dermatitis, and chronic hand eczema and for the treatment of discoid lupus erythematosus. Rohto is evaluating the product in early clinical development for ophthalmologic indications.
In 2014, the drug was licensed to Leo by Japan Tobacco for the development, registration and marketing worldwide excluding Japan for treatment of inflammatory skin conditions. In 2016, Japan Tobacco licensed the rights of co-development and commercialization in Japan to Torii. In 2018, Japan Tobacco licensed the Japanese rights of development and commercialization to Rohto for the treatment of ophthalmologic diseases.
Delgocitinib, sold under the brand name Corectim among others, is a medication used for the treatment of autoimmune disorders and hypersensitivity, including inflammatory skin conditions.[3] Delgocitinib was developed by Japan Tobacco and approved in Japan for the treatment of atopic dermatitis.[3] In the United States, delgocitinib is in Phase III clinical trials and the Food and Drug Administration has granted delgocitinib fast track designation for topical treatment of adults with moderate to severe chronic hand eczema.[4]
Delgocitinib works by blocking activation of the JAK-STAT signaling pathway which contributes to the pathogenesis of chronic inflammatory skin diseases.[5]
PATENTS
WO 2018117151
IN 201917029002
IN 201917029003
IN 201917029000
PATENTS
WO 2011013785
https://patents.google.com/patent/WO2011013785A1/en
[Production Example 6]: Synthesis of Compound 6
(1) Optically active substance of 2-benzylaminopropan-1-ol
To a solution of (S)-(+)-2-aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) in ethanol (500 ml) was added 5% palladium carbon (5.0 g) at room temperature and normal pressure. Hydrogenated for 8 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (111.2 g).
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.27 (4H, m), 7.23-7.18 (1H, m), 4.53-4.47 (1H, m), 3.76 (1H, d, J = 13.5 Hz) , 3.66 (1H, d, J = 13.5 Hz), 3.29-3.24 (2H, m), 2.65-2.55 (1H, m), 1.99 (1H, br s), 0.93 (3H, d, J = 6.4 Hz) .
(2) Optically active substance of [benzyl- (2-hydroxy-1-methylethyl) -amino] acetic acid tert-butyl ester
To a mixture of optically active 2-benzylaminopropan-1-ol (111.2 g), potassium carbonate (111.6 g) and N, N-dimethylformamide (556 ml) cooled to 0 ° C., tert-butyl bromoacetate was added. Ester (109 ml) was added dropwise over 20 minutes and stirred at room temperature for 19.5 hours. The mixture was acidified to pH 2 by adding 2M aqueous hydrochloric acid and 6M aqueous hydrochloric acid, and washed with toluene (1000 ml). The separated organic layer was extracted with 0.1 M aqueous hydrochloric acid (300 ml). The combined aqueous layer was adjusted to pH 10 with 4M aqueous sodium hydroxide solution and extracted with ethyl acetate (700 ml). The organic layer was washed successively with water (900 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted again with ethyl acetate (400 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (160.0 g).
1 H-NMR (DMSO-D 6 ) δ: 7.37-7.26 (4H, m), 7.24-7.19 (1H, m), 4.26 (1H, dd, J = 6.9, 3.9 Hz), 3.76 (1H, d, J = 14.1 Hz), 3.68 (1H, d, J = 13.9 Hz), 3.45-3.39 (1H, m), 3.29-3.20 (1H, m), 3.24 (1H, d, J = 17.2 Hz), 3.13 ( 1H, d, J = 17.0 Hz), 2.84-2.74 (1H, m), 1.37 (9H, s), 0.96 (3H, d, J = 6.8 Hz).
(3) Optically active substance of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester
(3)-(1) Optically active form of [benzyl- (2-chloro-1-methylethyl) -amino] acetic acid tert-butyl ester
To a solution of [benzyl- (2-hydroxy-1-methylethyl) -amino] acetic acid tert-butyl ester optically active substance (160.0 g) cooled to 0 ° C. in chloroform (640 ml) was added thionyl chloride (50.0 ml). Was added dropwise and stirred at 60 ° C. for 2 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution (1000 ml) and chloroform (100 ml) were added and stirred. The separated organic layer was washed with a saturated aqueous sodium chloride solution (500 ml), and the aqueous layer was extracted again with chloroform (450 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (172.9 g).
1 H-NMR (CDCl 3 ) δ: 7.40-7.22 (5H, m), 4.05-3.97 (0.4H, m), 3.93-3.81 (2H, m), 3.70-3.65 (0.6H, m), 3.44- 3.38 (0.6H, m), 3.29 (0.8H, s), 3.27 (1.2H, d, J = 2.4 Hz), 3.24-3.15 (0.6H, m), 3.05-2.99 (0.4H, m), 2.94 -2.88 (0.4H, m), 1.50 (1.2H, d, J = 6.4 Hz), 1.48 (3.6H, s), 1.45 (5.4H, s), 1.23 (1.8H, d, J = 6.8 Hz) .
(3)-(2) Optically active form of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester
[Benzyl- (2-chloro-1-methylethyl) -amino] acetic acid tert-butyl ester optically active substance (172.9 g) was dissolved in N, N-dimethylformamide (520 ml) and stirred at 80 ° C. for 140 minutes. did. The reaction mixture was cooled to 0 ° C., water (1200 ml) was added, and the mixture was extracted with n-hexane / ethyl acetate (2/1, 1000 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted again with n-hexane / ethyl acetate (2/1, 600 ml). The combined organic layers were concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 50/1 to 40/1) to give the title compound (127.0 g )
1 H-NMR (CDCl 3 ) δ: 7.37-7.29 (4H, m), 7.28-7.23 (1H, m), 4.05-3.97 (1H, m), 3.91 (1H, d, J = 13.5 Hz), 3.86 (1H, d, J = 13.7 Hz), 3.29 (2H, s), 3.03 (1H, dd, J = 13.9, 6.6 Hz), 2.91 (1H, dd, J = 13.9, 6.8 Hz), 1.50 (3H, d, J = 6.4 Hz), 1.48 (9H, s).
(4) Optically active substance of 1-benzyl-3-methylazetidine-2-carboxylic acid tert-butyl ester
To a solution of [benzyl- (2-chloropropyl) -amino] acetic acid tert-butyl ester optically active substance (60.0 g) cooled to −72 ° C. and hexamethylphosphoramide (36.0 ml) in tetrahydrofuran (360 ml), Lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 242 ml) was added dropwise over 18 minutes, and the temperature was raised to 0 ° C. over 80 minutes. A saturated aqueous ammonium chloride solution (300 ml) and water (400 ml) were sequentially added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (500 ml), and the separated aqueous layer was extracted again with ethyl acetate (300 ml). The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50/1 to 4/1). To give the title compound (50.9 g).
1 H-NMR (CDCl 3 ) δ: 7.34-7.21 (5H, m), 3.75 (1H, d, J = 12.6 Hz), 3.70-3.67 (1H, m), 3.58 (1H, d, J = 12.6 Hz ), 3.05-3.01 (1H, m), 2.99-2.95 (1H, m), 2.70-2.59 (1H, m), 1.41 (9H, s), 1.24 (3H, d, J = 7.1 Hz).
(5) Optically active substance of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester
1-Benzyl-3-methylazetidine-2-carboxylic acid tert-butyl ester optically active substance (43.5 g) and di-tert-butyl dicarbonate (38.2 g) in tetrahydrofuran / methanol (130 ml / 130 ml) solution 20% Palladium hydroxide carbon (3.5 g) was added thereto, and hydrogenated at 4 atm for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (48.0 g).
1 H-NMR (DMSO-D 6 ) δ: 4.44 (1H, d, J = 8.8 Hz), 3.99-3.77 (1H, m), 3.45-3.37 (1H, m), 3.00-2.88 (1H, m) , 1.45 (9H, s), 1.40-1.30 (9H, m), 1.02 (3H, d, J = 7.2 Hz).
(6) Optically active substance of 3-methyl-2- (3-methyl-but-2-enyl) -azetidine-1,2-dicarboxylic acid di-tert-butyl ester
Optically active substance (48.0 g) of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester cooled to -69 ° C. and 1-bromo-3-methyl-2-butene (25.4 ml) Lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 200 ml) was added to a tetrahydrofuran solution (380 ml). The reaction mixture was warmed to −20 ° C. in 40 minutes and further stirred at the same temperature for 20 minutes. A saturated aqueous ammonium chloride solution (200 ml) and water (300 ml) were successively added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1 / 1,500 ml). The separated organic layer was washed successively with water (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 15/1 to 8/1) to give the titled compound (44.5 g).
1 H-NMR (CDCl 3 ) δ: 5.29-5.21 (1H, m), 3.77-3.72 (1H, m), 3.49-3.44 (1H, m), 2.73-2.52 (3H, m), 1.76-1.74 ( 3H, m), 1.66-1.65 (3H, m), 1.51 (9H, s), 1.43 (9H, s), 1.05 (3H, d, J = 7.3 Hz).
(7) Optically active substance of 3-methyl-2- (2-oxoethyl) azetidine-1,2-dicarboxylic acid di-tert-butyl ester
3-methyl-2- (3-methyl-but-2-enyl) -azetidine-1,2-dicarboxylic acid di-tert-butyl ester optically active substance (44.5 g) in chloroform / cooled to −70 ° C. An ozone stream was passed through the methanol solution (310 ml / 310 ml) for 1 hour. To this reaction mixture, a solution of triphenylphosphine (44.7 g) in chloroform (45 ml) was added little by little, and then the mixture was warmed to room temperature. To this mixture were added saturated aqueous sodium thiosulfate solution (200 ml) and water (300 ml), and the mixture was extracted with chloroform (500 ml). The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (95.0 g). This product was subjected to the next step without further purification.
1 H-NMR (DMSO-D 6 ) δ: 9.65 (1H, t, J = 2.6 Hz), 3.79-3.74 (1H, m), 3.45-3.40 (1H, m), 2.99-2.80 (3H, m) , 1.46 (9H, s), 1.34 (9H, s), 1.06 (3H, d, J = 7.2 Hz).
(8) Optically active substance of 2- (2-benzylaminoethyl) -3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester
To a solution of the residue (95.0 g) obtained in (7) in tetrahydrofuran (300 ml) was added benzylamine (34 ml) at room temperature, and the mixture was stirred for 2 hours. The mixture was cooled to 0 ° C., sodium triacetoxyborohydride (83.3 g) was added, and the mixture was stirred at room temperature for 1.5 hours. Water (300 ml) was added to the reaction mixture, and the mixture was extracted with n-hexane / ethyl acetate (1/3, 600 ml). The separated organic layer was washed with water (300 ml) and saturated aqueous sodium chloride solution (200 ml), and then extracted twice with 5% aqueous citric acid solution (300 ml, 200 ml) and three times with 10% aqueous citric acid solution (250 ml × 3). . The combined aqueous layers were basified to pH 10 with 4M aqueous sodium hydroxide solution and extracted with chloroform (300 ml). The organic layer was washed with a saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (46.9 g).
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.26 (4H, m), 7.22-7.17 (1H, m), 3.74-3.65 (2H, m), 3.61 (1H, t, J = 7.8 Hz) , 3.28 (1H, t, J = 7.5 Hz), 2.76-2.66 (2H, m), 2.57-2.45 (1H, m), 2.15 (1H, br s), 2.05-1.89 (2H, m), 1.42 ( 9H, s), 1.27 (9H, s), 0.96 (3H, d, J = 7.1 Hz).
(9) Optically active substance of 2- (2-benzylaminoethyl) -3-methylazetidine-2-dicarboxylic acid dihydrochloride
2- (2-Benzylaminoethyl) -3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester optically active substance (46.5 g), 4M hydrochloric acid 1,4-dioxane (230 ml) and water (4.1 ml) was mixed and stirred at 80 ° C. for 2 hours. The mixture was concentrated under reduced pressure, azeotroped with toluene, and then slurry washed with n-hexane / ethyl acetate (1/1, 440 ml) to give the title compound (30.1 g).
1 H-NMR (DMSO-D 6 ) δ: 10.24 (1H, br s), 9.64 (2H, br s), 8.90 (1H, br s), 7.58-7.53 (2H, m), 7.47-7.41 (3H , m), 4.21-4.10 (2H, m), 4.02-3.94 (1H, m), 3.46-3.37 (1H, m), 3.20-3.10 (1H, m), 2.99-2.85 (2H, m), 2.69 -2.54 (2H, m), 1.10 (3H, d, J = 7.2 Hz).
(10) Optically active substance of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octan-5-one
To a solution of 2- (2-benzylaminoethyl) -3-methylazetidine-2-dicarboxylic acid dihydrochloride optically active substance (29.1 g) and N, N-diisopropylethylamine (65 ml) in chloroform (290 ml), At room temperature, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (41.3 g) was added and stirred for 4 hours. To this reaction mixture were added saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (100 ml), and the mixture was extracted with chloroform (200 ml). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 20/1 to 10/1) to give the titled compound (21.3 g).
1 H-NMR (DMSO-D 6 ) δ: 7.38-7.31 (2H, m), 7.30-7.22 (3H, m), 4.52 (1H, d, J = 14.8 Hz), 4.29 (1H, d, J = 14.8 Hz), 3.35-3.27 (2H, m), 3.22-3.17 (1H, m), 3.05 (2H, dd, J = 9.5, 4.0 Hz), 2.77-2.66 (1H, m), 2.16-2.10 (1H , m), 1.96-1.87 (1H, m), 0.94 (3H, d, J = 7.1 Hz).
(11) Optically active substance of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester
Concentrated sulfuric acid (4.8 ml) was slowly added dropwise to a suspension of lithium aluminum hydride (6.8 g) in tetrahydrofuran (300 ml) under ice cooling, and the mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octan-5-one optically active substance (21.3 g) in tetrahydrofuran (100 ml) at the same temperature. Stir for 45 minutes. Water (7.0 ml), 4M aqueous sodium hydroxide solution (7.0 ml) and water (14.0 ml) were sequentially added to the reaction mixture, and the mixture was stirred as it was for 30 minutes. To this mixture was added anhydrous magnesium sulfate and ethyl acetate (100 ml), and the mixture was stirred and filtered through celite. Di-tert-butyl dicarbonate (23.4 g) was added to the filtrate at room temperature and stirred for 3 hours. The mixture was concentrated under reduced pressure to a half volume and washed twice with a saturated aqueous ammonium chloride solution (200 ml × 2). N-Hexane (200 ml) was added to the separated organic layer, and the mixture was extracted 5 times with a 10% aqueous citric acid solution. The separated aqueous layer was basified with 4M aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1 to 20/1) to give the titled compound (15.6 g).
1 H-NMR (DMSO-D 6 ) δ: 7.34-7.27 (4H, m), 7.26-7.21 (1H, m), 3.84-3.69 (1H, m), 3.62-3.47 (2H, m), 3.19- 3.05 (1H, m), 3.02-2.92 (1H, m), 2.76-2.69 (1H, m), 2.47-2.24 (4H, m), 1.95-1.77 (1H, m), 1.36 (9H, s), 1.03 (3H, d, J = 7.0 Hz).
(12) Optically active substance of 3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester
20% of optically active form of 6-benzyl-3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester (10.0 g) in tetrahydrofuran / methanol (50 ml / 50 ml) solution Palladium hydroxide on carbon (2.0 g) was added and hydrogenated at 4 atm for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (7.3 g).
1 H-NMR (DMSO-D 6 ) δ: 3.88-3.71 (1H, m), 3.44-3.06 (2H, m), 3.02-2.64 (4H, m), 2.55-2.38 (1H, m), 2.31- 2.15 (1H, m), 1.81-1.72 (1H, m), 1.37 (9H, s), 1.07 (3H, d, J = 7.0 Hz).
(13) Optical activity of 3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester body
The optically active substance (6.9 g) of 3-methyl-1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester was converted into 4-chloro-7H-pyrrolo [2,3-d] pyrimidine ( 4.3 g), potassium carbonate (7.7 g) and water (65 ml) and stirred for 4 hours at reflux. The mixture was cooled to room temperature, water (60 ml) was added, and the mixture was extracted with chloroform / methanol (10/1, 120 ml). The organic layer was washed successively with water, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. To this mixture, silica gel (4 g) was added, stirred for 10 minutes, filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethyl acetate = 1/1, then chloroform / methanol = 50/1 to 20/1) to give the title compound (10.0 g). Obtained.
1 H-NMR (DMSO-D 6 ) δ: 11.59 (1H, br s), 8.09 (1H, s), 7.12-7.09 (1H, m), 6.64-6.59 (1H, m), 4.09-3.66 (5H , m), 3.39-3.21 (1H, m), 2.64-2.44 (2H, m), 2.27-2.06 (1H, m), 1.36 (3H, s), 1.21 (6H, s), 1.11 (3H, d , J = 6.5 Hz).
(14) Optically active form of 4- (3-methyl-1,6-diazaspiro [3.4] oct-6-yl) -7H-pyrrolo [2,3-d] pyrimidine dihydrochloride
Optically active form of 3-methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] octane-1-carboxylic acid tert-butyl ester (9 0.5 g), 4M hydrochloric acid 1,4-dioxane (50 ml), chloroform (50 ml) and methanol (100 ml) were mixed and stirred at 60 ° C. for 30 minutes. The mixture was concentrated under reduced pressure and azeotroped with toluene to give the title compound (9.3 g).
1 H-NMR (DMSO-D 6 ) δ: 12.91 (1H, br s), 9.97-9.64 (2H, m), 8.45-8.35 (1H, m), 7.58-7.47 (1H, m), 7.04-6.92 (1H, m), 4.99-4.65 (1H, m), 4.32-3.21 (7H, m), 3.04-2.90 (1H, m), 2.46-2.31 (1H, m), 1.27 (3H, d, J = 6.0 Hz).
(15) 3- [3-Methyl-6- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1,6-diazaspiro [3.4] oct-1-yl] -3-oxo Optically active form of propionitrile
4- (3-Methyl-1,6-diazaspiro [3.4] oct-6-yl) -7H-pyrrolo [2,3-d] pyrimidine dihydrochloride optically active substance (8.8 g) was converted to 1- The mixture was mixed with cyanoacetyl-3,5-dimethylpyrazole (6.8 g), N, N-diisopropylethylamine (20 ml) and 1,4-dioxane (100 ml) and stirred at 100 ° C. for 1 hour. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform / methanol (10/1). The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / methanol = 30/1 to 9/1). The residue obtained by concentration under reduced pressure was slurry washed with n-heptane / ethanol (2/1, 90 ml) to obtain a solid (7.3 g). The solid was slurried again with n-heptane / ethanol (5/1, 90 ml) to give the title compound as crystals 1 (6.1 g).
1 H-NMR (DMSO-D 6 ) δ: 11.60 (1H, br s), 8.08 (1H, s), 7.11 (1H, dd, J = 3.5, 2.4 Hz), 6.58 (1H, dd, J = 3.4 , 1.9 Hz), 4.18-4.14 (1H, m), 4.09-3.93 (3H, m), 3.84-3.73 (1H, m), 3.71 (1H, d, J = 19.0 Hz), 3.66 (1H, d, J = 18.7 Hz), 3.58 (1H, dd, J = 8.2, 6.0 Hz), 2.70-2.58 (2H, m), 2.24-2.12 (1H, m), 1.12 (3H, d, J = 7.1 Hz).
[Α] D = + 47.09 ° (25 ° C., c = 0.55, methanol)
1-Butanol (39 ml) was added to the obtained crystal 1 (2.6 g), and the mixture was heated and stirred at 100 ° C. After complete dissolution, the solution was cooled to room temperature by 10 ° C. every 30 minutes and further stirred at room temperature overnight. The produced crystals were collected by filtration, washed with 1-butanol (6.2 ml), and dried under reduced pressure to give crystals 2 (2.1 g) of the title compound.
PATENTS
WO 2017006968
WO 2018117152
WO 2018117151
PATENT
WO 2018117153
https://patentscope.wipo.int/search/zh/detail.jsf?docId=WO2018117153&tab=FULLTEXT
Janus kinase (JAK) inhibitors are of current interest for the treatment of various diseases including autoimmune diseases, inflammatory diseases, and cancer. To date, two JAK inhibitors have been approved by the U.S. Food & Drug Administration (FDA). Ruxolitinib has been approved for the treatment of primary myelofibrosis and polycythemia vera (PV), and tofacitinib has been approved for the treatment of rheumatoid arthritis. Other JAK inhibitors are in the literature. The compound 3-((3S,4R)-3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octan-1-yl)-3-oxopropanenitrile (Compound A) (see structure below) is an example of a spirocyclic JAK inhibitor reported in U.S. Pat. Pub. Nos. 2011/0136778 and International Pat. Pub. No. PCT/JP2016/070046.
[Chem. 1]
[Chem. 2]
Step 1
[Chem. 3]
A crude product of S-BBMO which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.36-7.13 (5H, m), 4.26 (1H, dd, J = 6.8, 3.9 Hz), 3.72 (2H, dd, J = 14.2, 6.8 Hz), 3.47-3.38 (1H, m), 3.30-3.08 (3H, m), 2.79 (1H, sext, J = 6.8 Hz), 1.35 (9H, s), 0.96 (3H, d, J = 6.8 Hz).
MS: m/z = 280 [M+H] +
[Chem. 4]
A crude product of R-BCAB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.28-7.11 (5H, m), 4.24-4.11 (1H, m), 3.80 (2H, d, J = 3.6 Hz), 3.24 (2H, d, J = 3.6 Hz), 2.98-2.78 (2H, m), 1.46-1.37 (12H, m).
MS: m/z = 298 [M+H] +
[Chem. 5]
A crude product of S-MABB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.28-7.25 (10H, m), 3.75 (1H, d, J = 12.7 Hz), 3.68 (1H, d, J = 1.4 Hz), 3.66 (1H, d, J = 6.7 Hz), 3.46 (2H, d, J = 12.7 Hz), 3.30-3.17 (2H, m), 2.95 (1H, dd, J = 6.2, 1.2 Hz), 2.77 (1H, dd, J = 6.1, 2.2 Hz), 2.65-2.55 (1H, m), 2.48-2.40 (2H, m), 1.35 (9H, s), 1.35 (9H, s), 1.12 (3H, d, J = 7.2 Hz), 1.09 (3H, d, J = 6.2 Hz).
MS: m/z = 262 [M+H] +
[Chem. 6]
S-MABB-HC which was prepared by the same process was measured about NMR, MS, and Cl-content.
1H-NMR (DMSO-d 6) δ: 11.08 (1H, br s), 10.94 (1H, br s), 7.52-7.42 (10H, m), 5.34 (1H, t, J = 8.4 Hz), 4.90 (1H, br s), 4.45-4.10 (5H, m), 3.92-3.49 (3H, br m), 3.10-2.73 (2H, br m), 1.35 (9H, s), 1.29 (9H, s), 1.24 (3H, d, J = 6.7 Hz), 1.17 (3H, d, J = 7.4 Hz).
MS: m/z = 262 [M+H-HCl] +
Cl content (ion chromatography): 11.9 % (in theory: 11.9 %).
[Chem. 7]
A crude product of S-MACB-HC which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 9.60 (br s, 1H), 4.97 (d, 1H, J = 9.2 Hz), 4.61 (d, 1H, J = 8.4 Hz), 4.01 (dd, 1H, J = 10.0, 8.4 Hz), 3.78-3.74 (m, 1H), 3.54 (dd, 1H, J = 9.6, 8.4 Hz), 3.35 (dd, 1H, J = 10.0, 6.0 Hz), 3.15-3.03 (m, 1H), 3.00-2.88 (m, 1H), 1.49 (s, 9H), 1.47 (s, 9H), 1.22 (d, 3H, J = 6.8 Hz), 1.14 (d, 3H, J = 7.2 Hz).
MS: m/z = 172 [M+H] + (free form)
[Chem. 8]
A crude product of S-ZMAB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.38-7.28 (m, 10H), 5.16-5.04 (m, 4H), 4.60 (d, 1H, J = 9.2 Hz), 4.18-4.12 (m, 2H), 4.04 (t, 1H, J = 8.6 Hz), 3.66 (dd, 1H, J = 7.6, 7.2 Hz), 3.50 (dd, 1H, J = 8.0, 5.2 Hz), 3.05-2.94 (m, 1H), 2.60-2.50 (m, 1H), 1.43 (br s, 18H), 1.33 (d, 3H, J = 6.5 Hz), 1.15 (d, 3H, J = 7.2 Hz).
MS: m/z = 328 [M+Na] +.
[Chem. 9]
A crude product of RS-ZMBB which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 7.38-7.29 (m, 5H), 5.09-4.96 (m, 2H), 3.91 (t, 0.4H, J = 8.0 Hz), 3.79 (t, 0.6H, J = 8.0 Hz), 3.55 (t, 0.4H, J = 7.2 Hz), 3.46 (t, 0.6H, J = 7.5 Hz), 3.14-3.04 (m, 1H), 2.83-2.72 (m, 2H), 1.38 (br s, 9H), 1.37 (br s, 3.6H), 1.34 (br s, 5.4H), 1.12-1.09 (m, 3H).
MS: m/z = 420 [M+H] +.
[Chem. 10]
RS-ZMAA-DN .2H 2O which was prepared by the same process was measured about NMR, MS, Na-content, and water-content.
1H-NMR (DMSO-d 6) δ: 7.32-7.22 (m, 5H), 4.97 (d, 1H, J = 12.7 Hz), 4.84 (d, 1H, J = 12.7 Hz), 3.79 (t, 1H, J = 8.0 Hz), 3.29 (d, 1H, J = 14.8 Hz), 3.16-3.12 (m, 1H), 2.17-2.09 (m, 2H), 1.07 (d, 3H, J = 6.9 Hz).
MS: m/z = 352 [M+H] + (anhydrate)
Na content (ion chromatography): 13.3 % (after correction of water content)(13.1 % in theory)
Water content (Karl Fischer’s method): 9.8 % (9.3 % in theory)
[Chem. 11]
RS-ZMAA which was prepared by the same process was measured about NMR and MS.
1H-NMR (DMSO-D 6) δ: 7.35-7.28 (m, 5H), 5.06-4.94 (m, 2H), 3.86 (dt, 1H, J = 48.4, 7.9 Hz), 3.50 (dt, 1H, J = 37.9, 7.4 Hz), 3.16-3.02 (br m, 1H), 2.91-2.77 (br m, 2H), 1.08 (d, 3H, J = 6.9 Hz)
MS: m/z = 308 [M+H] +.
[Chem. 12]
RS-ZMOO which was prepared by the same process was measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.39-7.30 (m, 5H), 5.10 (s, 2H), 4.15-4.01 (br m, 2H), 3.83-3.73 (br m, 3H), 3.48 (dd, 1H, J = 8.3, 6.4 Hz), 2.59-2.50 (br m, 1H), 2.46-2.40 (br m, 1H), 2.07-1.99 (m, 1H), 1.14 (d, 3H, J = 7.2 Hz)
MS: m/z = 280 [M+H]+.
[Chem. 13]
RS-ZMSS which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-D 6) δ: 7.37-7.27 (br m, 5H), 5.10-4.98 (m, 2H), 4.58-4.22 (br m, 4H), 3.84 (dt, 1H, J = 45.6, 8.1 Hz), 3.48-3.33 (br m, 1H), 3.17-3.10 (m, 6H), 2.81-2.74 (br m, 1H), 2.22-2.12 (m, 2H)
MS: m/z = 436 [M+H] +.
[Chem. 14]
1H-NMR (CDCl 3) δ: 7.35-7.20 (m, 10H), 5.08 (d, 2H, J = 23.6 Hz), 3.94 (q, 1H, J = 7.9 Hz), 3.73-3.42 (br m, 2H), 3.30-3.23 (m, 1H), 3.05 (dd, 1H, J = 19.7, 9.5 Hz), 2.79 (dt, 1H, J = 69.6, 6.1 Hz), 2.57-2.32 (br m, 4H), 1.96-1.89 (m, 1H), 1.09 (d, 3H, J = 6.9 Hz)
MS: m/z = 351 [M+H] +.
[Chem. 15]
SR-MDOZ which was prepared by the same process was evaporated to dryness and then measured about NMR and MS.
1H-NMR (CDCl 3) δ: 7.37-7.28 (m, 5H), 5.08 (dd, 2H, J = 16.8, 12.8 Hz), 4.00 (dd, 1H, J = 17.1, 8.3 Hz), 3.40-3.31 (m, 1H), 3.24 (d, 1H, J = 12.7 Hz), 3.00 (dd, 1H, J = 54.9, 12.4 Hz), 2.87-2.57 (m, 3H), 2.47-2.27 (m, 1H), 1.91-1.80 (m, 1H), 1.14 (d, 3H, J = 7.2 Hz)
MS: m/z = 261 [M+H] +.
[Chem. 16]
SR-MDOZ-OX which was prepared by the same process was measured about NMR, MS, and elementary analysis.
1H-NMR (DMSO-D 6) δ: 7.37-7.30 (m, 5H), 5.15-5.01 (m, 2H), 3.92 (dt, 1H, J = 43.5, 8.4 Hz), 3.48-3.12 (br m, 5H), 2.67-2.56 (m, 1H), 2.46-2.35 (m, 1H), 2.12-2.05 (m, 1H), 1.13 (d, 3H, J = 6.9 Hz)
MS: m/z = 261 [M+H] +
elementary analysis: C 58.4wt % , H 6.4wt % , N 7.9 % wt % (theoretically, C 58.3wt % , H 6.3wt % , N 8.0wt % )
[Chem. 17]
SR-MDPZ which was prepared by the same process was isolated as a solid from a mixture of ethyl acetate and n-heptane, and then measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.41-7.26 (br m, 3H), 7.22-7.08 (br m, 3H), 6.64-6.51 (br m, 1H), 5.07-4.91 (br m, 2H), 4.09-3.67 (br m, 5H), 3.47-3.32 (br m, 1H), 2.67-2.55 (br m, 2H), 2.21-2.15 (br m, 1H), 1.11 (d, 3H, J = 6.9 Hz).
MS: m/z = 378 [M+H] +
[Chem. 18]
SR-MDOP which was prepared by the same process was measured about NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.57 (br s, 1H), 8.07 (s, 1H), 7.10 (d, 1H, J = 3.2 Hz), 6.58 (d, 1H, J = 3.2 Hz), 3.92-3.59 (br m, 4H), 3.49 (dd, 1H, J = 8.3, 7.2 Hz), 2.93 (dd, 1H, J = 7.2, 6.1 Hz), 2.61-2.53 (m, 2H), 2.12-2.01 (br m, 2H), 1.10 (d, 3H, J = 6.9 Hz).
MS: m/z = 244 [M+H] +.
[Chem. 19]
Compound A mono-ethanolate which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.3 Hz), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.34 (t, 1H, J = 5.1 Hz), 4.16 (t, 1H, J = 8.3 Hz), 4.09-3.92 (m, 3H), 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 3.44 (dq, 2H, J = 6.7, 5.1 Hz), 2.69-2.60 (m, 2H), 2.23-2.13 (br m, 1H), 1.12 (d, 3H, J = 7.1 Hz), 1.06 (t, 3H, J = 6.7 Hz).
MS: m/z = 311 [M+H] +
[Chem. 20]
Compound A which was prepared by the same process was measured by NMR and MS.
1H-NMR (DMSO-d 6) δ: 11.59 (br s, 1H), 8.08 (s, 1H), 7.11 (dd, 1H, J = 3.5, 2.5 Hz), 6.58 (dd, 1H, J = 3.5, 1.8 Hz), 4.16 (t, 1H, J = 8.3 Hz), 4.09-3.93 (m, 3H), 3.84-3.73 (m, 1H), 3.71 (d, 1H, J = 19.0 Hz), 3.65 (d, 1H, J = 19.0 Hz), 3.58 (dd, 1H, J = 8.2, 5.9 Hz), 2.69-2.59 (m, 2H), 2.23-2.13 (m, 1H), 1.12 (d, 3H, J = 7.2 Hz).
MS: m/z = 311 [M+H] +
(1) Preparation of Single crystal
To 10 mg of Compound A in a LaPha ROBO Vial(R) 2.0 mL wide-mouthed vial was added 0.5 mL of chloroform. The vial was covered with a cap, in which Compound A was completely dissolved. In order to evaporate the solvent slowly, a hole was made on the septum attached in the cap with a needle of a TERUMO(R) syringe, and the vial was still stood at room temperature. The resulting single crystal was used in the structural analysis.
(2) Measuring instrument
Beam line: SPring-8 BL32B2
Detector: Rigaku R-AXIS V diffractometer
(3) Measuring method
The radiant light of 0.71068Å was irradiated to the single crystal to measure X-ray diffraction data.
(4) Assay method
Using the X-ray anomalous scattering effect of the chlorine atom in the resulting Compound A chloroform-solvate, the absolute configuration of Compound A was identified as (3S,4R). Based on the obtained absolute configuration of Compound A, the absolute configurations of each process intermediate were identified.
REFERENCES
1: Nakagawa H, Nemoto O, Yamada H, Nagata T, Ninomiya N. Phase 1 studies to assess the safety, tolerability and pharmacokinetics of JTE-052 (a novel Janus kinase inhibitor) ointment in Japanese healthy volunteers and patients with atopic dermatitis. J Dermatol. 2018 Jun;45(6):701-709. doi: 10.1111/1346-8138.14322. Epub 2018 Apr 17. PubMed PMID: 29665062; PubMed Central PMCID: PMC6001687.
2: Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study. Br J Dermatol. 2018 Feb;178(2):424-432. doi: 10.1111/bjd.16014. Epub 2018 Jan 15. PubMed PMID: 28960254.
3: Tanimoto A, Shinozaki Y, Yamamoto Y, Katsuda Y, Taniai-Riya E, Toyoda K, Kakimoto K, Kimoto Y, Amano W, Konishi N, Hayashi M. A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. Exp Dermatol. 2018 Jan;27(1):22-29. doi: 10.1111/exd.13370. Epub 2017 Jul 3. PubMed PMID: 28423239.
4: Nomura T, Kabashima K. Advances in atopic dermatitis in 2015. J Allergy Clin Immunol. 2016 Dec;138(6):1548-1555. doi: 10.1016/j.jaci.2016.10.004. Review. PubMed PMID: 27931536.
5: Amano W, Nakajima S, Yamamoto Y, Tanimoto A, Matsushita M, Miyachi Y, Kabashima K. JAK inhibitor JTE-052 regulates contact hypersensitivity by downmodulating T cell activation and differentiation. J Dermatol Sci. 2016 Dec;84(3):258-265. doi: 10.1016/j.jdermsci.2016.09.007. Epub 2016 Sep 13. PubMed PMID: 27665390.
6: Tanimoto A, Shinozaki Y, Nozawa K, Kimoto Y, Amano W, Matsuo A, Yamaguchi T, Matsushita M. Improvement of spontaneous locomotor activity with JAK inhibition by JTE-052 in rat adjuvant-induced arthritis. BMC Musculoskelet Disord. 2015 Nov 6;16:339. doi: 10.1186/s12891-015-0802-0. PubMed PMID: 26546348; PubMed Central PMCID: PMC4636776.
7: Amano W, Nakajima S, Kunugi H, Numata Y, Kitoh A, Egawa G, Dainichi T, Honda T, Otsuka A, Kimoto Y, Yamamoto Y, Tanimoto A, Matsushita M, Miyachi Y, Kabashima K. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol. 2015 Sep;136(3):667-677.e7. doi: 10.1016/j.jaci.2015.03.051. Epub 2015 Jun 24. PubMed PMID: 26115905.
8: Tanimoto A, Ogawa Y, Oki C, Kimoto Y, Nozawa K, Amano W, Noji S, Shiozaki M, Matsuo A, Shinozaki Y, Matsushita M. Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res. 2015 Jan;64(1):41-51. doi: 10.1007/s00011-014-0782-9. Epub 2014 Nov 12. PubMed PMID: 25387665; PubMed Central PMCID: PMC4286029.
References
- “Anzupgo EPAR”. European Medicines Agency. 25 July 2024. Retrieved 25 July 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- “Anzupgo PI”. Union Register of medicinal products. 23 September 2024. Retrieved 27 September 2024.
- Dhillon S (April 2020). “Delgocitinib: First Approval”. Drugs. 80 (6): 609–615. doi:10.1007/s40265-020-01291-2. PMID 32166597. S2CID 212681247.
- Park B (5 August 2020). “Delgocitinib Cream Gets Fast Track Status for Chronic Hand Eczema”. empr.com.
- Szalus K, Trzeciak M, Nowicki RJ (November 2020). “JAK-STAT Inhibitors in Atopic Dermatitis from Pathogenesis to Clinical Trials Results”. Microorganisms. 8 (11): 1743. doi:10.3390/microorganisms8111743. PMC 7694787. PMID 33172122.
- “Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22-25 July 2024”. European Medicines Agency (Press release). 25 July 2024. Retrieved 29 July 2024.
/////////Delgocitinib, デルゴシチニブ , JAPAN 2020, 2020 APPROVALS, Corectim, UNII-9L0Q8KK220, JTE-052, 9L0Q8KK220, LEO 124249A, LEO 124249, HY-109053, CS-0031558, D11046, GTPL9619, JTE-052A, JTE052, LP-0133 , ROH-201, atopic dermatitis
CC1CN(C12CCN(C2)C3=NC=NC4=C3C=CN4)C(=O)CC#N
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| Clinical data | |
|---|---|
| Trade names | Corectim, others |
| Other names | JTE-052; JTE-052A |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C16H18N6O |
| Molar mass | 310.361 g·mol−1 |
| 3D model (JSmol) | |
https://pubs.acs.org/doi/10.1021/acs.oprd.1c00031
https://www.chemicalbook.com/article/synthesis-of-delgocitinib.htm
Synthesis of Delgocitinib
Delgocitinib is synthesised using bromolactone as raw material by chemical reaction. The specific synthesis steps are as follows:
Synthesis of Delgocitinib
Dec 26，2023
Synthesis of Delgocitinib
Delgocitinib is synthesised using bromolactone as raw material by chemical reaction. The specific synthesis steps are as follows:
A stereocontrolled kilogram scale synthesis of delgocitinib has been disclosed, beginning with an SN2 reaction involving bromolactone 128 and benzyl amine to provide α-amino lactone 129, which was isolated as the HCl salt after precipitation from hydrochloric acid in ethyl acetate. Amine 129 was then acylated with enantiomerically pure acid chloride 131 (prepared by thionyl chloride treatment of commercial acid 130) to furnish lactone 132. In the crucial spirocyclic ring ringforming sequence of the synthesis, lactone 132 was treated with LHMDS to form an enolate that underwent SN2 displacement of the chloride, forming the spirolactone 133 and establishing both stereocenters with 98:2 dr and 96% ee.
The lactone ring of 133 was then opened by an attack of potassium phthalimide on the γ- carbon, and the resulting carboxylic acid was converted to the ethyl ester by treatment with ethyl iodide. Finally, treatment with diethylenetriamine released phthalimide, providing a free amine for subsequent cyclization to spirolactam 134 via the corresponding ethyl ester intermediate. This sequence took place in 80% yield over four steps and provided the spirolactam in >99% de after recrystallization.
The carbonyl groups within spirolactam 134 were then reduced with lithium aluminum hydride and aluminum chloride in THF, and the resulting diamine 135 was crystallized as a succinic acid salt in 86% yield. The SNAr reaction of 135 with chloropyrrolopyrimidine 136 followed by hydrogenative removal of the benzyl protecting group provided amine 137 in 92% yield over 2 steps. Finally, amine 137 was acylated with cyanoacetyl pyrazole 138 and recrystallized from n-butanol with 3 wt % BHT to provide delgocitinib in 86% yield, >99% ee, and >99% de.
Dotinurad ドチヌラド
Dotinurad
ドチヌラド
(3,5-dichloro-4-hydroxyphenyl)-(1,1-dioxo-2H-1,3-benzothiazol-3-yl)methanone
| Formula |
C14H9Cl2NO4S
|
|---|---|
| CAS |
1285572-51-1
|
| Mol weight |
358.1966
|
PMDA, Urece, APROVED JAPAN 2020/1/23, Antihyperuricemic
305EB53128UNII-305EB53128
1285572-51-1,
Dotinurad is a urate transporter inhibitor.
Patents
WO 2011040449
https://patents.google.com/patent/WO2011040449A1/en
Uric acid is produced by metabolizing a purine produced by the degradation of a nucleic acid in the body and adenosine triphosphate (ATP), which is an energy source of the living body, to xanthine, and further undergoes oxidation by xanthine oxidase or xanthine dehydrogenase. In humans, uric acid (dissociation constant pKa = 5.75) is the final metabolite of purines and exists in the body as free forms or salts.
Uric acid is normally excreted in the urine, but when uric acid production exceeds excretion and blood uric acid increases, hyperuricemia occurs. If a state in which the blood level of uric acid exceeds the upper limit of solubility (about 7 mg / dL) continues for a long period of time, crystals of urate (usually sodium salt) precipitate.
In the blood, the precipitated crystals deposit on cartilage tissue and joints, form precipitates and become gouty nodules, causing acute gouty arthritis, and then transition to chronic gouty arthritis.
When uric acid crystals are precipitated in urine, renal disorders such as interstitial nephritis (gouty kidney), urinary calculi, and the like are caused. After the seizures of acute gouty arthritis have subsided, drug therapy is given along with lifestyle improvement guidance to correct hyperuricemia.
Correcting hyperuricemia and appropriately managing uric acid levels are also important in preventing acute gouty arthritis, gouty kidneys, urinary tract stones, and the like.
Hyperuricemia is considered to be associated with a high rate of lifestyle-related diseases such as obesity, hyperlipidemia, impaired glucose tolerance, and hypertension (see Non-Patent Document 1 (pp7-9)). Increased serum uric acid levels are positively related to cardiovascular mortality, and higher serum uric acid levels increase mortality due to ischemic heart disease. It has been suggested that it is associated with the risk of death from disease (see Non-Patent Document 2).
Furthermore, serum uric acid levels have also been shown to be a powerful risk factor for myocardial infarction and stroke (see Non-Patent Document 3). To date, hyperuricemia is obesity, hyperlipidemia, dyslipidemia, impaired glucose tolerance, diabetes, metabolic syndrome, kidney disease (eg, renal failure, urine protein, end-stage renal disease (ESRD), etc.), heart It is known to be associated with vascular diseases (for example, hypertension, coronary artery disease, carotid artery disease, vascular endothelial disorder, arteriosclerosis, cardiac hypertrophy, cerebrovascular disease, etc.) or risk factors of these diseases (Non-Patent Documents 2 to 11) reference). In cerebrovascular dementia, it has also been reported that the concentration of uric acid in the cerebrospinal cord is increased (see Non-Patent Document 12).
Under such circumstances, it has been suggested that the treatment for lowering the blood uric acid level may delay the progression of kidney disease and reduce the risk of cardiovascular disease (Non-Patent Documents 5, 8, 13, 14), it has been reported that it should also be applied to asymptomatic hyperuricemia (see Non-Patent Document 14).
Therefore, reducing the blood uric acid level in the above-mentioned diseases is effective for the treatment or prevention of these diseases, and is considered to be important in terms of preventing recurrence of cardiovascular accidents and maintaining renal function.
The main factors that increase blood uric acid levels include excessive uric acid production and decreased uric acid excretion. Therefore, as a method for lowering blood uric acid level, it is conceivable to suppress the production of uric acid or promote the excretion of uric acid, and allopurinol is a drug having the former mechanism of action (uric acid production inhibitor). Benzbromarone, probenecid, JP-A 2006-176505 (Patent Document 1) and the like are known as drugs having the latter mechanism of action (uric acid excretion promoters).
According to the Japanese guidelines for treatment of hyperuricemia and gout, in principle, uric acid excretion-promoting agents are applied to hyperuricemia-reducing types and uric acid production-inhibiting agents are applied to excessive uric acid production types, respectively. (See Non-Patent Document 1 (pp31-32)).
In Japan, it is said that about 60% of hyperuricemia patients have a reduced uric acid excretion type, and about 25% are a mixed type of reduced uric acid excretion type and excessive uric acid production type (Non-patent Document 15). About 85% of the patients showed a decrease in uric acid excretion, and the average value of uric acid clearance was significantly lower than that of healthy individuals even in patients with excessive uric acid production, and the decrease in uric acid excretion was fundamental in all gout patients. Is also reported (Non-Patent Document 16).
Therefore, in hyperuricemia (especially gout), treatment for patients with reduced uric acid excretion is considered to be important, and the existence significance of uric acid excretion promoters is extremely large.
Among the major uric acid excretion promoters, probenecid is weakly used and is rarely used because of its gastrointestinal tract disorders and interactions with other drugs. On the other hand, severe liver damage has been reported for benzbromarone, which has a strong uric acid excretion promoting action and is widely used in Japan as a uric acid excretion promoting drug (see Non-Patent Document 17).
Benzbromarone or its analogs inhibit mitochondrial respiratory chain enzyme complex activity, uncoupling action, respiration inhibition, fatty acid β oxidation inhibition, mitochondrial membrane potential reduction, apoptosis, generation of reactive oxygen species, etc. Has been suggested to be involved in the development of liver damage (see Non-Patent Documents 18 and 19). Hexahydrate, which is the active body of benzbromarone, is also toxic to mitochondria.
Furthermore, benzbromarone has an inhibitory action on cytochrome P450 (CYP), which is a drug metabolizing enzyme. In particular, the inhibition against CYP2C9 is very strong, suggesting the possibility of causing a pharmacokinetic drug interaction (non-) (See Patent Documents 20 and 21).
Furthermore, although a nitrogen-containing fused ring compound having a URAT1 inhibitory action, which is a kind of uric acid transporter, and having a structure similar to that of the compound of the present invention is described in JP-A-2006-176505 (Patent Document 1), the effect is sufficient. In addition, no practical uric acid excretion promoter has been developed yet.
Recently, it has been found that the uric acid excretion promoting action depends on the urinary concentration of a drug having the same action, that is, the uric acid excretion promoting drug is excreted in the urine and exhibits a medicinal effect (Patent Document 2). Non-Patent Documents 22 and 23).
Therefore, a stronger pharmacological effect is expected if it is a uric acid excretion promoter that is excreted more in the urine, but the above existing uric acid excretion promoters have a very low concentration in urine, and a satisfactory activity can be obtained sufficiently. I can’t say that.
Regarding the urinary excretion of drugs, it is assumed that the administered drug is excreted as it is as an unchanged form or converted into an active metabolite and excreted. In the latter case, the active metabolite is produced. There is a risk that the individual difference in the amount becomes large, and in order to obtain stable drug efficacy and safety, a drug excreted as an unchanged substance is more desirable.
As described above, there is a demand for the development of a highly safe pharmaceutical having a high unchanged body urine concentration and a remarkable uric acid excretion promoting action as compared with existing uric acid excretion promoting drugs.
JP 2006-176505 A WO2005 / 121112
Treatment Guidelines for Hyperuricemia and Gout (1st Edition) pp7-9 and pp31-32, Gout and Nucleic Acid Metabolism, Volume 26, Supplement 1, 2002 Japan Gout and Nucleic Acid Metabolism Society JAMA 283: 2404-2410 (2000) Stroke 37: 1503-1507 (2006) Nephrology 9: 394-399 (2004) Semin. Nephrol. 25: 43-49 (2005)J. Clin. Hypertens. 8: 510-518 (2006) J. Hypertens. 17: 869-872 (1999) Curr. Med. Res. Opin. 20: 369-379 (2004) Curr. Pharm. Des. 11: 4139-4143 (2005)Hypertension 45: 991-996 (2005) Arch. Intern. Med. 169: 342-350 (2009) J. Neural. Transm. Park Dis. Dement. Sect. 6: 119-126 (1993) Am. J. Kidney Dis. 47: 51-59 (2006) Hyperuricemia and gout 9: 61-65 (2001) Japanese clinical trials 54: 3230-3236 (1996) Japanese clinical trial 54: 3248-3255 (1996) J. Hepatol. 20: 376-379 (1994) J. Hepatol. 35: 628-636 (2001) Hepatology 41: 925-935 (2005) Saitama Medical University Journal (J. Saitama. Med. School) 30: 187-194 (2004) Drug Metab. Dispos. 31: 967-971 (2003) 42nd Annual Meeting of the Japanese Gout and Nucleic Acid Metabolism General Assembly Program / Abstracts, p59 (2009) ACR 2008 Annual Scientific Meeting, No. 28
PATENT
JP 2011074017
PATENT
WO 2018199277
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018199277
//////////Dotinurad, Antihyperuricemic, JAPAN 2020, 2020 APPROVALS , ドチヌラド , VOFLAIHEELWYGO-UHFFFAOYSA-N, HY-109031, CS-0030545
C1N(C2=CC=CC=C2S1(=O)=O)C(=O)C3=CC(=C(C(=C3)Cl)O)Cl
IIIM-290
IIIM-290
4H-1-Benzopyran-4-one, 2-[2-(2,6-dichlorophenyl)ethenyl]-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-
| Molecular Weight |
462.32 |
|---|---|
| Formula |
C₂₃H₂₁Cl₂NO₅ |
| CAS No. |
2213468-64-3 |
CSIR-IIIM Jammu has filed an IND Application of “IIIM-290” to Drug Controller General of India for conducting Phase I/Phase II clinical trial of its capsule formulation in patients with locally advanced or metastatic pancreatic cancer. This IND candidate has emerged from the eight years of medicinal chemistry/ preclinical efforts of IIIM Jammu in the area of small molecule kinase inhibitors. IIIM-290 (NCE) is an orally bioavailable CDK inhibitor, obtained via semisynthetic modification of a natural product rohitukine. Institute has already secured a patent on this small molecule as well as on its oral capsule formulation.
IIIM-290 is a potent and oral CDK inhibitor with IC50s of 90 and 94 nM for CDK2/A and CDK9/T1.
PAPER
https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b01765
Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor
- Sandip B. Bharate
- Vikas Kumar
- Shreyans K. Jain
- Mubashir J. Mintoo
- Santosh K. Guru
- Vijay K. Nuthakki
- Mohit Sharma
- Sonali S. Bharate
- Sumit G. Gandhi
- Dilip M. Mondhe
- Shashi Bhushan
- Ram A. Vishwa
Abstract
Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.
Patent
IN201811026240
Patent
InventorRam A. VishwakarmaSandip B. BharateShashi BhushanDilip M. MondheShreyans K. JainSamdarshi MeenaSantosh K. GuruAnup S. PathaniaSuresh KumarAkanksha BehlMubashir J. MintooSonali S. BharatePrashant Joshi Current Assignee Council of Scientific and Industrial Research (CSIR)
https://patents.google.com/patent/US9932327B2/en
The disruption of any internal and external regulation of cellular growth leads to tumorogenesis by uncontrolled proliferation. This loss of control occurs at multiple levels in most of the cancer cases. Cyclin-dependent kinases (CDKs) have been recognized as key regulators of cell cycle progression. Alteration and deregulation of CDK activity have pathogenic link to the cancer. Number of cancers are associated with hyper-activation of CDKs as a result of mutation of the CDK genes or CDK inhibitor genes. Therefore, CDK inhibitors or modulators are of great interest to explore as novel therapeutic agents against cancer (Senderowicz, A. M. Leukemia 2001, 15, 1). Several classes of chemical inhibitors of CDK activity have been described (Zhang, J. et. al. Nat Rev Cancer. 2009, 9, 28) and some of them have reached to clinical pipeline for cancer.
Because CDK inhibitors are ATP competitive ligands; hence earlier they were typically described as purine class of compounds for example dimethylaminopurine, a first substance to be known as a CDK inhibitor (Neant, I. et al. Exp. Cell Res. 1988, 176, 68), olomoucine (Vesely, J. et al. Eur. J. Biochem. 1994, 224, 771) and roscovitine (Meijer, L. et al. Eur. J. Biochem. 1997, 243, 527). The IC50values of these purine class of compounds for CDK1/cyclin B are 120, 7 and 0.2-0.8 μM respectively (Gray, N. et al. Curr. Med. Chem. 1999, 6, 859). Some of the more potent members of this series have been prepared by the Schultz group using combinatorial approaches (Gray, N. S. et al. Science 1998, 281, 533). Number of synthetic flavoalkaloids having potent CDK inhibitory activity has been reviewed recently (Jain, S. K. et al. Mini–Rev. Med. Chem. 2012, 12, 632).
Specific CDKs operate in distinct phases of the cell cycle. CDK complexes with their respective type cyclin partners such as, complex of CDK2 and cyclin A is responsible for the cell’s progression from G1 phase to S phase (Sherr, C. J. Science 1996, 274, 1672). DNA synthesis (S phase) begins with the CDK mediated phosphorylation of Rb (retinoblastoma) protein. Phosphorylated Rb is released from its complex with E2F. The released E2F then promotes the transcription of numerous genes required for the cell to progress through S phase, including thymidylate synthase and dihydrofolate reductase which are required for cell progression (Hatakeyama, M. et. al, Cell Cycle Res. 1995, 1, 9; Zhang, H. S. et. al. Cell 1999, 97, 53). Majority of human cancers have abnormalities in some component of the Rb pathway because of hyper-activation of CDKs resulting from the over-expression of positive cofactors (cyclins/CDKs) or a decrease in negative factors (endogenous CDK inhibitors) or Rb gene mutations (Sausville, E. A. et. al, Pharmacol. Ther. 1999, 82, 285).
The CDK-9 is a member of the Cdc2-like family of kinases. Its cyclin partners are members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The CDK-9/cyclin T complexes appear to be involved in regulating several physiological processes. CDK9/cyclin T1 belongs to the P-TEFb complex, and is responsible for the phosphorylation of carboxyl terminal domain of the RNA Polymerase II, thus promoting general elongation. CDK-9 has also been described as the kinase of the TAK complex, which is homologous to the P-TEFb complex and is involved in HIV replication. CDK9 also appears to be involved in the differentiation program of several cell types, such as muscle cells, monocytes and neurons, suggesting that it may have a function in controlling specific differentiative pathways. In addition, CDK-9 seems to have an anti-apoptotic function in monocytes, that may be related to its control over differentiation of monocytes. This suggests the involvement of CDK-9 in several physiological processes in the cell, the deregulation of which may be related to the genesis of transforming events that may in turn lead to the onset of cancer. In addition, since the complex CDK-9/cyclin T1 is able to bind to the HIV-1 product Tat, the study of the functions of CDK-9/cyclin T may be of interest in understanding the basal mechanisms that regulate HIV replication (Falco, G. D. and Giordano A. Cancer Biol. Therapy 2002, 1, 337).
Rohitukine belongs to a class of chromone alkaloids and it was isolated by chemists at Hoechst India Ltd. in the early 1990’s from Dysoxylum binectariferum Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd., used for rheumatoid arthritis. Rohitukine was isolated as the constituent responsible for anti-inflammatory and immunomodulatory activity (Naik, R. G. et. al. Tetrahedron 1988, 44, 2081; U.S. Pat. No. 4,900,727, 1990). Medicinal chemistry efforts around this nature-derived flavone alkaloid led to discovery of two promising clinical candidates for treatment of cancer viz. flavopiridol of Sanofi-Aventis and P-276-00 of Piramal life sciences. Recently FDA has granted the orphan drug status to flavopiridol for treatment of chronic lymphocytic leukemia (CLL).
The molecular formula of rohitukine is C16H19NO5 and the structure has a molecular weight of 305.32 g/mol. The chemical structure of rohitukine (1) is shown below. The present invention reports new semi-synthetic analogs of rohitukine as promising inhibitors of cyclin-dependent kinases such as CDK-2 and CDK-9.
Synthesis of styryl analog 2-(2,6-dichlorostyryl)-5,7-dihydroxy-8-(3-hydroxy-1-methylpiperidin-4-yl)-4H-chromen-4-one (33)
This compound was synthesized using the procedure as described in example 4. Yellow solid; 1H NMR (DMSO-d6, 400 MHz): δ 7.68 (m, 2H), 7.61 (d, J=16 Hz, 1H), 7.49 (t, J=8 Hz, 1H), 7.14 (d, J=16 Hz, 1H), 6.41 (s, 1H), 5.85 (s, 1H), 4.53 (brs, 1H), 3.10-2.50 (m, 6H of piperidine), 2.65 (s, 3H), 1.62 (m, 1H); 13C NMR (DMSO-d6, 125 MHz): δ 179.68. 171.27, 159.20, 158.02, 154.03, 133.12, 131.49, 129.75, 128.35 (2C), 128.20, 127.90, 108.81, 106.79, 100.88, 100.52, 66.35, 59.82, 54.45, 43.15, 35.79, 22.01, 20.33, ESI-MS: m/z 462.01 [M+H]+; IR (CHCl3): νmax 3400, 2921, 1652, 1577, 1550, 1417, 1380, 1191, 1085 cm−1.
///////////IIIM-290, nda, india, phase 1, dcgi, CSIR, ROHITUKINE
|
OC1=C2C(OC(/C=C/C3=C(Cl)C=CC=C3Cl)=CC2=O)=C([C@]4([H])[C@H](O)CN(C)CC4)C(O)=C1 |
Zanubrutinib, ザヌブルチニブ , занубрутиниб , زانوبروتينيب ,
Zanubrutinib, BGB-3111
| Formula |
C27H29N5O3
|
|---|---|
| CAS |
1691249-45-2
|
| Mol weight |
471.5509
|
FDA , 2019/11/14, Brukinsa
ザヌブルチニブ ,
Antineoplastic, Bruton’s tyrosine kinase inhibitor, Mantle cell lymphoma
NEW PA
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023062504&_gid=202316
Zanubrutinib, sold under the brand name Brukinsa, is for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.[3]
It was approved for medical use in the United States in November 2019.[4][3][5][6]
Zanubrutinib is classified as a Bruton’s tyrosine kinase (BTK) inhibitor. It is administered orally.
History
Efficacy was evaluated in BGB-3111-206 (NCT03206970), a phase II open-label, multicenter, single-arm trial of 86 patients with mantle cell lymphoma (MCL) who received at least one prior therapy.[5] Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity.[5] Efficacy was also assessed in BGB-3111-AU-003 (NCT 02343120), a phase I/II, open-label, dose-escalation, global, multicenter, single-arm trial of B‑cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib administered orally at 160 mg twice daily or 320 mg once daily.[5][6]
The primary efficacy outcome measure in both trials was overall response rate (ORR), as assessed by an independent review committee.[5] In trial BGB-3111-206, FDG-PET scans were required and the ORR was 84% (95% CI: 74, 91), with a complete response rate of 59% (95% CI 48, 70) and a median response duration of 19.5 months (95% CI: 16.6, not estimable).[5] In trial BGB-3111-AU-003, FDG-PET scans were not required and the ORR was 84% (95% CI: 67, 95), with a complete response rate of 22% (95% CI: 9, 40) and a median response duration of 18.5 months (95% CI: 12.6, not estimable).[5] Trial 1 was conducted at 13 sites in China, and Trial 2 was conducted at 25 sites in the United States, United Kingdom, Australia, New Zealand, Italy, and South Korea.[6]
The U.S. Food and Drug Administration (FDA) granted zanubrutinib priority review, accelerated approval, breakthrough therapydesignation, and orphan drug designation.[3][5][7]
The FDA approved zanubrutinib in November 2019, and granted the application for Brukinsa to BeiGene USA Inc.[3][5][8]
PAPER
https://www.x-mol.com/paper/5799457
Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase Journal of Medicinal Chemistry ( IF 6.054 ) Pub Date: 2019-08-19 , DOI: 10.1021 / acs.jmedchem.9b00687
Yunhang Guo, Ye Liu, Nan Hu, Desheng Yu, Changyou Zhou, Gongyin Shi, Bo Zhang, Min Wei, Junhua Liu, Lusong Luo, Zhiyu Tang, Huipeng Song, Yin Guo, Xuesong Liu, Dan Su, Shuo Zhang, Xiaomin Song , Xing Zhou, Yuan Hong, Shuaishuai Chen, Zhenzhen Cheng, Steve Young, Qiang Wei, Haisheng Wang, Qiuwen Wang, Lei Lv, Fan Wang, Haipeng Xu, Hanzi Sun, Haimei Xing, Na Li, Wei Zhang, Zhongbo Wang, Guodong Liu, Zhijian Sun, Dongping Zhou, Wei Li, Libin Liu, Lai Wang, Zhiwei Wang
 |
Bruton’s tyrosine kinase (Btk) belongs to the Tec tyrosine kinase family (Vetrie et al., Nature 361: 226-233, 1993; Bradshaw, Cell Signal. 22: 1175-84, 2010). Btk is primarily expressed in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al., J. Immunol. 152: 557-565, 1994) and is localized in bone marrow, spleen and lymph node tissue. Btk plays important roles in B-cell receptor (BCR) and FcR signaling pathways, which involve in B-cell development, differentiation (Khan, Immunol. Res. 23: 147, 2001). Btk is activated by upstream Src-family kinases. Once activated, Btk in turn phosphorylates PLC gamma, leading to effects on B-cell function and survival (Humphries et al., J. Biol.Chem. 279: 37651, 2004).
[0003] These signaling pathways must be precisely regulated. Mutations in the gene encoding Btk cause an inherited B-cell specific immunodeficiency disease in humans, known as X-linked agammaglobulinemia (XLA) (Conley et al., Annu. Rev. Immunol. 27: 199-227, 2009). Aberrant BCR-mediated signaling may result in dysregulated B-cell activation leading to a number of autoimmune and inflammatory diseases. Preclinical studies show that Btk deficient mice are resistant to developing collagen- induced arthritis. Moreover, clinical studies of Rituxan, a CD20 antibody to deplete mature B-cells, reveal the key role of B-cells in a number of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis (Gurcan et al, Int. Immunopharmacol. 9: 10-25, 2009). Therefore, Btk inhibitors can be used to treat autoimmune and/or inflammatory diseases.
[0004] In addition, aberrant activation of Btk plays an important role in pathogenesis of B-cell lymphomas indicating that inhibition of Btk is useful in the treatment of hematological malignancies (Davis et al, Nature 463: 88-92, 2010). Preliminary clinical trial results showed that the Btk inhibitor PCI-32765 was effective in treatment of several types of B-cell lymphoma (for example, 54thAmerican Society of Hematology (ASH) annual meeting abstract, Dec. 2012: 686 The Bruton’s Tyrosine Kinase (Btk) Inhibitor, Ibrutinib (PCI- 32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multic enter, Open-Label, Phase I Study). Because Btk plays a central role as a mediator in multiple signal transduction pathways, inhibitors of Btk are of great interest as anti-inflammatory and/or anti-cancer agents {Mohamed et al., Immunol. Rev. 228: 58-73, 2009; Pan, Drug News perspect 21: 357-362, 200%; Rokosz et al., Expert Opin. Ther. Targets 12: 883-903, 2008; Uckun et al., Anti-cancer Agents Med. Chem. 7: 624-632, 2007; Lou et al, J. Med. Chem. 55(10): 4539-4550, 2012).
[0005] International application WO2014173289A disclosed a series of fused heterocyclic compounds as Btk inhibitors. In particular, WO2014173289A disclosed
(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetra-hydropyrazolo[l,5-a]pyrimi dine-3-carboxamide (hereinafter C
Compound 1
[0006] Compound 1 is a potent, specific and irreversible BTK kinase inhibitor. The data generated in preclinical studies using biochemical, cell based and animal studies suggested that Compound 1 could offer significant benefit in inhibiting tumor growth in B-cell malignancies. As Compound 1 was shown to be more selective than ibrutinib for inhibition of BTK vs. EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, and TEC, it is expected to give rise to less side-effects than ibrutinib in clinic. In addition, Compound 1 showed significantly less inhibition of rituximab-induced antigen-dependent cell-mediated cytotoxicity (ADCC) than ibrutinib due to weaker ITK inhibition, and therefore may provide better efficacy when combined with rituximab or other ADCC-dependent antibody in treating B-cell malignancies.
[0007] Preclinical safety evaluation has demonstrated that Compound 1 was safer than ibrutinib in terms of the overall tolerance and severe toxicities in both rat and dog single and repeat dose toxicity studies up to 28 days. Additionally, Compound 1 had better bioavailability without accumulation issues observed for ibrutinib. These unique characteristics warrant further evaluation of Compound 1 in clinical studies.
[0008] However, Compound 1 was found to be an amorphous form according to the preparation method for Compound 27 in WO 2014173289A, which was further confirmed by the X-Ray Powder Diffraction pattern of FIG. 7A. The amorphous form was shown to have a low glass transition temperature as shown in FIG. 7B, indicating some difficulties in the drug formulation with the amorphous form, such as low stability and hard to purify. Therefore, it’s necessary to develop a new form of Compound 1 which possesses characteristics such as high melting point and better stability, suitable for drug formulation.
Scheme 1: Preparation of Compound 1 and deuterium-labeled Compound 1
Deuterium-Labeled Compound 1
Step 15: Synthesis of
(S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolori,5-a1pyrimi dine-3-carboxamide (Compound 1
[0105] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHC03 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and
stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.
[0106] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.
Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)
-4,5,6,7-tetrahydropyrazolori,5-a1pyrimidine-3-carboxamide (Compound 1, alternative method)
[0107] A mixture of CHsCN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCCb (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3%> w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.
Step 16: Preparation of Crystalline Form A of Compound 1
[0108] The above cake of Compound 1 was dissolved in 7.0 volumes of DCM, and then swapped to solvent EA. After recrystallization from EA/MTBE, the cakes was collected by centrifugation, and was dried under vacuum. This gave 4.44 Kg product (Yield: 70.2%).
[0109] The product was then characterized by X-ray powder diffraction (XRPD) pattern method, which was generated on a PANalytical Empyrean X-ray powder diffractometer with the XRPD parameters as follows: X-Ray wavelength (Cu, ka, Kal (A): 1.540598, Ka2(A): 1.544426; Ka2/Kal intensity ratio: 0.50); X-Ray tube setting (45 Kv, 40mA); divergence slit (automatic); scan mode (Continuous); scan range (°2TH) (3°-40); step size (°2TH) (0.0131); scan speed (°/min) (about 10). The XRPD result found the resultant product as a crystalline shown in FIG. 1.
[0110] The differential scanning calorimetry (DSC) curves shown as in FIG. 2 was generated on a TA Q2000 DSC from TA Instruments. The DSC parameters used includes: temperature (25°C-desired temperature); heating rate (10°C/min) ; method (ramp); sample pan (aluminum, crimped); purge gas (N2). DSC result showed a sharp melting point at 139.4°C (onset temperature).
[0111] The thermo-gravimetric analysis (TGA) curves shown as in FIG. 3 was generated on a TA Q5000 TGA from TA Instruments. The TGA parameters used includes: temperature
(RT-desired temperature); heating rate (10°C/min); method (ramp); sample pan (platinum, open); purge gas (N2). TGA result showed is anhydrous with no weight loss even up to 110 °C.
[0112] The proton nuclear magnetic resonance ^H-NMR) shown as in FIG. 4 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. ¾-NMR (DMSO-de) δ 7.50 (d, J= 8.6 Hz, 2H), 7.46-7.38 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.08 (d, J= 7.6 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.85-6.72 (m, 1H), 6.67 (s, 1H), 6.07 (dd, J= 16.8, 2.2 Hz, 1H), 5.64 (dd, J= 10.4 Hz, 2.2 Hz, 1H), 4.55-4.38 (m, 1H), 4.17-3.94 (m, 2H), 3.33-3.22 (m, 2H), 3.08-2.88 (m, 1H), 2.67-2.51 (m, 1H), 2.36-2.15 (m, 1H), 2.12-1.82 (m, 2H), 1.79-1.65 (m, 1H), 1.63-1.49 (m, 1H), 1.38-1.08 (m, 2H).
[0113] The carbon nuclear magnetic resonance (13C-NMR) shown as in FIG. 5 was collected on a Bruker 400M NMR Spectrometer in DMSO-de. 13C-NMR spectra for Crystalline Form A of Compound 1.
Step 15: Synthesis of (S)-7-(1-acrvlovlpiperidin-4-vl)-2-(4-phenoxvphenyl)-4.5.6.7-tetrahvdropvrazolo[1.5-a1pvrimidine-3-carboxamide (Compound 1)
[0119] Under N2 atmosphere, ACN (12.0 v), water (12.5 v), BG-13 (8.0 Kg, 1.0 eq), and NaHCO3 (2.5 eq.) were added to a reactor. The mixture was then cooled to -5-0 °C. To the mixture, the solution of acryloyl chloride (1.1 eq.) in MeCN (0.5 v) was added dropwise and stirred until the reaction was completed. EA (6.0 v) was then added to the reactor, and stirred. The organic phase was collected. The aqueous layer was further extracted with EA (3.0 v). The organic phases were combined and washed with brine. The organic layer was collected and concentrated.
[0120] The residue was purified by silica gel (2 wt) column, eluted with 3% w/w methanol in DCM (21.0 v). The Compound 1 solution was collected and concentrated under vacuum. The residue was precipitated from EA/MTBE (2.0 v). The cake was collected by centrifugation as the product.
Step 15: Synthesis of (S)-7-(l-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl) -4.5.6.7-tetrahvdropvrazolori.5-a1pvrimidine-3-carboxamide (Compound 1. alternative method)
[0121] A mixture of CH3CN (10.0 v), purified water (5.0 v), NaOH (1.5 eq.) and BG-13 (1.0 eq.) was stirred to get a clear solution. EtOAc (6.0 v) was then charged to the reaction and separated. The organic phase was collected and washed with 15% brine (3.0 v) twice. The organic phase prepared above was concentrated and the solvent was swapped to CH3CN (residue volume: NMT 5.0 v). CH3CN (7.5 v) and purified water (12.5 v) were charged and cooled to 15-20°C. L-(+)-tartaric acid (0.5 eq) and NaHCO3 (2.5 eq.) were charged to the reaction mixture. A solution of acryloyl chloride (1.1 eq.) in CH3CN (0.5 v) was charged drop-wise to the reaction mixture. After the reaction was completed, EtOAc (6.0 v) was charged to the reaction mixture and organic layer was collected. Aqueous phase was further extracted with EA (3.0 v). The organic layers were combined, washed with 15% brine (5.0 v) and concentrated. The solvent was swapped to DCM (volume of residue: 1.5-2.0 v) and purified by silica gel column (silica gel: 100-200 mush, 2.0 w/ w; eluent: 3% w/ w MeOH in DCM (about 50 v). The collected solution was concentrated and swapped to EtOAc (4.0 v). MTBE (6.4 v) was charged drop-wise to residue at 50°C. The mixture was then cooled to 5°C and the cake was collected centrifugation.
References
- ^ “Zanubrutinib (Brukinsa) Use During Pregnancy”. Drugs.com. 3 January 2020. Retrieved 26 January 2020.
- ^ “Zanubrutinib”. DrugBank. Retrieved 15 November 2019.
- ^ Jump up to:a b c d “FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage”. U.S. Food and Drug Administration (FDA) (Press release). 14 November 2019. Retrieved 15 November 2019.
This article incorporates text from this source, which is in the public domain. - ^ “Brukinsa (zanubrutinib) FDA Approval History”. Drugs.com. 14 November 2019. Archived from the original on 15 November 2019. Retrieved 15 November 2019.
- ^ Jump up to:a b c d e f g h i “FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma”. U.S. Food and Drug Administration (FDA)(Press release). 15 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b c “Drug Trials Snapshots Brukinsa”. U.S. Food and Drug Administration (FDA). 14 November 2019. Retrieved 26 January 2020. This article incorporates text from this source, which is in the public domain.
- ^ “Zanubrutinib Orphan Drug Designation and Approval”. U.S. Food and Drug Administration (FDA). 28 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
- ^ “Drug Approval Package: Brukinsa”. U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 28 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
External links
- “Zanubrutinib”. Drug Information Portal. U.S. National Library of Medicine.
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| Clinical data | |
|---|---|
| Trade names | Brukinsa |
| Other names | BGB-3111 |
| AHFS/Drugs.com | Monograph |
| License data |
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| Pregnancy category |
|
| Routes of administration |
By mouth |
| Drug class | Bruton’s tyrosine kinase(BTK) inhibitor |
| Legal status | |
| Legal status |
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| Identifiers | |
| CAS Number | |
| PubChem CID | |
| PubChem SID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| Chemical and physical data | |
| Formula | C27H29N5O3 |
| Molar mass | 471.5509 g·mol−1 |
| 3D model (JSmol) | |
/////////////////Zanubrutinib, FDA 2019, ザヌブルチニブ , занубрутиниб , زانوبروتينيب , BGB-3111
Teprotumumab-trbw
Tepezza (teprotumumab-trbw)
Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease
UNIIY64GQ0KC0A
CAS number1036734-93-6
R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001
Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).
FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020
Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.
“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”
Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.
Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.
The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.
The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).[1]
The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache.[1] Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.[1]
It is a human monoclonal antibody developed by Genmab and Roche. It binds to IGF-1R.
Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, non-small cell lung cancer and sarcoma.[2][3] Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.
Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials.[4] It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema.[5] It was granted Breakthrough Therapy, Orphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.[6]
In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis.[7] In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED.[8] On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.[9]
History[edit]
Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.[1]
Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo.[1] Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.[1]
The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation.[1] The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.[1]
References
- ^ Jump up to:a b c d e f g h “FDA approves first treatment for thyroid eye disease”. U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020. This article incorporates text from this source, which is in the public domain.
- ^ https://clinicaltrials.gov/ct2/show/NCT01868997
- ^ http://adisinsight.springer.com/drugs/800015801
- ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
- ^ http://adisinsight.springer.com/drugs/800015801
- ^ http://www.genmab.com/product-pipeline/products-in-development/teprotumumab
- ^ Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”. The New England Journal of Medicine. 376 (18): 1748–1761. doi:10.1056/NEJMoa1614949. PMC 5718164. PMID 28467880.
- ^ “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”. Horizon Pharma plc. Retrieved 22 March 2019.
- ^ “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”. Horizon Therapeutics plc. Retrieved 27 August 2019.
External links
- “Teprotumumab”. Drug Information Portal. U.S. National Library of Medicine.
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | IGF-1R |
| Clinical data | |
| Other names | teprotumumab-trbw, RG-1507 |
| ATC code |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| DrugBank | |
| ChemSpider |
|
| UNII | |
| KEGG | |
| ChEMBL | |
| ECHA InfoCard | 100.081.384  |
| Chemical and physical data | |
| Formula | C6476H10012N1748O2000S40 |
| Molar mass | 145.6 kg/mol g·mol−1 |
/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza, Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS, active thyroid eye disease, Teprotumumab
https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease
ENCORAFENIB, エンコラフェニブ
ENCORAFENIB, エンコラフェニブ
UNII:8L7891MRB6
Formula:C22H27ClFN7O4S, Average: 540.01
1269440-17-6
- BRAFTOVI
- NVP-LGX818
- NVP-LGX-818-NXA
- NVP-LGX818-NXA
- ENCORAFENIB [USAN]
- ENCORAFENIB [WHO-DD]
- ENCORAFENIB
- ENCORAFENIB [INN]
- METHYL N-((2S)-1-((4-(3-(5-CHLORO-2-FLUORO-3-(METHANESULFONAMIDO)PHENYL)(-1-(PROPAN-2-YL)-1H-PYRAZOL-4-YL(PYRIMIDIN-2-YL)AMINO)PROPAN-2-YL)CARBAMATE
- CARBAMIC ACID, N-((1S)-2-((4-(3-(5-CHLORO-2-FLUORO-3-((METHYLSULFONYL)AMINO)PHENYL)-1-(1-METHYLETHYL)-1H-PYRAZOL-4-YL)-2-PYRIMIDINYL)AMINO)-1-METHYLETHYL)-, METHYL ESTER
- LGX818
- LGX-818
Encorafenib, also known as BRAFTOVI, is a kinase inhibitor. Encorafenib inhibits BRAF gene, which encodes for B-raf protein, which is a proto-oncogene involved in various genetic mutations Label. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which impacts cell division, differentiation, and secretion. Mutations in this gene, most frequently the V600E mutation, are the most commonly identified cancer-causing mutations in melanoma, and have been isolated in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of the lung 6.
On June 27, 2018, the Food and Drug Administration approved encorafenib and Binimetinib(BRAFTOVI and MEKTOVI, Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test Label.
Array Biopharma (a wholly owned subsidiary of Pfizer ), under license from Novartis , and licensees Pierre Fabre and Ono Pharmaceutical have developed and launched the B-Raf kinase inhibitor encorafenib . In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.
Encorafenib (trade name Braftovi) is a drug for the treatment of certain melanomas. It is a small molecule BRAF inhibitor [1] that targets key enzymes in the MAPK signaling pathway. This pathway occurs in many different cancers including melanoma and colorectal cancers.[2] The substance was being developed by Novartis and then by Array BioPharma. In June 2018, it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[3][4]
The most common (≥25%) adverse reactions in patients receiving the drug combination were fatigue, nausea, diarrhea, vomiting, abdominal pain, and arthralgia.[3]
Indication
Used in combination with Binimetinib in metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test 5.
Associated Conditions
Pharmacodynamics
Encorafenib has shown improved efficacy in the treatment of metastatic melanoma 3.
Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis 7.
Once-daily dosing of single-agent encorafenib has a distinct tolerability profile and shows varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic stage melanoma 7.
Mechanism of action
Encorafenib is a kinase inhibitor that specifically targets BRAF V600E, as well as wild-type BRAF and CRAF while tested with in vitro cell-free assays with IC50 values of 0.35, 0.47, and 0.3 nM, respectively. Mutations in the BRAF gene, including BRAF V600E, result in activated BRAF kinases that mahy stimulate tumor cell growth. Encorafenib is able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and significantly reduce ligand binding to these kinases at clinically achievable concentrations (≤ 0.9 μM) Label.
In efficacy studies, encorafenib inhibited the in vitro cell growth of tumor cell lines that express BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing the BRAF V600E mutation, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression Label.
Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib result in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. In addition to the above, the combination of encorafenib and binimetinib acted to delay the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared with the administration of either drug alone Label.
Pharmacology
Encorafenib acts as an ATP-competitive RAF kinase inhibitor, decreasing ERK phosphorylation and down-regulation of CyclinD1.[5]This arrests the cell cycle in G1 phase, inducing senescence without apoptosis.[5] Therefore it is only effective in melanomas with a BRAF mutation, which make up 50% of all melanomas.[6] The plasma elimination half-life of encorafenib is approximately 6 hours, occurring mainly through metabolism via cytochrome P450 enzymes.[7]
Clinical trials
Several clinical trials of LGX818, either alone or in combinations with the MEK inhibitor MEK162,[8] are being run. As a result of a successful Phase Ib/II trials, Phase III trials are currently being initiated.[9]
History
Approval of encorafenib in the United States was based on a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT01909453) in 577 patients with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma.[3] Patients were randomized (1:1:1) to receive binimetinib 45 mg twice daily plus encorafenib 450 mg once daily, encorafenib 300 mg once daily, or vemurafenib 960 mg twice daily.[3] Treatment continued until disease progression or unacceptable toxicity.[3]
The major efficacy measure was progression-free survival (PFS) using RECIST 1.1 response criteria and assessed by blinded independent central review.[3] The median PFS was 14.9 months for patients receiving binimetinib plus encorafenib, and 7.3 months for the vemurafenib monotherapy arm (hazard ratio 0.54, 95% CI: 0.41, 0.71, p<0.0001).[3] The trial was conducted at 162 sites in Europe, North America and various countries around the world.[4]
SYN
PATENT
WO2010010154 , expiry , EU states, 2029, US in 2030 with US154 extension.
WO 2011025927
WO 2016089208
Patent
WO-2020011141
Novel deuterated analogs of diarylpyrazole compounds, particularly encorafenib are B-RAF and C-RAF kinase inhibitors, useful for treating proliferative diseases such as melanoma and colorectal cancer. Family members of the product case, WO2010010154 , expire in most of the EU states until 2029 and will expire in the US in 2030 with US154 extension. In January 2020, the US FDA’s Orange Book was seen to list encorafenib patents such as US8946250 , US8501758 , US9314464 and US9763941 , expiring in the range of 2029-2032. At that time Orange Book also reported that encorafenib as having NCE exclusivity expiring on July 27, 2023.
PAPER
European journal of cancer (Oxford, England : 1990) (2018), 88, 67-76.
References
- ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”. Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.
- ^ Burotto M, Chiou VL, Lee JM, Kohn EC (November 2014). “The MAPK pathway across different malignancies: a new perspective”. Cancer. 120 (22): 3446–56. doi:10.1002/cncr.28864. PMC 4221543. PMID 24948110.
- ^ Jump up to:a b c d e f g “FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations”. U.S. Food and Drug Administration (FDA)(Press release). 27 June 2018. Archived from the original on 18 December 2019. Retrieved 28 June 2018. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b “Drug Trial Snapshot: Braftovi”. U.S. Food and Drug Administration (FDA). 16 July 2018. Archived from the original on 19 December 2019. Retrieved 18 December 2019. This article incorporates text from this source, which is in the public domain.
- ^ Jump up to:a b Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S (January 2016). “Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells”. Cancer Letters. 370 (2): 332–44. doi:10.1016/j.canlet.2015.11.015. PMID 26586345.
- ^ Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, et al. (July 2012). “A landscape of driver mutations in melanoma”. Cell. 150 (2): 251–63. doi:10.1016/j.cell.2012.06.024. PMC 3600117. PMID 22817889.
- ^ Koelblinger P, Thuerigen O, Dummer R (March 2018). “Development of encorafenib for BRAF-mutated advanced melanoma”. Current Opinion in Oncology. 30 (2): 125–133. doi:10.1097/CCO.0000000000000426. PMC 5815646. PMID 29356698.
- ^ “18 Studies found for: LGX818”. Clinicaltrials.gove.
- ^ Clinical trial number NCT01909453 for “Study Comparing Combination of LGX818 Plus MEK162 and LGX818 Monotherapy Versus Vemurafenib in BRAF Mutant Melanoma (COLUMBUS)” at ClinicalTrials.gov
External links
- “Encorafenib”. Drug Information Portal. U.S. National Library of Medicine.
- Li Z, Jiang K, Zhu X, Lin G, Song F, Zhao Y, Piao Y, Liu J, Cheng W, Bi X, Gong P, Song Z, Meng S: Encorafenib (LGX818), a potent BRAF inhibitor, induces senescence accompanied by autophagy in BRAFV600E melanoma cells. Cancer Lett. 2016 Jan 28;370(2):332-44. doi: 10.1016/j.canlet.2015.11.015. Epub 2015 Nov 14. [PubMed:26586345]
- Koelblinger P, Thuerigen O, Dummer R: Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018 Mar;30(2):125-133. doi: 10.1097/CCO.0000000000000426. [PubMed:29356698]
- Moschos SJ, Pinnamaneni R: Targeted therapies in melanoma. Surg Oncol Clin N Am. 2015 Apr;24(2):347-58. doi: 10.1016/j.soc.2014.12.011. Epub 2015 Jan 24. [PubMed:25769717]
- Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M, Liszkay G, Garbe C, Schadendorf D, Krajsova I, Gutzmer R, Chiarion-Sileni V, Dutriaux C, de Groot JWB, Yamazaki N, Loquai C, Moutouh-de Parseval LA, Pickard MD, Sandor V, Robert C, Flaherty KT: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018 May;19(5):603-615. doi: 10.1016/S1470-2045(18)30142-6. Epub 2018 Mar 21. [PubMed:29573941]
- FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
- BRAF B-Raf proto-oncogene, serine/threonine kinase [ Homo sapiens (human) ] [Link]
- Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma [Link]
- Encorafenib FDA label [File]
- Encorafenib review [File]
 |
|
| Clinical data | |
|---|---|
| Trade names | Braftovi |
| Other names | LGX818 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a618040 |
| License data |
|
| Routes of administration |
Oral |
| Drug class | Antineoplastic Agents |
| ATC code | |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C22H27ClFN7O4S |
| Molar mass | 540.011 g/mol g·mol−1 |
| 3D model (JSmol) | |
///////////ENCORAFENIB, 1269440-17-6, BRAFTOVI, NVP-LGX818, LGX818, LGX 818, エンコラフェニブ ,
COC(=O)N[C@@H](C)CNc1nccc(n1)c2cn(nc2c3cc(Cl)cc(NS(=O)(=O)C)c3F)C(C)C
patent
[TABLE 0001]
| APCI | Atmospheric pressure chemical dissociation |
| HPLC | High performance liquid chromatography |
| TLC | TLC |
| h | hour |
| DMF | N, N-dimethylformamide |
| K 2 CO 3 | Potassium carbonate |
| DCM | Dichloromethane |
| THF | Tetrahydrofuran |
| CH 3 MgBr | Methyl magnesium bromide |
| PTSA | p-Toluenesulfonic acid |
| TFA | Trifluoroacetate |
| NMP | N-methylpyrrolidone |
| Diguanidinium carbonate | Guanidine carbonate |
| MTBE | Methyl tert-butyl ether |
| POCl 3 | Phosphorus oxychloride |
| DMSO | Dimethyl sulfoxide |
| Pd (dppf) Cl 2 | [1,1′-Bis (diphenylphosphino) ferrocene] Palladium dichloride |
| Dioxane | Dioxane |
| TsCl | 4-toluenesulfonyl chloride |
| Boc | Tert-butoxy carbon |
| DIPEA | N, N-diisopropylethylamine |
| CDCl 3 | Deuterated chloroform |
| TEA | Triethylamine |
| DMAP | 4-dimethylaminopyridine |
| Na 2 CO 3 | Sodium carbonate |
| HCl | hydrochloric acid |
[表 0002]
| MsCl | Methanesulfonyl chloride |
| Tol | Toluene |
GRAPIPRANT
GRAPIPRANT
- Molecular FormulaC26H29N5O3S
- Average mass491.605 Da
CAS 415903-37-6
UNII-J9F5ZPH7NB, CJ 023423, CJ-023423,
Phase II, Arrys Therapeutics, CANCER,
PAIN, AskAt Phase II,
- N-[[[2-[4-(2-Ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]amino]carbonyl]-4-methylbenzenesulfonamide
- 1-[2-[4-(2-Ethyl-4,6-dimethylimidazo[4,5-c]pyridin-1-yl)phenyl]ethyl]-3-(4-methylphenyl)sulfonylurea
- 2-Ethyl-4,6-dimethyl-1-[4-[2-[[[[(4-methylphenyl)sulfonyl]amino]carbonyl]amino]ethyl]phenyl]-1H-imidazo[4,5-c]pyridine
- AAT 007
- CJ 023423
- Grapiprant
- MR 10A7
- RQ 00000007
- RQ 7
Synonyms and Mappings
- 415903-37-6
- GRAPIPRANT [GREEN BOOK]
- CJ-023
- GRAPIPRANT [INN]
- GRAPIPRANT [WHO-DD]
- MR-10A7
- AAT-007
- MR10A7
- RQ-00000007
- RQ-7
- GRAPIPRANT [USAN]
- GRAPIPRANT
- 2-ETHYL-4,6-DIMETHYL-1-(4-(2-(((((4-METHYLPHENYL)SULFONYL)AMINO)CARBONYL)AMINO)ETHYL)PHENYL)-1H-IMIDAZO(4,5-C)PYRIDINE
- N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYLBENZENESULFONAMIDE
- CJ 023423
- BENZENESULFONAMIDE, N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-
- CJ-023,423
- N-(((2-(4-(2-ETHYL-4,6-DIMETHYL-1H-IMIDAZO(4,5-C)PYRIDIN-1-YL)PHENYL)ETHYL)AMINO)CARBONYL)-4-METHYL-BENZENESULFONAMIDE
- CJ-023423
SYN
Arrys Therapeutics (under license from AskAt ) and affiliate Ikena Oncology (formerly known as Kyn Therapeutics ) are developing ARY-007 , an oral formulation of grapiprant, for treating cancers; in December 2019, preliminary data were expected in 2020
Grapiprant (trade name Galliprant) is a small molecule drug that belongs in the piprant class. This analgesic and anti-inflammatory drug is primarily used as a pain relief for mild to moderate inflammation related to osteoarthritis in dogs. Grapiprant has been approved by the FDA’s Center for Veterinary Medicine and was categorized as a non-cyclooxygenase inhibiting non-steroidal anti-inflammatory drug (NSAID) in March 2016.[1]
Preclinical studies also indicate that grapiprant is not only efficacious as a acute pain but also in chronic pain relief and inflammation drug. The effect of the drug is directly proportional to the dosage and its effects were comparable to human medication such as rofecoxib and piroxicam.[2]
Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).
Grapiprant is also used in humans, and was researched to be used as a pain control and inflammation associated with osteoarthritis. The effect of grapiprant could be explained through the function of prostaglandin E2, in which acts as a pro-inflammatory mediator of redness of the skin, edema and pain which are the typical signs of inflammation. The effect of PGE2 stems from its action through the four prostaglandin receptor subgroups EP1, EP2, EP3 and EP4, in which the prostaglandin EP4 receptor acts as the main intermediary of the prostaglandin-E2-driven inflammation. Grapiprant is widely accepted in veterinary medicine due to its specific and targeted approach to pain management in dogs. The serum concentration of grapiprant is increased when used in conjunction with other drugs such as acetaminophen, albendazole, and alitretinoin.
Common side effects are intestinal related effects such as mild diarrhea, appetite loss, and vomiting.[3] Additionally, it is found that it might lead to reduced tear production due to it being a sulfa-based medication and also reduced albumin levels.
Grapiprant, a prostanoid EP4 receptor antagonist, is in phase II clinical trials at AskAt for the treatment of chronic pain. Phase I/II clinical trials are ongoing at Arrys Therapeutics in combination with pembrolizumab for the treatment of patients with microsatellite stable colorectal cancer and in patients with advanced or metastatic PD-1/L1 refractory non-small cell lung cancer (NSCLC).
Medical uses
Grapiprant is used once a day as an oral pain relief for dogs with inflammation-related osteoarthritis. It is a non-steroidal anti-inflammatory (NSAID) that functions as a targeted action to treat osteoarthritis pain and inflammation in dogs.
Mechanism of action
Grapiprant acts as a specific antagonist that binds and blocks the prostaglandin EP4 receptor, one out of the four prostaglandin E2 (PGE2) receptor subgroups. The EP4 receptor then mediates the prostaglandin-E2-elicited response to pain, and hence grapiprant was proven to be effective in the decrease of pain in several inflammatory pain models of rats. It was also proven to be effective in reducing osteoarthritis-related pain in humans, which serves as a proof for its mechanism of action. The approximate calculation for canine efficacy dose is between the range of 1.3 and 1.7 mg/kg, in conjunction with a methylcellulose suspending agent. Based on the calculations from the comparisons of binding affinity of grapiprant to the EP4 receptors of dogs, rats, and humans, the study of plasma and serum protein binding determinations, the effective doses determined in inflammation pain models of rats, and human-related clinical studies, it is evaluated that Grapiprant should be administered just once a day. The approved dose of the commercial Grapiprant tablet by the FDA for the pain relief and inflammation associated with osteoarthritis to dogs is reported to be 2 mg/kg a day.[4]
Absorption
Studies in animals such as horses have shown the presence of Grapiprant in serum 72 hours with a concentration >0.005 ng/ml after the initial administration of a dose of 2 mg/kg. Grapiprant is expeditiously absorbed and the reported serum concentration was reported to be 31.9 ng/ml in an amount of time of 1.5 hours. The actual body exposure to grapiprant after administration of one dose was shown to be 2000 ng.hr/ml. The degree and rate at which grapiprant is absorbed into the body, presents a mean bioavailability of 39%. A significant reduction in the bioavailability, concentration time and maximal concentration were reported to have occurred after food intake.[1] And thus, grapiprant is usually not administered with food as it will not be as efficient.[5]
Distribution
The volume of distribution in cat studies was reported to be 918 ml/kg.[1]
Route of elimination
Following an oral administration, the majority of the dose was metabolized within the first 72 hours. Equine studies have shown that grapiprant is present in urine 96 hours after the first administration of a dose of 2 mg/kg and has a concentration >0.005 ng/ml. From the excreted dose conducted in horses, it is found that 55%, 15% and 19% of the orally-administered dose was excreted in bile, urine, and faeces respectively.[1]
Toxicity
Safety studies conducted on grapiprant have demonstrated that it generally possesses an exceptional safety profile and a wide safety margin in veterinary studies.[6] In animal studies, a research on 2.5-12 times overdose was conducted for grapiprant and the study resulted in soft-blobs and mucous-filled faeces, occasional bloody stools and emesis.
PATENT
WO-2020014465
Novel crystalline forms of grapiprant and their salts eg HCl (designated as Form A), useful for inhibiting prostaglandin EP4 receptor activity and treating cancers.
Prostaglandins are mediators of pain, fever and other symptoms associated with inflammation. Prostaglandin E2 (PGE2) is the predominant eicosanoid detected in inflammation conditions. In addition, it is also involved in various physiological and/or pathological conditions such as hyperalgesia, uterine contraction, digestive peristalsis, awakeness, suppression of gastric acid secretion, blood pressure, platelet function, bone metabolism, angiogenesis or the like.
[0003] Four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) displaying different pharmacological properties exist. The EP4 subtype, a Gs-coupled receptor, stimulates cAMP production as well as PI3K and GSK3P signaling, and is distributed in a wide variety of tissue suggesting a major role in PGE2-mediated biological events. Various EP4 inhibitors have been described previously, for example, in WO 2002/032900, WO 2005/021508, EiS 6,710,054, and US 7,238,714, the contents of which are incorporated herein by reference in their entireties.
[0004] Accordingly, there is a need for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. The present invention addresses such a need.
It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and/or reducing severity of a proliferative disorder associated with prostaglandin EP4 receptor activity. In general, salt forms and co-crystal forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of proliferative disorders associated with prostaglandin EP4 receptor activity, as described in detail herein. Such compounds are represented by the chemical structure below, denoted as compound A (also known as grapiprant):
A
or a pharmaceutically acceptable salt thereof.
United States Patent 7,960,407, filed March 1, 2006 and issued June 14, 2011 (“the ‘407 patent,” the entirety of which is hereby incorporated herein by reference), describes certain EP4 inhibitor compounds. Such compounds include compound A:
or a pharmaceutically acceptable salt thereof.
[0037] Compound A, N-[({2-[4-(2-Ethyl-4,6-dimethyl-lH-imidazo[4,5-c]pyridin-l-yl) phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide, is described in detail in the ‘407
patent, including its synthetic route. The ‘407 patent also discloses a variety of physical forms of compound A.
[0038] It would be desirable to provide a solid form of compound A (e.g., as a co-crystal thereof or salt thereof) that imparts characteristics such as improved aqueous solubility, stability and ease of formulation. Accordingly, the present invention provides both co-crystal forms and salt forms of compound A:
A.
PATENT
WO 2002032900
PATENT
WO 2002032422
Family members of the product case ( WO0232422 ) of grapiprant have protection in most of the EU states until October 2021 and expire in the US in October 15, 2021.
PATENT
WO 2003086371
PATENT
WO2020014445 covering combinations of grapiprant and an immuno-oncology agent.
WO 2005102389
WO 2006095268
US 7960407
US 20190314390
References
- ^ Jump up to:a b c d “Grapiprant”. http://www.drugbank.ca. Retrieved 2019-05-15.
- ^ PubChem. “Grapiprant”. pubchem.ncbi.nlm.nih.gov. Retrieved 2019-05-15.
- ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”. VIN.com.
- ^ Nagahisa, A.; Okumura, T. (2017). “Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs”. Journal of Veterinary Pharmacology and Therapeutics. 40 (3): 285–292. doi:10.1111/jvp.12349. ISSN 1365-2885. PMID 27597397.
- ^ Paul Pion, D. V. M.; Spadafori, Gina (2017-08-08). “Veterinary Partner”. VIN.com.
- ^ Kirkby Shaw, Kristin; Rausch-Derra, Lesley C.; Rhodes, Linda (February 2016). “Grapiprant: an EP4 prostaglandin receptor antagonist and novel therapy for pain and inflammation”. Veterinary Medicine and Science. 2 (1): 3–9. doi:10.1002/vms3.13. ISSN 2053-1095. PMC 5645826. PMID 29067176.
 |
|
| Clinical data | |
|---|---|
| Trade names | Galliprant |
| Routes of administration |
Oral |
| ATCvet code | |
| Pharmacokinetic data | |
| Bioavailability | 6.6 L/kg, high volume of distribution |
| Elimination half-life | 5.86 hours in horses |
| Excretion | Urine |
| Identifiers | |
| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C26H29N5O3S |
| Molar mass | 491.61 g·mol−1 |
| 3D model (JSmol) | |
//////////////GRAPIPRANT, 415903-37-6, UNII-J9F5ZPH7NB, CJ 023423, CJ-023423, RQ-00000007, MR10A7, Galliprant, Phase II, Arrys Therapeutics, CANCER, PAIN, AskAt
CCC1=NC2=C(N1C3=CC=C(C=C3)CCNC(=O)NS(=O)(=O)C4=CC=C(C=C4)C)C=C(N=C2C)C
Brilliant blue G , ブリリアントブルーG ,
Brilliant blue G
FDA 2019, 12/20/2019, TISSUEBLUE, New Drug Application (NDA): 209569
Company: DUTCH OPHTHALMIC, PRIORITY; Orphan
OPQ recommends APPROVAL of NDA 209569 for commercialization of TissueBlue (Brilliant Blue G Ophthalmic Solution), 0.025%
Neuroprotectant
sodium;3-[[4-[[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]-2-methylcyclohexa-2,5-dien-1-ylidene]methyl]-N-ethyl-3-methylanilino]methyl]benzenesulfonate
| Formula |
C47H48N3O7S2. Na
|
|---|---|
| CAS |
6104-58-1
|
| Mol weight |
854.0197
|
ブリリアントブルーG, C.I. Acid Blue 90
UNII-M1ZRX790SI
M1ZRX790SI
6104-58-1
Brilliant Blue G
Derma Cyanine G
SYN
////////////Brilliant blue G , ブリリアントブルーG , C.I. Acid Blue 90, FDA 2019, PRIORITY, Orphan
CCN(CC1=CC(=CC=C1)S(=O)(=O)[O-])C2=CC(=C(C=C2)C(=C3C=CC(=[N+](CC)CC4=CC(=CC=C4)S(=O)(=O)[O-])C=C3C)C5=CC=C(C=C5)NC6=CC=C(C=C6)OCC)C.[Na+]
- Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, hydroxide, inner salt, monosodium salt
- Benzenemethanaminium, N-[4-[[4-[(4-ethoxyphenyl)amino]phenyl][4-[ethyl[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylene]-3-methyl-2,5-cyclohexadien-1-ylidene]-N-ethyl-3-sulfo-, inner salt, monosodium salt (9CI)
- Brilliant Indocyanine G (6CI)
- C.I. Acid Blue 90 (7CI)
- C.I. Acid Blue 90, monosodium salt (8CI)
- Acid Blue 90
- Acid Blue G 4061
- Acid Blue PG
- Acid Bright Blue G
- Acid Brilliant Blue G
- Acid Brilliant Cyanine G
- Acidine Sky Blue G
- Amacid Brilliant Cyanine G
- Anadurm Cyanine A-G
- BBG
- Benzyl Cyanine G
- Biosafe Coomassie Stain
- Boomassie blue silver
- Brilliant Acid Blue G
- Brilliant Acid Blue GI
- Brilliant Acid Blue J
- Brilliant Acid Cyanine G
- Brilliant Blue G
- Brilliant Blue G 250
- Brilliant Blue J
- Brilliant Indocyanine GA-CF
- Bucacid Brilliant Indocyanine G
- C.I. 42655
- CBB-G 250
- Colocid Brilliant Blue EG
- Coomassie Blue G
- Coomassie Blue G 250
- Coomassie Brilliant Blue G
- Coomassie Brilliant Blue G 250
- Coomassie G 250
- Cyanine G
- Daiwa Acid Blue 300
- Derma Cyanine G
- Derma Cyanine GN 360
- Dycosweak Acid Brilliant Blue G
- Eriosin Brilliant Cyanine G
- Fenazo Blue XXFG
- Impero Azure G
- Kayanol Cyanine G
- Lerui Acid Brilliant Blue G
- Milling Brilliant Blue 2J
- NSC 328382
- Optanol Cyanine G
- Orient Water Blue 105
- Orient Water Blue 105S
- Polar Blue G
- Polar Blue G 01
- Polycor Blue G
- Sandolan Cyanine N-G
- Sellaset Blue B
- Serva Blue G
- Serva Blue G 250
- Silk Fast Cyanine G
- Simacid Blue G 350
- Sumitomo Brilliant Indocyanine G
- Supranol Cyanin G
- Supranol Cyanine G
- TissueBlue
- Triacid Fast Cyanine G
- Water Blue 105
- Water Blue 105S
- Water Blue 150
- Xylene Brilliant Cyanine G
Fluorodopa F 18, フルオロドパ (18F), флуородопа (18F) , فلورودوبا (18F) , 氟[18F]多巴 ,
Fluorodopa F 18
2019/10/10, fda 2019,
| Formula |
C9H10FNO4
|
|---|---|
| Cas |
92812-82-3
|
| Mol weight |
215.1784
|
Diagnostic aid (brain imaging), Radioactive agent, for use in positron emission tomography (PET)
CAS 92812-82-3
フルオロドパ (18F)
Fluorodopa, also known as FDOPA, is a fluorinated form of L-DOPA primarily synthesized as its fluorine-18isotopologue for use as a radiotracer in positron emission tomography (PET).[1] Fluorodopa PET scanning is a valid method for assessing the functional state of the nigrostriatal dopaminergic pathway. It is particularly useful for studies requiring repeated measures such as examinations of the course of a disease and the effect of treatment
In October 2019, Fluorodopa was approved in the United States for the visual detection of certain nerve cells in adult patients with suspected Parkinsonian Syndromes (PS).[2][3]
The U.S. Food and Drug Administration (FDA) approved Fluorodopa F 18 based on evidence from one clinical trial of 56 patients with suspected PS.[2] The trial was conducted at one clinical site in the United States.[2]
PAPER
A one-pot two-step synthesis of 6-[18F]fluoro-L-DOPA ([18F]FDOPA) has been developed involving Cu-mediated radiofluorination of a pinacol boronate ester precursor. The method is fully automated, provides [18F]FDOPA in good activity yield (104 ± 16 mCi, 6 ± 1%), excellent radiochemical purity (>99%) and high molar activity (3799 ± 2087 Ci mmol−1), n = 3, and has been validated to produce the radiotracer for human use.
![Graphical abstract: One-pot synthesis of high molar activity 6-[18F]fluoro-l-DOPA by Cu-mediated fluorination of a BPin precursor](https://pubs.rsc.org/en/Image/Get?imageInfo.ImageType=GA&imageInfo.ImageIdentifier.ManuscriptID=C9OB01758E&imageInfo.ImageIdentifier.Year=2019 "Graphical abstract")
PATENT
KR 2019061368
The present invention relates to an L-dopa precursor compd., a method for producing the same, and a method for producing 18F-labeled L-dopa using the same. The method of prepg. 18F-labeled L-dopa I using the L-dopa precursor II [A = halogen-(un)substituted alkyl; W, X, Y = independently protecting group] can improve the labeling efficiency of 18F. After the labeling reaction, sepn. and purifn. steps of the product can be carried out continuously and it can be performed with on-column labeling (a method of labeling through the column). The final product I, 18 F-labeled L-dopa, can be obtained at a high yield relative to conventional methods. Further, it has an advantage that it is easy to apply various methods such as bead labeling.
PAPER
Science (Washington, DC, United States) (2019), 364(6446), 1170-1174.
PAPER
European Journal of Organic Chemistry (2018), 2018(48), 7058-7065.
PATENT
WO 2018115353
CN 107311877
References
- ^ Deng WP, Wong KA, Kirk KL (June 2002). “Convenient syntheses of 2-, 5- and 6-fluoro- and 2,6-difluoro-L-DOPA”. Tetrahedron: Asymmetry. 13 (11): 1135–1140. doi:10.1016/S0957-4166(02)00321-X.
- ^ Jump up to:a b c “Drug Trials Snapshots: Fluorodopa F 18”. U.S. Food and Drug Administration (FDA). 27 November 2019. Archived from the original on 27 November 2019. Retrieved 27 November 2019. This article incorporates text from this source, which is in the public domain.
- ^ “Drug Approval Package: Fluorodopa F18”. U.S. Food and Drug Administration (FDA). 20 November 2019. Archived from the original on 27 November 2019. Retrieved 26 November 2019. This article incorporates text from this source, which is in the public domain.
 |
|
| Clinical data | |
|---|---|
| Other names | 6-fluoro-L-DOPA, FDOPA |
| License data |
|
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C9H10FNO4 |
| Molar mass | 215.18 g/mol g·mol−1 |
| 3D model (JSmol) | |
//////////////////Fluorodopa F 18, フルオロドパ (18F), FDA 2019, флуородопа (18F) , فلورودوبا (18F) , 氟[18F]多巴 , radio labelled
N[C@@H](CC1=CC(O)=C(O)C=C1[18F])C(O)=O
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
