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Ritlecitinib, PF 06651600

August 5, 2019 11:40 am / Leave a comment

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Ritlecitinib

PF-06651600

CAS 1792180-81-4

C₁₅H₁₉N₅O, 285.34, UNII-2OYE00PC25

Fda approved Litfulo, 6/23/2023, To treat severely patchy hair loss
Drug Trials Snapshot

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one

Image result for PF-06651600

1-[(2S,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-piperidinyl]-2-propen-1-one malonate

PF-06651600 malonate
CAS: 2140301-97-7 (malonate)
Chemical Formula: C18H23N5O5

Molecular Weight: 389.412

PHASE 2 alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.

Ritlecitinib, sold under the brand name Litfulo, is a medication used for the treatment of severe alopecia areata (hair loss).^[6] Ritlecitinib is a kinase inhibitor which inhibits Janus kinase 3 and tyrosine kinase.^[6]^[9]^[10]

The most common side effects include headache, diarrhea, acne, rashes, eczema, fever, mouth ulcers, dizziness, shingles rash, and abnormal findings in some laboratory test results.^[11]

Ritlecitinib was approved for medical use in the United States in June 2023,^[6]^[11]^[12] in the European Union in September 2023,^[7] and in Canada in November 2023.^[4]

Pfizer is developing ritlecitinib, an irreversible, covalent and selective dual JAK3/TEC inhibitor, for treating AA, RA, vitiligo and inflammatory bowel diseases, including UC and CD. In July 2021, this drug was reported to be in phase 3 clinical development.

PF-06651600 is a potent and selective JAK3 inhibitor. PF-06651600 is a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor PF-06651600 led to its evaluation in several human clinical studies. JAK3 was among the first of the JAKs targeted for therapeutic intervention due to the strong validation provided by human SCID patients displaying JAK3 deficiencies

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitors in development as potential medicines. PF-06651600 is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile, and ADME properties, this JAK3-specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Supported by positive results from a Phase 2 study, 1 was granted Breakthrough Therapy designation by the FDA on Sept. 5, 2018 for treatment of alopecia areata.

SYN

PAPER

J. Med. Chem. 2017, 60 (5), 1971–1993, DOI: 10.1021/acs.jmedchem.6b01694

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01694

Paper

Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600,

Yong Tao*

Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX

Publication Date:July 19, 2019

https://doi.org/10.1021/acs.oprd.9b00198

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO₂ with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00198

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate (1·TsOH)

1·TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. Mp 199 °C. Rotomers observed for NMR spectroscopies. ¹H NMR (400 MHz, DMSO-d6): δ ppm 12.68 (brs, 1H), 9.22 (brs, 1H), 8.40 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1.2 Hz, 1H), 6.84 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1.91–1.72 (m, 4H), 1.24–1.17 (m, 3H). ¹³C NMR (100 MHz, DMSO-d6): δ ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51, 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41, 25.22, 21.28, 16.97, 15.51. HRMS (ESI) m/z: calculated for C₁₅H₂₀N₅O [M + H]⁺286.1668; observed 286.1692.

PAPER

Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.

PATENT

WO2015083028

PATENT

WO 2015083028

https://patents.google.com/patent/WO2015083028A1

PATENT

WO 2020084435

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020084435&tab=PCTDESCRIPTION&_cid=P12-KIL68Y-23557-1

1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one has the structural formula:

The synthesis of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is described in WO2015/083028, commonly assigned to the assignee of the present invention and which is incorporated herein by reference in its entirety. 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is useful as an inhibitor of protein kinases, such as the enzyme Janus Kinase (JAK) and as such is useful therapy as an immunosuppressive agent for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, alopecia, vitiligo, Alzheimer’s disease, leukemia and other indications where immunosuppression would be desirable. See ACS Chem. Biol. , 2016, 11 (12), pp 3442-3451 . The present invention relates to a novel p-toluenesulfonic acid salt and crystalline solid form of the said salt of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one that demonstrate improved properties for use in a pharmaceutical dosage form, particularly for oral dosage forms.

Preparations

Scheme 1. Synthesis of 1

Scheme 2. Alternate Synthesis of Intermediates 7 and 10

1. K₂C0₃, MIBK/water 1. H₂, H₂O

2. EtOAc, aq. NaCI Pd(OH)₂/C (wet)

3. MeOH, H₂0 2. NaOH, MeOH

7 + 8 – _► 9 – – 10 . H₂O

89% 89%

Scheme 3. First Alternate Preparation of 1

Scheme 4. Second Alternate Preparation of 1

Preparation 1

ferf-Butyl (6-methylpyridin-3-yl)carbamate (3). To a 3000L reactor was charged 2 (72.00 kg, 665.8 mol) and THF (660 kg). A solution of NH4CI (1 .07 kg , 20 mol) in water (72 kg, 4000 mol) was added. The mixture was heated to 57 °C and Di-f-butyl dicarbonate (220.0 kg, 1003 mol) was added slowly with rinse of THF (45 kg) while maintaining the temperature between 55 – 60 °C. The mixture was stirred at 55 – 60 °C for 10 h. Upon reaction completion, the slurry was cooled to 20 °C and ethyl acetate (654 kg) and water (367 kg) were added. The organic phase was separated, washed by water (2 x 360 kg) and stirred with active carbon (22 kg) for 5 h. The mixture was filtered through a layer of diatomaceous earth (22 kg) with THF rinse and the filtrates were concentrated under vacuum at <40 °C to a residual volume of ~370 L. n-Heptane (500 kg) was added slowly over 1 h and the resulting slurry was cooled to 20 °C and stirred for 2 h. The solid was collected by centrifuge with an n-heptane wash (420 kg), then dried at 45 °C under vacuum for 20 h to give 3 (131 .15 kg, 629.7 mol) as a white powder in 94.5% yield. HPLC purity: 99.9%. ¹H NMR (400 MHz, DMSO-c/6): d ppm 9.42 (brs, 1 H), 8.48 (d, J = 1 .9 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 2.38 (s, 3H), 1 .49 (s, 9H). ¹³C NMR (100 MHz, DMSO-d₆y d ppm 153.34, 151 .56, 139.75, 134.13, 126.10, 123.09, 79.87, 28.56, 23.70. HRMS (ESI) m/z: calculated for C11H17N2O2 [M + H]⁺ 209.1290; observed 209.1285.

Preparation 2

ferf-Butyl (6-methylpiperidin-3-yl)carbamate (rac-4). To a 3000L reactor was charged 3 (137.0 kg, 667.8 mol), ethanol (988 kg) and acetic acid (139 kg). The reactor was purged with nitrogen three times and 5 wt% Rhodium on carbon (wet, 27.4 kg, 20 wt% loading relative to 3) was added. The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 47 °C. The mixture was stirred at 45 – 60 °C under hydrogen pressure at 0.34 – 0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and flushed with nitrogen. The mixture was filtered through a layer of diatomaceous earth (20 kg) with an ethanol rinse (1320 kg) and the filtrates were concentrated under vacuum at <50 °C to a residual volume of ~350 L. n-Heptane (571 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of~350 L. This operation was repeated twice until the residual acetic acid <8.0%. Ethanol (672 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of ~350 L. This operation was repeated twice until the residual n-heptane was <0.2% and water was <0.2%. Ethanol (889 kg) was added and the solution (1254 kg) was transferred to drums for use in the subsequent classical resolution step. Achiral HPLC assay indicated that the solution contained 10.8 wt% of the total reduced product (rac-4) in 96% mass recovery and chiral SFC showed that the solution contained 36.3% of the desired stereoisomer cis-4.

Preparation 3

ferf-Butyl ((3R,6S)-6-methylpiperidin-3-yl)carbamate (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid salt (15). To a 2000L reactor (R1 ) was charged rac-4 as a 10.8 wt% solution in ethanol (620.5 kg, ~312.7 mol. of all 4 isomers). The solution was concentrated under vacuum at <45 °C to a residual volume of ~210 L and then cooled to 20 °C. To a 3000 L reactor (R2) was charged (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid 14 (47.0 kg, 136.1 mol) and ethanol (1 125 kg). With high speed agitation, reactor R2 was heated to 70 °C, stirred at 68 – 70 °C for ~2 h to dissolve all solid 14, and then seeded with crystalline 15 (1 1 g). The solution containing 4 in reactor R1 was slowly transferred to reactor R2 over 30 min with ethanol rinse (160 kg). Reactor R2 was stirred at ~74 °C for 3 h and then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 16 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg). The wet cake (with 97.1 % e.e.) was charged back to reactor R2. The slurry was heated to 74 °C and the mixture was stirred for 17 h. The mixture was then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 4 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg) and dried at 35 °C under vacuum for 25 h to give 15 (56.05 kg, 100.2 mol) as a white powder in 30.7% yield over 2 steps. Chiral HPLC purity: 99.1 %. ¹H NMR (400 MHz, DMSO-d₆): d ppm 9.46 (d, J = 7.0 Hz, 1 H), 9.07 (d, J = 2.2 Hz, 2H), 8.96 (t, J = 2.2 Hz, 1 H), 7.49 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3, 1 H), 7.1 1 (m, 1 H), 5.31 (d, J = 7.0 Hz, 1 H), 3.66 (m, 1 H), 2.98 (m, 3H), 1 .63 (m, 2H), 1 .45 (m, 2H), 1 .40 (s, 9H), 1 .1 1 (d, J = 6.7 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): d ppm 172.71 , 161 .71 , 155.42, 148.51 , 141 .27, 137.70, 128.29, 128.25, 128.02, 127.05, 121 .12, 78.49, 59.74, 50.66, 46.29, 43.34, 28.66, 26.88, 26.1 1 , 18.60.

Preparation 4

Benzyl (2S,5R)-5-amino-2-methylpiperidine-1 -carboxylate hydrochloride (7^»HCI) -telescoped process. To a 2000L reactor was charged 15 (70.0 kg, 125 mol) and MTBE (500 kg). The mixture was cooled to 12 °C and 6.9 wt% aqueous NaOH solution (378 kg, 652 mol) was added slowly while maintaining the temperature between 10 – 25 °C. The mixture was stirred at 18 °C for 1 h . The organic phase was separated and washed with 3.8 wt% aqueous NaOH solution (2 x 221 kg) and then 25 wt% aqueous NaCI solution (2 x 220 kg). The organic layer (containing the free base cis-4) was concentrated under vacuum at <40 °C to a residual volume of ~300 L and then cooled to 20 °C. NaHCOs (53 kg, 632 mol) and water (200 kg) were added and the mixture was cooled to 7 °C. Benzyl chloroformate (32.30 kg, 189.3 mol) was added slowly while maintaining the temperature between 5 – 20 °C. The mixture was stirred at 17 °C for 20 h. Upon reaction completion, the mixture was cooled to 12 °C, 25 wt% aqueous ammonium hydroxide solution (79 kg, 1 160 mol) was added slowly while maintaining the temperature between 10 – 20 °C, and the mixture was stirred at 15 °C for 1 h. The organic phase was separated and washed with 25 wt% aqueous NaCI solution (3 x 90 kg). The organic layer (containing 5) was concentrated under vacuum at <45 °C to a residual volume of ~150 L. Isopropyl acetate (310 kg) was added and the mixture was concentrated under vacuum at <45 °C to a residual volume of ~150 L. This operation was repeated twice to meetthe criteria of water <0.1 % (by KF). Isopropyl acetate (130 kg) was then added and the mixture was cooled to -3 °C. 4-5N HCI in methanol (181 kg, ~730 mol) was added slowly while maintaining the temperature between -5 to 5 °C, and the mixture was stirred at 3 °C for 12 h. Upon reaction completion, the mixture was cooled to -3 °C and MTBE (940 kg) was added slowly while maintaining the temperature between -5 to 5 °C. The resulting slurry was stirred at 3 °C for 3 h. The solid was collected by centrifuge with MTBE washes (4 x 70 kg), and then dried at 45 °C under vacuum for 20 h to give 7^»HCI (28.60 kg, 100.4 mol) as a white powder in 80.3% yield. Achiral HPLC purity: 100%. Chiral SFC purity: 99.8% e.e. ¹H NMR (400 MHz, DMSO-d₆): d ppm 8.36 (brs, 3H), 7.37 (m, 5H), 5.09 (s, 2H), 4.31 (m, 1 H), 4.16 (d, J = 8.2 Hz, 1 H), 3.00 (m, 2H), 1 .82 (m, 2H), 1 .59 (m, 2H), 1 .1 1 (d, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): d ppm 154.71 , 137.24, 128.92, 128.34, 128.00, 66.89, 47.20, 45.66, 40.68, 28.16, 23.02, 15.67. HRMS (ESI) m/z. calculated for C H N O [M + H]⁺ 249.1603; observed 249.1598.

Preparation 5

Benzyl (2S, 5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2 -methyl-piperidine-1 -carboxylate (9). To a 2000L reactor was charged 7^»HCI (88.6 kg, 31 1 .12 mol), 8 (56.0 kg, 298 mol), K₂C0₃ (133.0 kg, 962.3 mol), water (570 kg) and MIBK (101 kg). The mixture was heated to 90 °C and stirred at this temperature for 22 h. Upon reaction completion, the mixture was cooled to 56 °C and ethyl acetate (531 kg) was added. After cooling the mixture to 22 °C, the organic phase was separated, washed with water (570 kg) and concentrated under vacuum at <40 °C to a residual volume of ~220 L. Methanol (360 kg) was added slowly over a period of 1 h and the mixture concentrated under vacuum at <50 °C to a residual volume of ~220 L. This operation was repeated three times until residual MIBK reached <5 wt%. Methanol (270 kg) was added, followed by seeding with 9 (120 g). The mixture was stirred at 22 °C for >4 h and water (286 kg) was added slowly over 4 h. The slurry was stirred for 10 h and the solid was then collected by centrifuge. The wet cake (165.6 kg) was charged back to a clean reactor and water (896 kg) was added. The slurry was heated to 55 °C and stirred at this temperature for 7 h; and then cooled to 22 °C and stirred at this temperature for 2 h. The solid was collected by centrifuge with water wash (3 x 170 kg) and dried at 55 °C under vacuum for 20 h to give 9 (106.62 kg, 266.6 mol) as a white powder in 89.5% yield. Achiral HPLC purity: 99.7%. ¹H NMR (400 MHz, DMSO-d₆): d ppm 1 1 .71 (brs, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.38 (m, 5H), 7.10 (s, 1 H), 6.57 (d, J = 2.7 Hz, 1 H), 5.1 1 (m, 2H), 4.39 (m, 1 H), 4.17 (m, 1 H), 4.01 (m, 1 H), 3.36 (s, 2H), 2.77 (m, 1 H), 1 .73-1 .81 (m, 4H), 1 .16 (d, J = 6.6 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): d ppm 156.65, 154.74, 153.04, 151 .31 , 137.43, 128.89, 128.27, 127.96, 122.13, 101 .65, 99.51 , 66.75, 49.10, 47.32, 45.64, 42.98, 29.05, 25.08. HRMS (ESI) m/z. calculated for C20H22CIN5O2 [M + H]⁺ 400.1540; observed 400.1535.

Preparation 6

N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-dlpyrimidin-4-amine monohydrate (10·H₂O) To a 1600L reactor was charged water (570 kg). The reactor was purged with nitrogen three times. 10% Pd(OH)₂/C (wet, 3.2 kg) and 9 (53.34 kg, 133.2 mol) were added with water rinses (2 x 55 kg). The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 77 °C. The mixture was stirred at 75 – 80 °C under a hydrogen pressure of 0.34 -0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and purged with nitrogen. The mixture was filtered through a layer of diatomaceous earth (8 kg) with a water rinse (460 kg), and the filtrates were transferred to a 3000L reactor. Methanol (260 kg) was added, followed by slow addition of 50 wt% aqueous sodium hydroxide (12.0 kg , 150 mol) while maintaining the temperature between 15 – 25 °C. The slurry was heated to 55 °C and stirred for 2 h; then cooled to 22 °C and stirred for 10 h. The solid was collected by centrifuge with a 10:1 water/methanol wash (3 x 1 10 kg) and then dried at 55 °C under vacuum for 20 h to give 10·H₂O (30.90 kg, 266.6 mol) as a white powder in 89.1 % yield. Achiral HPLC purity: 99.7%. Chiral SFC

purity: 99.8% e.e. ¹H NMR (400 MHz, DMSO-d₆): d ppm 1 1 .48 (brs, 1 H), 8.08 (s, 1 H), 7.07 (s, 1 H), 6.85 (d, J = 7.3 Hz, 1 H), 6.64 (s, 1 H), 4.16 (m, 1 H), 3.35 (brs, 2H), 2.96 (d, J = 12.7 Hz, 1 H), 2.82 (d, J = 12.7 Hz, 1 H), 2.67 (m, 1 H), 2.04 (brs, 1 H), 1 .92 (m, 1 H), 1 .63 (m, 1 H), 1 .44 (m, 1 H), 1 .33 (m, 1 H), 1 .03 (d, J = 6.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): d ppm 155.95, 151 .87, 150.74, 121 .20, 102.97, 99.20, 51 .27, 49.94, 44.78, 29.97, 28.69, 22.35. HRMS (ESI) m/z\ calculated for C12H17N5 [M + H]⁺ 232.1562; observed 232.1558.

Preparation 7

1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (1 ). To a 100L reactor was charged water (18.0 L), 10·H₂q (3.60 kg, 14.4 mol) and THF (36.0 L). The mixture was heated to 53 °C and stirred for 15 min to dissolve all the solids. The solution was then cooled to 18 °C and K3PO4 (6.38 kg, 30.1 mol) was added. The mixture was stirred at 18 °C for 10 min to dissolve all the solids, and then cooled to 10 °C. 3-Chloropropionyl chloride (2.20 kg, 17.3 mol) was added while maintaining the temperature <20 °C. The mixture was then stirred at 20 °C for 2 h. Upon reaction completion, 2 N aqueous NaOH solution (23.50 kg, 43.76 mol) was added while maintaining the temperature <25 °C. The mixture was stirred at 22 °C for >12 h until the elimination reaction was complete (11 <0.2%). KH2PO4 (10.32 kg, 75.8 mol) was added and the mixture was stirred at 20 °C for 10 min. The organic phase was separated and then washed with 23.5 wt% aqueous NaCI solution (2 x 8.5 kg). The isolated organic phase was concentrated under vacuum at <30 °C to a residual volume of ~10 L, whereupon MEK (39.6 L) was added. This operation was repeated once or twice until residual THF was <1 % and water was <2%. MgS0₄ (0.96 kg), Silica gel (4.90 kg) and Darco™ G-60 (0.48 kg) were added to the MEK solution, and the mixture was stirred at 20 °C for 1 h, then filtered through a layer of Diatomaceous Earth with a MEK rinse (76 L). The combined filtrates were concentrated under vacuum at <30 °C to a residual volume of ~8 L. The concentration of the residual solution was measured by qNMR, and the solution was transferred to a container with a rinse using the calculated amount of MEK to adjust the final concentration to 30 wt%. Thus, a 30 wt% solution of 1 in MEK (1 1 .09 kg, 1 1 .66 mol of 1) with 98.7% purity was obtained in 81 % yield, which was stored in a cold room (2 – 8 °C) for the next step.

Preparation 8

1 -((2S,5R)-5-((7H-pyrrolo[2,3-cdpyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one p-toluenesulfonate (1^»TsOH). To a 20L reactor was charged a 30 wt% solution of 1 in MEK (9.80 kg, 10.30 mol of 1) and silica gel (0.74 kg). The mixture was stirred at 22 °C for 15 min and filtered through a 0.45 micron Teflon cartridge filter with a MEK rinse (7.89 kg, 9.8 L), collecting in a 100L reactor. Water (1 .27 L) was added, followed by a solution of p-toluenesulfonic acid monohydrate (2.18 kg, 1 1 .3 mol) in MEK (4.75 kg, 5.9 L) with a MEK rinse (3.14 kg, 3.9 L), followed by the addition of 1 ^»TsOH seed (188 g, 0.41 mol). The mixture was stirred at 22 °C for

4 h to form a slurry and MEK (31 .56 kg, 39.2 L) was added slowly over a period of 3 h. The slurry was stirred at 22 °C for an additional 2 h and then filtered. The cake was washed with MEK (4.02 kg, 5 L) and then dried at 50 °C under vacuum for 10 h to give 1 ^»TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. m.p. 199 °C. Rotomers observed for NMR spectroscopies. Ή NMR (400 MHz, DMSO-d₆): d ppm 12.68 (brs, 1 H), 9.22 (brs, 1 H), 8.40 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1 H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1 .2 Hz, 1 H), 6.84 (m, 1 H), 6.13 (m, 1 H), 5.70 (m, 1 H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1 H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1 .91 -1 .72 (m, 4H), 1 .24-1 .17 (m, 3H). ¹³C NMR (100 MHz, DMSO-c/6): d ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51 , 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41 , 25.22, 21 .28, 16.97, 15.51 . HRMS (ESI) m/z: calculated for Ci₅H₂oN₅0 [M + H]⁺ 286.1668; observed 286.1692.

Comparative Example

Preparation of 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methyl-piperidin-1 -yl)prop-2-en-1 -one Malonic Acid Salt (Form 1 )

A 250 ml_ round bottom flask was charged with 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (4.10 g, 14.4 mmol), MEK (Methyl Ethyl Ketone (15.0 ml_/g, 687 mmol, 49.5 g, 61 .5 ml_)). To the solution, malonic acid (0.950 equiv. 13.7 mmol, 1 .42 g) was added in one portion. The mixture was heated to 50 °C and stirred at 50 °C for 15min. The heating was turned off and the slurry was stirred for 16 hours. The resulting white slurry was filtered. The filter cake was washed with MEK (2 X 5 ml_) and dried in a vacuum oven (40 °C) for 2 hours give 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one malonic acid salt (Form 1) (4.48 g, 1 1 .5 mmol, 4.48 g, 80.1 % Yield) as white powder.

PATENT

WO-2021136482

Improved process for preparing ritlecitinib (PF06651600), useful for treating alopecia areata (AA), rheumatoid arthritis (RA), Crohn’s disease (CD) and ulcerative colitis (UC). Also claims novel intermediates of ritlecitinib and their preparation method.

PATENT

CN111732591

crystalline polymorphic form of ritlecitinib L-tartrate. Jiangsu Alicorn focuses on developing generic, innovative and first-line drugs, whose website lists an undisclosed JAK inhibitor under its product’s list.

REFERENCES

1: D’Amico F, Fiorino G, Furfaro F, Allocca M, Danese S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin Investig Drugs. 2018 Jul;27(7):595-599. doi: 10.1080/13543784.2018.1492547. Epub 2018 Jul 6. Review. PubMed PMID: 29938545.

2: Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, Colonna M. Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunol. 2018 Jan;11(1):50-60. doi: 10.1038/mi.2017.38. Epub 2017 May 17. PubMed PMID: 28513593; PubMed Central PMCID: PMC5693788.

3: Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem. 2017 Mar 9;60(5):1971-1993. doi: 10.1021/acs.jmedchem.6b01694. Epub 2017 Feb 16. PubMed PMID: 28139931.

4: Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. Epub 2016 Nov 10. PubMed PMID: 27791347.

5: Walker G, Croasdell G. The European League Against Rheumatism (EULAR) – 17th Annual European Congress of Rheumatology (June 8-11, 2016 – London, UK). Drugs Today (Barc). 2016 Jun;52(6):355-60. doi: 10.1358/dot.2016.52.6.2516435. PubMed PMID: 27458612.

References

^ Jump up to:^a ^b “Litfulo (ritlecitinib)”. Therapeutic Goods Administration (TGA). 30 July 2024. Retrieved 12 October 2024.
^ https://www.tga.gov.au/resources/prescription-medicines-registrations/litfulo-pfizer-australia-pty-ltd
^ “Litfulo Product information”. Health Canada. 13 February 2024. Retrieved 3 March 2024.
^ Jump up to:^a ^b ^c “Summary Basis of Decision for Litfulo”. Health Canada. 18 July 2024. Retrieved 28 August 2024.
^ “Regulatory Decision Summary for Litfulo”. Health Canada. 29 November 2023. Retrieved 2 April 2024.
^ Jump up to:^a ^b ^c ^d ^e ^f “Litfulo- ritlecitinib capsule”. DailyMed. U.S. National Library of Medicine. 23 June 2023. Archived from the original on 29 August 2023. Retrieved 28 August 2023.
^ Jump up to:^a ^b ^c ^d “Litfulo EPAR”. European Medicines Agency. 18 September 2023. Archived from the original on 19 September 2023. Retrieved 20 September 2023.
^ “Litfulo Product information”. Union Register of medicinal products. 18 September 2023. Archived from the original on 1 October 2023. Retrieved 1 October 2023.
^ “Ritlecitinib”. Inxight Drugs. Archived from the original on 25 June 2023. Retrieved 24 June 2023.
^ Ramírez-Marín HA, Tosti A (February 2022). “Evaluating the Therapeutic Potential of Ritlecitinib for the Treatment of Alopecia Areata”. Drug Design, Development and Therapy. 16: 363–374. doi:10.2147/DDDT.S334727. PMC 8860347. PMID 35210753.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “Drug Trials Snapshots: Litfulo”. U.S. Food and Drug Administration. 23 June 2023. Retrieved 29 April 2024. This article incorporates text from this source, which is in the public domain.
^ “FDA Approves Pfizer’s Litfulo (Ritlecitinib) for Adults and Adolescents With Severe Alopecia Areata” (Press release). Pfizer. 23 June 2023. Archived from the original on 25 June 2023. Retrieved 24 June 2023 – via Business Wire.
^ Kansteiner F (26 June 2023). “Pfizer’s Litfulo enters the scene in alopecia with adolescent nod to rival Lilly’s Olumiant”. Fierce Pharma. Archived from the original on 8 July 2023. Retrieved 18 September 2023.

External links

Clinical trial number NCT03732807 for “PF-06651600 for the Treatment of Alopecia Areata (ALLEGRO-2b/3)” at ClinicalTrials.gov

Ritlecitinib
Clinical data

Trade names	Litfulo
Other names	PF-06651600
AHFS/Drugs.com	Monograph
MedlinePlus	a624015
License data	US DailyMed: Ritlecitinib
Pregnancy category	AU: D^[1]
Routes of administration	By mouth
ATC code	L04AF08 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)^[2]^[1] CA: ℞-only^[3]^[4]^[5] US: ℞-only^[6] EU: Rx-only^[7]^[8]
Identifiers
show IUPAC name
CAS Number	1792180-81-4 as salt: 2192215-81-7
PubChem CID	118115473
IUPHAR/BPS	9559
DrugBank	DB14924 as salt: DBSALT003482
ChemSpider	59718512 as salt: 81368003
UNII	2OYE00PC25 as salt: EAG4T1459K
KEGG	as salt: D11970
ChEBI	CHEBI:229233
ChEMBL	ChEMBL4085457
Chemical and physical data
Formula	C₁₅H₁₉N₅O
Molar mass	285.351 g·mol⁻¹
3D model (JSmol)	Interactive image
show SMILES
show InChI

////////////PF-06651600, PF 06651600, PF06651600, Breakthrough Therapy designation, PHASE 2, alopecia areata, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, Ritlecitinib, Litfulo

C=CC(N1[C@@H](C)CC[C@@H](NC2=C3C(NC=C3)=NC=N2)C1)=O

SYN 01

July 31, 2019 9:34 am / Leave a comment

SYN-01, SYN-510

Synthena AG

Preclinical

Synthena , presumed to be under license from University of Bern , is investigating (presumably SYN-01 ), a lead from the tricyclo(tc)-DNA based antisense oligonucleotides (AON) developed using its proprietary tricyclo-DNA technology platform, for the treatment of Duchenne muscular dystrophy. In January 2017, the drug was listed as being in preclinical development.

Patent

WO-2019142135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019142135&tab=PCTDESCRIPTION&_cid=P22-JYQVON-19722-1

Process for preparing tricyclo-deoxyribonucleic acid (tc-DNA) which may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Antisense technology is an effective means for reducing the expression of specific gene products and can therefore be useful in therapeutic, diagnostic, and research applications.

Generally, the principle behind antisense technology is that an antisense oligomeric compound (a sequence of nucleotides or analogues thereof) hybridizes to a target nucleic acid and modulates gene expression activities or function, such as transcription and/or translation.

[003] Antisense oligomeric compounds may be prepared from chemically-modified antisense oligonucleotides, which may include a variety of different structural variations depending upon the therapeutic strategy. For example, tricyclo-deoxyribonucleic acids (tc-DNA) are conformationally constrained DNA analogs.

[004] There is a need in the field for processes that allow for the bulk preparation of tc-DNA nucleoside precursors that may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Example 4 – Cvclopropanation of Compound 17 with Carbenoid Prepared from CH2I2 and Et₂Zn in the Absence of Additives

[00127] According to the following scheme, compound 17 was converted to tc-DNA Nucleoside Precursor 18 using the cyclopropanation conditions set forth in Examples 4 to 7 :

[00128] 1.07 g purified a-anomer (3.736 mmol) 17 was dissolved in 37 ml of dry CH₂C1₂ and cooled to 0 °C (ice). Subsequently, 22.3 ml (22.3 mmol, 6 eq.) Et₂Zn 1.0 M in hexane (Aldrich) were added dropwise and stirred under Ar for 30 min at 0 °C. Then, 3.02 ml (37.2 mmol, 10 eq.) of CH₂I₂ were added dropwise over 15 min at the same temperature and stirred for further 2 h at 0 °C. Afterwards the cooling bath was removed and the mixture was stirred for additional 21 h at ambient temperature. TLC showed substantial amount of unreacted a- 17. It was diluted by addition of EtOAc and quenched with 50 mL of sat. aqueous NH₄Cl. Extractive work-up provided 1.79 g of crude which was purified by chromatography on silica-gel giving 0.43 g (39%) of 18 and 0.49 g of mixture of compound 17 and 18 (approximately 20:80).

PATENT

WO2018193428

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018193428

claiming a composition comprising an oligomeric compound having tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a lipid moiety.

EXAMPLE 1

Inventive compositions for the treatment of Duchenne muscular dystrophy

Evaluation of efficacy

[00464] Adult mdx mice were treated weekly over 4 weeks with intravenous injections of different 13-mer AONs targeting the donor splice site of exon 23 of the dystrophin pre-mRNA (M23D: +2-11), namely with either SY-0308, SY-0210 and the inventive SY-0299, SY-0343, SY-0442 and SY-0455. SY-0308 (also named “tcDNA-PO M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: l, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorodiester linkage groups, and p being a phosphate moiety at the 5′ end. SY-0210 (also named “tcDNA-PS M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: 1, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorothioate linkage groups, and p being a phosphate moiety at the 5′ end. The inventive composition SY-0343 is herein interchangeably referred to as “Palm-2PS-tcDNA-PO M23D” which is depicted in the following:

[00465] The inventive composition SY-0442 is herein interchangeably referred to as “Palm-lPS-tcDNA-PO M23D” which is depicted in the following:

[00466] The inventive composition SY-0299 is herein interchangeably referred to as “Palm-2PO-tcDNA-PO M23D” which is depicted in the following:

//////////////////SYN-01, SYN 01, SYN01, preclinical , Duchenne muscular dystrophy, University of Bern,

LK-01, Apomorphine

July 31, 2019 9:33 am / Leave a comment

LK-01

Leukos Biotech S.L.

APL-130277, H-001, Apokyn

(-)-10,11-dihydroxyaporphine

(-)-Apomorphine

(6aR)-6-Methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol

(R)-(-)-Apomorphine

(R)-6-Methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol

200-360-0 [EINECS]

41372-20-7 [RN]

4H-Dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7-tetrahydro-6-methyl-, (6aR)-

4H-Dibenzo[de,g]quinoline-10,11-diol, 5,6,6a,7-tetrahydro-6-methyl-, (R)-

6ab-Aporphine-10,11-diol

R-(-)-Apomorphine

Apomorphine

CAS Registry Number: 58-00-4

CAS Name: (6aR)-5,6,6a,7-Tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol

Additional Names: 6ab-aporphine-10,11-diol

Molecular Formula: C17H17NO2

Molecular Weight: 267.32

Percent Composition: C 76.38%, H 6.41%, N 5.24%, O 11.97%

Literature References: Dopamine (D1 and D2) receptor agonist. Synthetic opiate obtained by treating morphine with concd HCl: A. Matthiessen, C. R. A. Wright, Proc. R. Soc. London Ser. B17, 455 (1869). Structure: R. Pschorr et al.,Ber.35, 4377 (1902). Configuration: H. Corrodi, E. Hardegger, Helv. Chim. Acta38, 2038 (1955). Total synthesis of (±)-form: J. L. Neumeyer et al.,J. Pharm. Sci.59, 1850 (1970); of (+)- and (-)-forms: V. J. Ram, J. L. Neumeyer, J. Org. Chem.46, 2830 (1981). Toxicity data: J. Z. Ginos et al.,J. Med. Chem.18, 1194 (1975). Clinical evaluation in impotence: J. P. W. Heaton et al.,Urology45, 200 (1995). Historical review: J. L. Neumeyer et al., in Apomorphine and Other Dopaminomimeticsvol. 1, G. L. Gessa, G. U. Corsini, Eds. (Raven, New York, 1981) p 1-17. Comprehensive description: F. J. Muhtadi, M. S. Hifnawy, Anal. Profiles Drug Subs.20, 121-166 (1991). Review of pharmacology and clinical efficacy in Parkinson’s disease: D. Muguet et al.,Biomed. Pharmacother.49, 197-209 (1995); in erectile dysfunction: F. Giuliano, J. Allard, Int. J. Impotence Res.14, Suppl. 1, S53-S56 (2002).

Properties: Hexagonal plates from chloroform and petr ether, dec 195°; subl in high vacuum. Oxidizes rapidly in air and becomes green. Sol in alcohol, acetone, chloroform. Slightly sol in water, benzene, ether, petr ether. Solns darken rapidly. pKb 7.0; pKa 8.92. uv max (98% alc): 336, 399 nm.

pKa: pKb 7.0; pKa 8.92

Absorption maximum: uv max (98% alc): 336, 399 nm

Apomorphine hydrochloride hemihydrate

CAS 41372-20-7

Derivative Type: Hydrochloride

CAS Registry Number: 314-19-2; 41372-20-7 (hemihydrate)

Trademarks: Apokinon (Aguettant); Apokyn (Mylan Bertek); Apomine (Faulding); Britaject (Britannia); Ixense (Takeda); Uprima (TAP)

Molecular Formula: C17H17NO2.HCl

Molecular Weight: 303.78

Percent Composition: C 67.21%, H 5.97%, N 4.61%, O 10.53%, Cl 11.67%

Properties: Small crystals (usually hemihydrate). Dec and turn green on exposure to light and air. [a]D25 -48° (c = 1.2). uv spectrum: Csokan, Z. Anal. Chem.124, 344 (1942). pH of aq soln (1 in 300) = 4.8. One gram dissolves in 50 ml water, 17 ml water at 80°, 50 ml alcohol. Very slightly sol in chloroform and ether. LD50 i.p. in mice: 145 mg/g (Ginos).

Optical Rotation: [a]D25 -48° (c = 1.2)

Toxicity data: LD50 i.p. in mice: 145 mg/g (Ginos)

Derivative Type: Diacetate (ester)

CAS Registry Number: 6191-56-6

Additional Names: Diacetylapomorphine

Molecular Formula: C21H21NO4

Molecular Weight: 351.40

Percent Composition: C 71.78%, H 6.02%, N 3.99%, O 18.21%

Properties: mp 127-128°, [a]D24 -88° (c = 1.12 in 0.1N HCl).

Melting point: mp 127-128°

Optical Rotation: [a]D24 -88° (c = 1.12 in 0.1N HCl)

Therap-Cat: Antiparkinsonian; emetic. In treatment of male erectile dysfunction.

Therap-Cat-Vet: Emetic.

Keywords: Antiparkinsonian; Dopamine Receptor Agonist; Emetic; Impotence Therapy.

Leukos Biotech (following its spin-off from Jose Carreras Leukaemia Research Institute) is developing LK-01 , a solid form of apomorphine for the sc treatment of acute myeloid leukemia (AML) and the phase II trial results were expected later in 2019.

Apomorphine (brand names Apokyn, Ixense, Spontane, Uprima) is a type of aporphine having activity as a non-selective dopamine agonist which activates both D₂-like and, to a much lesser extent, D₁-like receptors.^[1] It also acts as an antagonist of 5-HT₂ and α-adrenergic receptors with high affinity. The compound is historically a morphine decomposition product made by boiling morphine with concentrated acid, hence the –morphine suffix. Contrary to its name, apomorphine does not actually contain morphine or its skeleton, nor does it bind to opioid receptors. The apo– prefix relates to it being a morphine derivative (“[comes] from morphine”).

Historically, apomorphine has been tried for a variety of uses, including as a way to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), for treating stereotypies (repeated behaviour) in farmyard animals, and more recently in treating erectile dysfunction. Currently, apomorphine is used in the treatment of Parkinson’s disease. It is a potent emetic and should not be administered without an antiemetic such as domperidone. The emetic properties of apomorphine are exploited in veterinary medicine to induce therapeutic emesis in canines that have recently ingested toxic or foreign substances.

Apomorphine was also used as a private treatment of heroin addiction, a purpose for which it was championed by the author William S. Burroughs. Burroughs and others claimed that it was a “metabolic regulator” with a restorative dimension to a damaged or dysfunctional dopaminergic system. There is more than enough anecdotal evidence to suggest that this offers a plausible route to an abstinence-based model; however, no clinical trials have ever tested this hypothesis. A recent study indicates that apomorphine might be a suitable marker for assessing central dopamine system alterations associated with chronic heroin consumption.^[2] There is, however, no clinical evidence that apomorphine is an effective and safe treatment regimen for opiate addiction.^[3]

Uses

Apomorphine is used in advanced Parkinson’s disease intermittent hypomobility (“off” episodes), where a decreased response to an anti-Parkinson drug such as L-DOPA causes muscle stiffness and loss of muscle control.^[4]^[5] While apomorphine can be used in combination with L-DOPA, the intention is usually to reduce the L-DOPA dosing, as by this stage the patient often has many of dyskinesias caused by L-DOPA and hypermobility periods.^[6]^[7] When an episode sets in, the apomorphine is injected subcutaneously, and signs subside. It is used an average of three times a day.^[6] Some people use portable mini-pumps that continuously infuse them with apomorphine, allowing them to stay in the “on” state and using apomorphine as an effective monotherapy.^[7]^[8]

Contraindications

The main and absolute contraindication to using apomorphine is the concurrent use of adrenergic receptor antagonists; combined, they cause a severe drop in blood pressure and fainting.^[6]^[5] Alcohol causes an increased frequency of orthostatic hypotension (a sudden drop in blood pressure when getting up), and can also increase the chances of pneumonia and heart attacks.^[6] Dopamine antagonists, by their nature of competing for sites at dopamine receptors, reduce the effectiveness of the agonistic apomorphine.^[6]^[5]

IV administration of apomorphine is highly discouraged, as it can crystallize in the veins and create a blood clot (thrombus) and block a pulmonary artery (pulmonary embolism).^[6]^[5]

Side effects

Nausea and vomiting are common side effects when first beginning therapy with apomorphine;^[9] antiemetics such as trimethobenzamide or domperidone, dopamine antagonists,^[10] are often used while first starting apomorphine. Around 50% of people grow tolerant enough to apomorphine’s emetic effects that they can discontinue the antiemetic.^[5]^[6]

Other side effects include orthostatic hypotension and resultant fainting, sleepiness, dizziness, runny nose, sweating, paleness, and flushing. More serious side effects include dyskenesias (especially when taking L-DOPA), fluid accumulation in the limbs (edema), suddenly falling asleep, confusion and hallucinations, increased heart rate and heart palpitations, and persistent erections(priaprism).^[5]^[6]^[11] The priaprism is caused by apomorphine increasing arterial blood supply to the penis. This side effect has been exploited in studies attempting to treat erectile dysfunction.^[12]

Pharmacology

Mechanism of action

Apomorphine’s R-enantiomer is an agonist of both D₁ and D₂ dopamine receptors, with higher activity at D₂.^[6]^[10] The members of the D₂ subfamily, consisting of D₂, D₃, and D₄receptors, are inhibitory G protein–coupled receptors. The D₄ receptor in particular is an important target in the signaling pathway, and is connected to several neurological disorders.^[13] Shortage or excess of dopamine can prevent proper function and signaling of these receptors leading to disease states.^[14]

Apomorphine improves motor function by activating dopamine receptors in the nigrostriatal pathway, the limbic system, the hypothalamus, and the pituitary gland.^[15] It also increases blood flow to the supplementary motor area and to the dorsolateral prefrontal cortex (stimulation of which has been found to reduce the tardive dyskinesia effects of L-DOPA).^[16]^[17]Parkinson’s has also been found to have excess iron at the sites of neurodegeneration; both the R- and S-enantiomers of apomorphine are potent iron chelators and radical scavengers.^[10]^[18]

Apomorphine also reduces the breakdown of dopamine in the brain (though it inhibits its synthesis as well).^[19]^[20] It is a powerful upregulator of certain neural growth factors,^[21] in particular NGF and BDNF, epigenetic downregulation of which has been associated with addictive behaviour in rats.^[22]^[23]

Apomorphine causes vomiting by acting on dopamine receptors in the chemoreceptor trigger zone of the medulla; this activates the nearby vomiting center.^[15]^[20]^[24]

Pharmacokinetics

While apomorphine has lower bioavailability when taken orally, due to not being absorbed well in the GI tract and undergoing heavy first-pass metabolism,^[18]^[8] it has a bioavailability of 100% when given subcutaneously.^[6]^[15] It reaches peak plasma concentration in 10–60 minutes. Ten to twenty minutes after that, it reaches its peak concentration in the cerebrospinal fluid. Its lipophilic structure allows it to cross the blood–brain barrier.^[6]^[15]

Apomorphine possesses affinity for the following receptors (note that a higher K_i indicates a lower affinity):^[25]^[26]^[27]

Dopamine
Receptor	K_i (nM)	Action
D₁	484	(partial) agonist^a
D₂	52	partial agonist (IA = 79% at D_2S; 53% at D_2L)
D₃	26	partial agonist (IA = 82%)
D₄	4.37	partial agonist (IA = 45%)
D₅	188.9	(partial) agonist^a
^aThough its efficacies at D₁ and D₅ are unclear, it is known to act as an agonist at these sites.^[28]

Serotonin
Receptor	K_i (nM)	Action
5-HT_1A	2,523	partial agonist
5-HT_1B	2,951	no action
5-HT_1D	1,230	no action
5-HT_2A	120	antagonist
5-HT_2B	132	antagonist
5-HT_2C	102	antagonist

Norepinephrine/Epinephrine
Receptor	K_i (nM)	Action
α_1A-adrenergic	1,995	antagonist
α_1B-adrenergic	676	antagonist
α_1D-adrenergic	64.6	antagonist
α_2A-adrenergic	141	antagonist
α_2B-adrenergic	66.1	antagonist
α_2C-adrenergic	36.3	antagonist

It has a K_i of over 10,000 nM (and thus negligible affinity) for β-adrenergic, H₁, and mACh.^[1]

Apomorphine has a high clearance rate (3–5 L/kg/hr) and is mainly metabolized and excreted by the liver.^[15] It is likely that while the cytochrome P450 system plays a minor role, most of apomorphine’s metabolism happens via auto-oxidation, O-glucuronidation, O-methylation, N-demethylation, and sulfation.^[6]^[15]^[20] Only 3–4% of the apomorphine is excreted unchanged and into the urine. The half-life is 30–60 minutes, and the effects of the injection last for up to 90 minutes.^[6]^[7]^[15]

Toxicity depends on the route of administraion; the LD₅₀s in mice were 300 mg/kg for the oral route, 160 mg/kg for intraperitoneal, and 56 mg/kg intravenous.^[29]

Chemistry

Properties

Apomorphine has a catechol structure similar to that of dopamine.^[19]

Synthesis

Several techniques exist for the creation of apomorphine from morphine. In the past, morphine had been combined with hydrochloric acid at high temperatures (around 150 °C) to achieve a low yield of apomorphine, ranging anywhere from 0.6% to 46%.^[30]

More recent techniques create the apomorphine in a similar fashion, by heating it in the presence of any acid that will promote the essential dehydration rearrangement of morphine-type alkaloids, such as phosphoric acid. The method then deviates by including a water scavenger, which is essential to remove the water produced by the reaction that can react with the product and lead to decreased yield. The scavenger can be any reagent that will irreversibly react with water such as phthalic anhydride or titanium chloride. The temperature required for the reaction varies based upon choice of acid and water scavenger. The yield of this reaction is much higher: at least 55%.^[30]

Conversion of Morphine (I) to Apomorphine (II) in the presence of acid following the example of the morphine skeleton dehydration rearrangement, outlined by Bentley.^[31]

History

The pharmacological effects of the naturally-occurring analog aporphine in the blue lotus (N. caerulea)^[32] were known to the ancient Egyptians and Mayans,^[33] with the plant featuring in tomb frescoes and associated with entheogenic rites. It is also observed in Egyptian erotic cartoons, suggesting that they were aware of its erectogenic properties.

The modern medical history of apomorphine begins with its synthesis by Arppe in 1845^[34] from morphine and sulfuric acid, although it was named sulphomorphide at first. Matthiesen and Wright (1869) used hydrochloric acid instead of sulfuric acid in the process, naming the resulting compound apomorphine. Initial interest in the compound was as an emetic, tested and confirmed safe by London doctor Samuel Gee,^[35] and for the treatment of stereotypies in farmyard animals.^[36] Key to the use of apomorphine as a behavioural modifier was the research of Erich Harnack, whose experiments in rabbits (which do not vomit) demonstrated that apomorphine had powerful effects on the activity of rabbits, inducing licking, gnawing and in very high doses convulsions and death.

Treatment of alcoholism

Apomorphine was one of the earliest used pharmacotherapies for alcoholism. The Keeley Cure (1870s to 1900) contained apomorphine, among other ingredients, but the first medical reports of its use for more than pure emesis come from James Tompkins^[37] and Charles Douglas.^[38]^[39] Tompkins reported, after injection of 6.5 mg (“one tenth of a grain”):

In four minutes free emesis followed, rigidity gave way to relaxation, excitement to somnolence, and without further medication the patient, who before had been wild and delirious, went off into a quiet sleep.

Douglas saw two purposes for apomorphine:

[it can be used to treat] a paroxysm of dipsomania [an episode of intense alcoholic craving]… in minute doses it is much more rapidly efficient in stilling the dipsomaniac craving than strychnine or atropine… Four or even 3m [minim – roughly 60 microlitres] of the solution usually checks for some hours the incessant demands of the patient… when he awakes from the apomorphine sleep he may still be demanding alcohol, though he is never then so insistent as before. Accordingly it may be necessary to repeat the dose, and even to continue to give it twice or three times a day. Such repeated doses, however, do not require to be so large: 4 or even 3m is usually sufficient.

This use of small, continuous doses (1/30th of a grain, or 2.16 mg by Douglas) of apomorphine to reduce alcoholic craving comes some time before Pavlov‘s discovery and publication of the idea of the “conditioned reflex” in 1903. This method was not limited to Douglas; the Irish doctor Francis Hare, who worked in a sanatorium outside London from 1905 onwards, also used low-dose apomorphine as a treatment, describing it as “the most useful single drug in the therapeutics of inebriety”.^[40] He wrote:

In (the) sanatorium it is used in three different sets of circumstances: (1) in maniacal or hysterical drunkenness: (2) during the paroxysm of dipsomania, in order to still the craving for alcohol; and (3) in essential insomnia of a special variety… [after giving apomorphine] the patient’s mental condition is entirely altered. He may be sober: he is free from the time being from any craving from alcohol. The craving may return, however, and then it is necessary to repeat the injection, it may be several times at intervals of a few hours. These succeeding injections should be quite small, 3 to 6 min. being sufficient. Doses of this size are rarely emetic. There is little facial pallor, a sensation as of the commencement of sea-sickness, perhaps a slight malaise with a sudden subsidence of the craving for alcohol, followed by a light and short doze.

He also noted there appeared to be a significant prejudice against the use of apomorphine, both from the associations of its name and doctors being reluctant to give hypodermic injections to alcoholics. In the US, the Harrison Narcotics Tax Act made working with any morphine derivatives extremely hard, despite apomorphine itself not being an opiate.

In the 1950s the neurotransmitter dopamine was discovered in the brain by Kathleen Montagu, and characterised as a neurotransmitter a year later by Arvid Carlsson, for which he would be awarded the Nobel Prize.^[41] A. N. Ernst then discovered in 1965 that apomorphine was a powerful stimulant of dopamine receptors.^[42] This, along with the use of sublingual apomorphine tablets, led to a renewed interest in the use of apomorphine as a treatment for alcoholism. A series of studies of non-emetic apomorphine in the treatment of alcoholism were published, with mostly positive results.^[43]^[44]^[45]^[46]^[47] However, there was little clinical consequence.

Parkinson’s disease

The use of apomorphine to treat “the shakes” was first suggested by Weil in France in 1884,^[48] although seemingly not pursued until 1951.^[49] Its clinical use was first reported in 1970 by Cotzias et al.,^[50] although its emetic properties and short half-life made oral use impractical. A later study found that combining the drug with the antiemetic domperidoneimproved results significantly.^[51] The commercialization of apomorphine for Parkinson’s disease followed its successful use in patients with refractory motor fluctuations using intermittent rescue injections and continuous infusions.^[52]

Aversion therapy

Aversion therapy in alcoholism had its roots in Russia in the early 1930s,^[53] with early papers by Pavlov, Galant and Sluchevsky and Friken,^[54] and would remain a strain in the Soviet treatment of alcoholism well into the 1980s. In the US a particularly notable devotee was Dr Voegtlin,^[55] who attempted aversion therapy using apomorphine in the mid to late 1930s. However, he found apomorphine less able to induce negative feelings in his subjects than the stronger and more unpleasant emetic emetine.

In the UK, however, the publication of J Y Dent’s (who later went on to treat Burroughs) 1934 paper “Apomorphine in the treatment of Anxiety States”^[56] laid out the main method by which apomorphine would be used to treat alcoholism in Britain. His method in that paper is clearly influenced by the then-novel idea of aversion:

He is given his favourite drink, and his favourite brand of that drink… He takes it stronger than is usual to him… The small dose of apomorphine, one-twentieth of a grain [3.24mg], is now given subcutaneously into his thigh, and he is told that he will be sick in a quarter of an hour. A glass of whisky and water and a bottle of whisky are left by his bedside. At six o’clock (four hours later) he is again visited and the same treatment is again administered… The nurse is told in confidence that if he does not drink, one-fortieth [1.62mg] of a grain of apomorphine should be injected during the night at nine o’clock, one o’clock, and five o’clock, but that if he drinks the injection should be given soon after the drink and may be increased to two hourly intervals. In the morning at about ten he is again given one or two glasses of whisky and water… and again one-twentieth of a grain [3.24mg] of apomorphine is injected… The next day he is allowed to eat what he likes, he may drink as much tea as he likes… He will be strong enough to get up and two days later he leaves the home.

However, even in 1934 he was suspicious of the idea that the treatment was pure conditioned reflex – “though vomiting is one of the ways that apomorphine relives the patient, I do not believe it to be its main therapeutic effect.” – and by 1948 he wrote:^[3]

It is now twenty-five years since I began treating cases of anxiety and alcoholism with apomorphine, and I read my first paper before this Society fourteen years ago. Up till then I had thought, and, unfortunately, I said in my paper, that the virtue of the treatment lay in the conditioned reflex of aversion produced in the patient. This statement is not even a half truth… I have been forced to the conclusion that apomorphine has some further action than the production of a vomit.

This led to his development of lower-dose and non-aversive methods, which would inspire a positive trial of his method in Switzerland by Dr Harry Feldmann^[57] and later scientific testing in the 1970s, some time after his death. However, the use of apomorphine in aversion therapy had escaped alcoholism, with its use to treat homosexuality leading to the death of a British Army Captain Billy Clegg HIll in 1962,^[58] helping to cement its reputation as a dangerous drug used primarily in archaic behavioural therapies.

Opioid addiction

In his Deposition: Testimony Concerning a Sickness in the introduction to later editions of Naked Lunch (first published in 1959), William S. Burroughs wrote that apomorphine treatment was the only effective cure to opioid addiction he has encountered:

The apomorphine cure is qualitatively different from other methods of cure. I have tried them all. Short reduction, slow reduction, cortisone, antihistamines, tranquilizers, sleeping cures, tolserol, reserpine. None of these cures lasted beyond the first opportunity to relapse. I can say that I was never metabolically cured until I took the apomorphine cure… The doctor, John Yerbury Dent, explained to me that apomorphine acts on the back brain to regulate the metabolism and normalize the blood stream in such a way that the enzyme stream of addiction is destroyed over a period of four to five days. Once the back brain is regulated apomorphine can be discontinued and only used in case of relapse.

He goes on to lament the fact that as of his writing, little to no research has been done on apomorphine or variations of the drug to study its effects on curing addiction, and perhaps the possibility of retaining the positive effects while removing the side effect of vomiting.

Despite his claims throughout his life, Burroughs never really cured his addiction and was back to using opiates within years of his apomorphine “cure”.^[59] However, he insisted on apomorphine’s effectiveness in several works and interviews.^{[citation needed]}

Society and culture

Apomorphine has a vital part in Agatha Christie‘s detective story Sad Cypress.
The 1965 Tuli Kupferberg song “Hallucination Horrors” recommends apomorphine at the end of each verse as a cure for hallucinations brought on by a humorous variety of intoxicants; the song was recorded by The Fugs and appears on the album Virgin Fugs.

Research

There is renewed interest in the use of apomorphine to treat addiction, in both smoking cessation^[60] and alcoholism.^[61] As the drug is old, out of patent, and safe for use in humans, it is a viable target for repurposing.

Flow chart depicting the role of apomorphine in Alzheimer’s disease.

Apomorphine has been researched as a possible treatment for erectile dysfunction and female hypoactive sexual desire disorder, though the arousal effects were found not to be reliable enough. One large study found that only 39.4% got erections (compared to baseline 13.1); another found that apomorphine was successful 45–51% of the time, but the placebo also worked 36% of the time.^[12]^[62] Nonetheless, it was under development as a treatment for erectile dysfunction by TAP Pharmaceuticals under the brand name Uprima. In 2000, TAP withdrew its new drug application after an FDA review panel raised questions about the drug’s safety, due to many clinical trial subjects fainting after taking the drug.^[63]

Alzheimer’s disease

Apomorphine is reported to be an inhibitor of amyloid beta protein (Aβ) fiber formation, whose presence is a hallmark of Alzheimer’s disease (AD), and a potential therapeutic under the amyloid hypothesis.^[64] While it promotes oligomerization of the Aβ40 group of molecules, it inhibits more advanced fibril formation; this is thought to be due to the autoxidation that occurs at the hydroxyl groups. Once this functional group was altered, the inhibitory effect could be seen to decrease, reducing either the indirect or direct interference of the fibril formation.^[64]

The protective effects of apomorphine were tested in mouse models with mutations in genes related to AD, such as the amyloid precursor protein gene. Apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze. The levels of the aberrant proteins that lead to neuronal disruption were also tested in the brains of mice. Treatment was seen to decrease the intraneuronal levels of the more aggressive Aβ42 molecule when compared to the control mice. This result is consistent with the finding that another protein linked to AD, tau protein, was seen to decrease with apomorphine treatment.^[65]

Veterinary use

Apomorphine is used to inducing vomiting in dogs the after ingestion of various toxins or foreign bodies. It can be given subcutaneously, intramuscularly, intravenously, or, when a tablet is crushed, in the conjunctiva of the eye.^[66]^[67] The oral route is ineffective, as apomorphine cannot cross the blood–brain barrier fast enough, and blood levels don’t reach a high enough concentration to stimulate the chemoreceptor trigger zone.^[66] It can remove around 40–60% of the contents in the stomach.^[68]

One of the reasons apomorphine is a preferred drug is its reversibility:^[69] in cases of prolonged vomiting, the apomorphine can be reversed with dopamine antagonists like the phenothiazines (for example, acepromazine). Giving apomorphine after giving acepromazine, however, will no longer stimulate vomiting, because apomorphine’s target receptors are already occupied.^[66] An animal who undergoes severe respiratory depression due to apomorphine can be treated with naloxone.^[66]^[67]

Apomorphine does not work in cats, who have too few dopamine receptors.^[66]

PATENT

WO-2019141673

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019141673&tab=PCTDESCRIPTION&_cid=P12-JYQPE2-75984-1

Novel crystalline forms of apomorphine or its palmitate or hydrochloride salt useful treating acute myeloid leukemia, Parkinson’s disease, sexual dysfunction and solid tumors. Also claims the process for preparing apomorphine palmitic acid cocrystal salt.

Apomorphine (APO) is a commercial available medical drug with the chemical formula C-₁₇H-₁₇NO₂ and structure:

Apomorphine (APO) has been described for treatment of different medical indications – for instance:

– WO2015/197839A1 : leukemia such as acute myeloid leukemia (AML);

– WO2016/103262A2: Parkinson’s disease;

– WO02/39879A2: sexual dysfunction in a patient taking antidepressant medication;

– W02004/082630A2: neurological function of an individual who has a brain injury.

Apomorphine hydrochloride (HCI) is a salt present in commercially available medical products (e.g. APO-Go® PFS or Apokyn®).

A common side effect of administering apomorphine hydrochloride by e.g. subcutaneous injection is e.g. the development of subcutaneous nodules at the injection site, which can become infected, necessitating treatment or surgical involvement.

In relation to this problem – above discussed WO2016/103262A2 describes an alternative solid form of apomorphine, which is e.g. an alcohol solvate crystal of apomorphine free base, wherein the solvate forming solvent is (C-_|-C₈) alkanol, preferably isopropanol (IPA – i.e. a solid crystalline form of apomorphine-IPA.

Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid found with the chemical formula CH₃(CH₂)₁₄COOH.

Palmitate is the salt and ester of palmitic acid.

A herein relevant synonyms name may e.g. be palmitoate.

Beside apomorphine hydrochloride, above discussed WO2015/197839A1 and W02004/082630A2 provide a list of other possible suitable pharmaceutically acceptable salts – palmitic acid (or synonyms like palmitate or palmitoate) is not mentioned in the lists of these two WO documents.

As discussed in the review article of Schultheiss et al. (“Pharmaceutical Cocrystals and Their Physicochemical Properties”; Crystal Growth & Design, Vol. 9, No. 6, 2009, p. 2950-2967) – solid-state chemists call upon a variety of different strategies when attempting to alter the chemical and physical solid-state properties of active pharmaceutical ingredients (APIs), namely, the formation of salts, polymorphs, hydrates, solvates, and cocrystals.

Salt formation is one of the primary solid-state approaches used to modify the physical properties of APIs, and it is estimated that over half of the medicines on the market are administered as salts. However, a limitation within this approach is that the API must possess a suitable (basic or acidic)

ionizable site. In comparison, cocrystals (multicomponent assemblies held together by freely reversible, noncovalent interactions) offer a different pathway, where any API regardless of acidic, basic, or ionizable groups, could potentially be cocrystallized.

Above discussed WO02/39879A2 also provides a long list of suitable pharmaceutically acceptable salts and mentions palmitoate (see page 5, line 16).

However, in all herein relevant experimental work of this WO document was used apomorphine hydrochloride and a palmitic acid based salt is simply mentioned in a list – i.e. a palmitic acid based salt is not a preferred salt.

Alternatively expressed, by reading this WO document the skilled person has in practice no motivation to use any other solid form than apomorphine-HCI – one reason for this is that apomor-phine-HCI is used in all herein relevant experimental work of this WO document.

PATENT

WO2018130685

claiming synergistic combination comprising antimetabolite antineoplastic agent (eg cytarabine ) and type 1 serotonin receptor antagonist (5-HTR1) (eg apomorphine ), useful for treating cancer.

SYN

Image result for Apomorphine SYNTHESIS

https://journals.lww.com/clinicalneuropharm/Abstract/2015/05000/Effective_Delivery_of_Apomorphine_in_the.3.aspx

PAPER

Small, L. et al.: J. Org. Chem. (JOCEAH) 5, 334 (1940)

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^ Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J (February 2011). “Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation” (PDF). Annals of Neurology. 69 (2): 248–56. doi:10.1002/ana.22319. PMID 21387370.
^ Jump up to:^a ^b ^c ^d ^e Bill RL (2016). Clinical Pharmacology and Therapeutics for Veterinary Technicians – E-Book. Elsevier Health Sciences. p. 94. ISBN 978-0-323-44402-6.
^ Jump up to:^a ^b Khan SN, Hooser SB (2012). Common Toxicologic Issues in Small Animals, an Issue of Veterinary Clinics: Small Animal Practice – E-Book. Elsevier Health Sciences. p. 310. ISBN 978-1-4557-4325-4.
^ Plumb, Donald C. (2011). “Apomorphine”. Plumb’s Veterinary Drug Handbook (7th ed.). Stockholm, Wisconsin: Wiley. pp. 77–79. ISBN 978-0-470-95964-0.
^ Peterson ME, Talcott PA (2006). Small Animal Toxicology. Elsevier Health Sciences. p. 131. ISBN 978-0-7216-0639-2.

Apomorphine
Clinical data


Trade names	Apokyn
AHFS/Drugs.com	Monograph
MedlinePlus	a604020
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	SQ
ATC code	G04BE07 (WHO) N04BC07 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	100% following injection
Protein binding	~50%
Metabolism	Hepatic, phase II
Onset of action	10–20 min
Elimination half-life	40 minutes
Duration of action	60–90 min
Excretion	Hepatic
Identifiers
IUPAC name [show]
CAS Number	58-00-4
PubChem CID	6005
IUPHAR/BPS	33
DrugBank	DB00714
ChemSpider	5783
UNII	F39049Y068
KEGG	D07460
ChEBI	CHEBI:48538
ChEMBL	ChEMBL53
CompTox Dashboard (EPA)	DTXSID8022614
ECHA InfoCard	100.000.327
Chemical and physical data
Formula	C₁₇H₁₇NO₂
Molar mass	267.322 g/mol g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES [hide] OC1=C(O)C(C2=CC=CC3=C2[C@@H](C4)N(C)CC3)=C4C=C1
InChI [hide] InChI=1S/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3/t13-/m1/s1 Key:VMWNQDUVQKEIOC-CYBMUJFWSA-N

Apomorphine

- ATC:N04BC07
Use:emetic, erectile dysfunction
Chemical name:(R)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo[de,g]quinoline-10,11-diol
Formula:C₁₇H₁₇NO₂

MW:267.33 g/mol
CAS-RN:58-00-4
InChI Key:VMWNQDUVQKEIOC-UHFFFAOYSA-N
InChI:InChI=1S/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3
EINECS:200-360-0
LD₅₀:56 mg/kg (M, i.v.); >100 mg/kg (M, p.o.)

///////////// LK-01, LK 01 , LK01, Apomorphine

CN1CCC2=C3C1CC4=C(C3=CC=C2)C(=C(C=C4)O)O.CN1CCC2=C3C1CC4=C(C3=CC=C2)C(=C(C=C4)O)O.O.Cl.Cl

SY-008

July 29, 2019 10:09 am / Leave a comment

Acetic acid;(2S,3R,4S,5S,6R)-2-[[4-[[4-[(E)-4-(2,9-diazaspiro[5.5]undecan-2-yl)but-1-enyl]-2-methylphenyl]methyl]-5-propan-2-yl-1H-pyrazol-3-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol.png

SY-008

CAS 1878218-66-6

FREE FORM 1480443-32-0

SGLT1 inhibitor (type 2 diabetes),

β-D-Glucopyranoside, 4-[[4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)-1-buten-1-yl]-2-methylphenyl]methyl]-5-(1-methylethyl)-1H-pyrazol-3-yl, acetate (1:1)

acetic acid;(2S,3R,4S,5S,6R)-2-[[4-[[4-[(E)-4-(2,9-diazaspiro[5.5]undecan-2-yl)but-1-enyl]-2-methylphenyl]methyl]-5-propan-2-yl-1H-pyrazol-3-yl]oxy]-6-(hydroxymethyl)oxane-3,4,5-triol

4-{4-[(1E)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl beta-D-glucopyranoside acetate

MF H₅₀ N₄ O₆ . C₂ H₄ O₂

MW 58.8 g/mol,C₃₅H₅₄N₄O₈

Originator Eli Lilly

Developer Eli Lilly; Yabao Pharmaceutical Group
Class Antihyperglycaemics; Small molecules
Mechanism of Action Sodium-glucose transporter 1 inhibitors

Phase I Diabetes mellitus

28 Aug 2018 No recent reports of development identified for phase-I development in Diabetes-mellitus in Singapore (PO)
24 Jun 2018 Biomarkers information updated
12 Mar 2018 Phase-I clinical trials in Diabetes mellitus (In volunteers) in China (PO) (NCT03462589)
Eli Lilly is developing SY 008, a sodium glucose transporter 1 (SGLT1) inhibitor, for the treatment of diabetes mellitus. The approach of inhibiting SGLT1 could be promising because it acts independently of the beta cell and could be effective in both early and advanced stages of diabetes. Reducing both glucose and insulin may improve the metabolic state and potentially the health of beta cells, without causing weight gain or hypoglycaemia. Clinical development is underway in Singapore and China.

As at August 2018, no recent reports of development had been identified for phase-I development in Diabetes-mellitus in Singapore (PO).

Suzhou Yabao , under license from Eli Lilly , is developing SY-008 , an SGLT1 inhibitor, for the potential oral capsule treatment of type 2 diabetes in China. By April 2019, a phase Ia trial was completed

PATENT

WO 2013169546

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013169546&recNum=43&docAn=US2013039164&queryString=EN_ALL:nmr%20AND%20PA:(ELI%20LILLY%20AND%20COMPANY)%20&maxRec=4416

The present invention is in the field of treatment of diabetes and other diseases and disorders associated with hyperglycemia. Diabetes is a group of diseases that is characterized by high levels of blood glucose. It affects approximately 25 million people in the United States and is also the 7^th leading cause of death in U.S. according to the 201 1 National Diabetes Fact Sheet (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the absorption of carbohydrates, such as glucose. More specifically, SGLTl is responsible for transport of glucose across the brush border membrane of the small intestine. Inhibition of SGLTl may result in reduced absorption of glucose in the small intestine, thus providing a useful approach to treating diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives with human SGLTl inhibitory activity which are further disclosed as useful for the prevention or treatment of a disease associated with hyperglycemia, such as diabetes. In addition, WO 201 1/039338 discloses certain pyrazole derivatives with SGLT1/SGLT2 inhibitor activity which are further disclosed as being useful for treatment of bone diseases, such as osteoporosis.

There is a need for alternative drugs and treatment for diabetes. The present invention provides certain novel inhibitors of SGLTl which may be suitable for the treatment of diabetes.

Accordingly, the present invention provides a compound of Formula II:

Preparation 1

Synthesis of (4-bromo-2-methyl-phenyl)methanol.

Scheme 1, step A: Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in

tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under the reduced pressure to give a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). 1H NMR (CDCI3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).

Alternative synthesis of (4-bromo-2-methyl-phenyl)methanol.

Borane-dimethyl sulfide complex (2M in THF; 1 16 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.1 13 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3 °C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5°C, and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHC0₃ solution (200 mL) and dried over Na₂S0₄. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+l-18).

Preparation 2

Synthesis of 4-bromo- l-2-methyl-benzene.

Scheme 1, step B: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4-bromo-2-methyl-phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and

-Cl-

dimethylformamide (0.025 mol, 2.0 mL) at 0°C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. ^XH NMR (CDC1₃): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).

Alternative synthesis of 4-bromo- 1 -chloromethyl-2-methyl-benzene. Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further

methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (IN; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na₂S0_4. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). ^XH NMR (300.1 1 MHz, CDC1₃): δ 7.36-7.30 (m, 2H), 7.18 (d, J= 8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).

Preparation 3

Synthesis of 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol.

Extract with ethyl acetate (200 mL), wash extract with water (200 rnL) and brine (200 mL), dry over a₂S04, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120 °C for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40 °C to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+l), 309.0 (M-l).

Alternative synthesis of 4-r(4-bromo-2-methyl-phenyl)methyl1-5-isopropyl- !H-pyrazol- 3-oL

A solution of 4-bromo- 1 -chloromethyl-2-methyl-benzene (13.16 g, 59.95 mmoles) in acetonitrile (65.8 mL) is prepared. Potassium carbonate (24.86 g, 179.9 mmol), potassium iodide (1 1.94 g, 71.94 mmol) and methyl 4-methyl-3-oxo valerate (8.96 mL; 62.95 mmol) are added. The resulting mixture is stirred at ambient temperature for 20 hours. Hydrochloric acid (2N) is added to give pH 3. The solution is extracted with ethyl acetate (100 ml), the organic phase is washed with brine (100 ml) and dried over Na₂S0₄. The mixture is filtered and concentrated under reduced pressure. The residue is dissolved in toluene (65.8 mL) and hydrazine monohydrate (13.7 mL, 0.180 mol) is added. The resulting mixture is heated to reflux and water is removed using a Dean and Stark apparatus. After 3 hours the mixture is cooled to 90 °C and additional hydrazine monohydrate (13.7 mL; 0.180 mol) is added and the mixture is heated to reflux for 1 hour. The mixture is cooled and concentrated under reduced pressure. The resulting solid is triturated with water (200 mL), filtered and dried in a vacuum oven over P2O5 at 60°C. The solid is triturated in iso-hexane (200 mL) and filtered to give the title compound (14.3 g; 77.1% yield). MS (m/z): 309/31 1 (M+l).

Preparation 4

Synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra- O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step D: To a 1L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (20 g, 64.7 mmol), alpha-D-glucopyranosyl bromide tetrabenzoate (50 g, 76 mmol), benzyltributylammonium chloride (6 g, 19.4 mmol), dichloromethane (500 mL), potassium carbonate (44.7 g, 323 mmol) and water (100 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (500mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to yield the title compound (37 g, 64 mmol). MS (ml 2): 889.2 (M+l), 887.2 (M-l).

Preparation 5

Synthesis of 4- {4-[( lis)-4-hydroxybut- 1 -en- 1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- 1H- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step E: Add 3-buten-l-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90 °C for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+l).

Preparation 6

Synthesis of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside.

Scheme 1, step F: Add 3,3,3-triacetoxy-3-iodophthalide (134 mg, 0.96 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (280 mg, 0.32 mmol) and sodium bicarbonate (133.8 mg, 1.6 mmol) in dichloromethane (20 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (270 mg, 0.31 mmol). MS (m/z): 876.5 (M+l), 874.5 (M-l).

Preparation 7

Synthesis of tert-butyl 2- {(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 1, step G: Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4- {4-[(lis)-4-oxybut- 1 -en-1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2-dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol).

MS (m/z): 1115.6 (M+1).

Preparation 8

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D- glucopyranoside dihydrochloride.

Scheme 1, step H: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 0.6 mL, 2.4 mmol) to a solution of tert-butyl 2-{(3is)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (275 mg, 0.25 mmol) in dichloromethane (5 mL). After overnight (18 hours) at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (258 mg, 0.24 mmol). MS (m/z): 1015.6 (M+l).

Example 1

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 1, step I: Add sodium hydroxide (0.5 mL, 0.5 mmol, 1.0 M solution) to a solution of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride (258 mg, 0.24 mmol) in methanol (2 mL). After 2 hours at 40 °C, concentrate to remove the solvent under reduced pressure to give a residue, which is purified by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 um C18XBridge ODB column, solvent A – 1¾0 w NH₄HCO₃ @ pH 10, solvent B – MeCN to yield the title compound as a solid (46 mg, 0.08 mmol). MS (m/z): 598.8 (M+l), 596.8 (M-l).

Preparation 9

Synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra- O-acetyl-beta-D-glucopyranoside.

Scheme 2, step A: To a 1 L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (24 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammomum chloride (5 g, 15.5 mmol), dichloromethane (250 mL), potassium carbonate (32 g, 323 mmol) and water (120 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (450 mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (36.5 g, 57 mmol). MS (m/z): 638.5 (M+l), 636.5 (M-l).

Alternative synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

(32.18 g, 232.9 mmol), dichloromethane (250 mL) and water (120 mL) are combined and the mixture is stirred at ambient temperature for 18 hours. The mixture is partitioned between dichloromethane (250 mL) and water (250 mL). The organic phase is washed with brine (250 mL), dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (eluting with 10% ethyl acetate in dichloromethane to 70% ethyl acetate in dichloromethane) to give the title compound (36.5 g, 74% yield). MS (m/z): 639/641 (M+l).

Preparation 10

Synthesis of 4- {4-[( lis)-4-hydroxybut- 1 -en- 1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- 1H- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Scheme 2, step B: Add 3-buten-l-ol (6.1 mL, 70 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90 °C for 2 hours, cool, and concentrate to remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (7.5 g, 11.9 mmol). MS (m/z): 631.2 (M+l), 629.2 (M-l).

Preparation 11

Synthesis of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Scheme 2, step C: Add 3,3,3-triacetoxy-3-iodophthalide (2.1g, 4.76 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside ( 1.5 g, 2.38 mmol) and sodium bicarbonate (2 g, 23.8 mmol) in dichloromethane (50 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL), wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (0.95 g, 1.51 mmol). MS (m/z): 628.8(M+1), 626.8 (M-l).

Preparation 12

Synthesis of tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0- acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 2, Step D: Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4- {4-[(lis)-4-oxybut- 1 -en-1 -yl]-2-methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2-dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol).

MS (m/z): 866.8, 867.8 (M+l), 864.8, 865.8 (M-l).

Preparation 13

Synthesis oftert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,8- diazaspiro[4.5]decane-8-carboxylate.

The title compound is prepared essentially by the method of Preparation 12. S (m/z): 852.8, 853.6 (M+l), 850.8, 851.6 (M-l).

Preparation 14

Synthesis oftert-butyl 9-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-3,9- diazaspiro[5.5]undecane-3-carboxylate.

The title compound is prepared essentially by the method of Preparation 12. S (m/z): 866.8, 867.6 (M+l), 864.8, 865.6 (M-l).

Preparation 15

Synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2- methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D- glucopyranoside dihydrochloride.

Scheme 2, step E: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 1.5 mL, 5.8 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]- lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 0.58 mmol) in dichloromethane (20 mL). After 2 hours at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (480 mg, 0.57 mmol).

MS (m/z): 767.4 (M+l).

Preparation 16

Synthesis of 4-{4-[(lE)-4-(2,8-diazaspiro[4.5]dec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5- (propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

dihydrochloride.

The title compound is prepared essentially by the method of Preparation 15. MS (m/z): 752.8, 753.8 (M+1), 750.8 (M-1).

First alternative synthesis of Example 1

First alternative synthesis of 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en- 2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 2, step F: Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4-{4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (480 mg, 0.24 mmol). After 18 hours (overnight) at room temperature, concentrate to dryness under reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 urn C18XBridge ODB column, solvent A – H₂0 w NH₄HCO₃ @ pH 10, solvent B – MeCN to yield the title compound as a solid (50 mg, 0.08 mmol).

MS (m/z): 598.8 (M+1), 596.8 (M-1). 1H MR (400.31 MHz, CD3OD): δ 7.11 (d, J=1.3

Hz, 1H), 7.04 (dd, J=1.3,8.0 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 15.8 Hz, 1H), 6.16 (dt, J= 15.8, 6.3 Hz, 1H), 5.02 (m, 1H), 3.81 (d, J= 11.7 Hz, 1H), 3.72 (d, J= 16.8 Hz, 1H), 3.68 (d, J= 16.8 Hz, 1H) , 3.64 (m, 1H), 3.37-3.29 (m, 4H), 2.79 (m, 1H), 2.72 (t, J= 5.8 Hz, 4H), 2.44-2.33 (m, 6H), 2.30 (s, 3H), 2.26 ( broad s, 2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.36 (m, 2H), 1.1 1 (d, J= 7.0 Hz, 3H), 1.10 (d, J= 7.0 Hz, 3H).

Example 2

Synthesis of 4- {4-[(lE)-4-(2,8-diazaspiro[4.5]dec-2-yl)but-l-en-l-yl]-2-methylbi

(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

O H

The title compound is prepared essentially by the method of the first alternative synthesis of Example 1. MS (m/z): 584.7 (M+l), 582.8 (M-l).

Example 3

Synthesis of 4- {4-[( 1 E)-4-(3 ,9-diazaspiro[5.5]undec-3 -yl)but- 1 -en- 1 -yl]-2- methylbenzyl} -5-(propan-2-yl)- lH-pyrazol-3-yl beta-D-glucopyranoside.

The title compound is prepared essentially by first treating the compound of Prearation 14 with HC1 as discussed in Preparation 15 then treating the resulting hydrochloride salt with triethyl amine as discussed in the first alternative synthesis of Example 1. MS (m/z): 598.8, 599.8 (M+l), 596.8, 597.8 (M-l).

Example 1 Preparation 17

Synthesis of tert-butyl 4-but-3- nyl-4,9-diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step A: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgSC^, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). iH MR (300.11 MHz, CDC1₃): δ 3.43-3.31 (m, 4H),

2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.44 (s, 17H).

Preparation 18

Synthesis of tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]- 4,9-diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step B: Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5, 5-tetramethyl-1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65 °C for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ~4cm thick pad of silica gel, eluting with dichloromethane (2 x 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield), !H NMR (300.1 1 MHz, CDC1₃): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H),

3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70 – 1.13 (m, 29H).

Preparation 19

Synthesis of tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D- glucopyranosyl)oxy]- lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate.

Scheme 3, step C: A solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (20 g, 31.3 mmol), tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (16.3 g, 37.5 mmol) and potassium carbonate (12.97 g, 93.82 mmol) in tetrahydrofuran (200 mL) and water (40 mL) is degassed for 15 min by bubbling nitrogen gas through it. Pd(OAc)2 (140 mg, 625 μιηοΐ) and 2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-l, r-biphenyl (0.596 g, 1.25 mmol) are added and the reaction is heated to reflux for 16 h. The solution is cooled to ambient temperature and methanol (200 mL) is added. After 30 minutes the solvent is removed under reduced pressure. The mixture is partitioned between ethyl acetate (500 mL) and brine (500 ml) adding aqueous MgS0₄ (1M; 500 ml) to aid the phase separation. The layers are separated and the organic layer is dried over MgS0₄ and filtered through a 10 cm pad of silica gel, eluting with ethyl acetate (-1.5 L). The filtrate is discarded and the silica pad is flushed with 5% MeOH in THF (2 L). The methanolic filtrate is concentrated under reduced pressure to give the title compound (20. lg, 92%).

MS (m/z): 699 (M+l).

Second alternative Synthesis of Example 1

Second alternative synthesis of 4- {4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-l-en-l- yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 3, step D: Trifluoroacetic acid (32.2 mL; 0.426 mol) is added to a solution of tert-butyl 2- {(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (14.87 g; 21.28 mmol) in dichloromethane (149 mL) cooled in iced water. The solution is allowed to warm to room temperature. After 30 minutes, the mixture is slowly added to ammonia in MeOH (2M; 300 mL), applying cooling as necessary to maintain a constant temperature. The solution is stirred at room temperature for 15 min. The mixture is concentrated under reduced pressure and the residue is purified using SCX-2 resin. The basic filtrate is concentrated under reduced pressure and the residue is triturated/sonicated in ethyl acetate, filtered and dried. The resulting solid is dissolved in MeOH (200ml) and concentrated in vacuo. This is repeated several times give the title compound (12.22 g, yield 96%). MS (m/z): 599 (M+l). [a]_D²⁰ = -12 ° (C=0.2, MeOH).

PATENT

WO 2015069541

https://patents.google.com/patent/WO2015069541A1

4-{4-[(1 E)-4-(2,9-DIAZASPIRO[5.5]UNDEC-2-YL)BUT-1 -EN-1

-YL]-2-METHYLBENZYL}-5-(PROPAN-2-YL)-1 H-PYRAZOL-3-YL

BETA-D- GLUCOPYRANOSIDE ACETATE

The present invention relates to a novel SGLT1 inhibitor which is an acetate salt of a pyrazole compound, to pharmaceutical compositions comprising the compound, to methods of using the compound to treat physiological disorders, and to intermediates and processes useful in the synthesis of the compound.

The present invention is in the field of treatment of diabetes and other diseases and disorders associated with hyperglycemia. Diabetes is a group of diseases that is characterized by high levels of blood glucose. It affects approximately 25 million people in the United States and is also the 7^th leading cause of death in U.S. according to the 2011 National Diabetes Fact Sheet (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the absorption of carbohydrates, such as glucose. More specifically, SGLT1 is responsible for transport of glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 may result in reduced absorption of glucose in the small intestine, thus providing a useful approach to treating diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives with human SGLT1 inhibitory activity which are further disclosed as useful for the prevention or treatment of a disease associated with hyperglycemia, such as diabetes. In addition, WO 2011/039338 discloses certain pyrazole derivatives with SGLT1/SGLT2 inhibitor activity which are further disclosed as being useful for treatment of bone diseases, such as osteoporosis.

There is a need for alternative drugs and treatment for diabetes. The present invention provides an acetate salt of a pyrazole compound, which is an SGLT1 inhibitor, and as such, may be suitable for the treatment of certain disorders, such as diabetes. Accordingly, the present invention provides a compound of Formula I:

or hydrate thereof.

Preparation 1

(4-bromo-2-methyl-phenyl)methanol

Scheme 1, step A: Add borane-tetrahydrofuran complex (0.2 mol, 200 mL, 1.0 M solution) to a solution of 4-bromo-2-methylbenzoic acid (39 g, 0.18 mol) in

tetrahydrofuran (200 mL). After 18 hours at room temperature, remove the solvent under the reduced pressure to give a solid. Purify by flash chromatography to yield the title compound as a white solid (32.9 g, 0.16 mol). !H NMR (CDCI3): δ 1.55 (s, 1H), 2.28 (s, 3H), 4.61 (s, 2H), 7.18-7.29 (m, 3H).

Alternative synthesis of (4-bromo-2-methyl-phenyl)mefhanol.

Borane-dimethyl sulfide complex (2M in THF; 116 mL, 0.232 mol) is added slowly to a solution of 4-bromo-2-methylbenzoic acid (24.3 g, 0.113 mol) in anhydrous tetrahydrofuran (THF, 146 mL) at 3 °C. After stirring cold for 10 min the cooling bath is removed and the reaction is allowed to warm slowly to ambient temperature. After 1 hour, the solution is cooled to 5°C, and water (100 mL) is added slowly. Ethyl acetate (100 mL) is added and the phases are separated. The organic layer is washed with saturated aqueous NaHC0₃ solution (200 mL) and dried over Na₂S0₄. Filtration and concentration under reduced pressure gives a residue which is purified by filtration through a short pad of silica eluting with 15% ethyl acetate/iso-hexane to give the title compound (20.7 g, 91.2% yield). MS (m/z): 183/185 (M+l-18).

Preparation 2

4-bromo- 1 -chloromethyl -2 -methyl -benzene

Scheme 1, step B: Add thionyl chloride (14.31 mL, 0.2 mol,) to a solution of (4- bromo-2 -methyl -phenyl)methanol (32.9 g, 0.16 mol) in dichloromethane (200 mL) and dimethylformamide (0.025 mol, 2.0 mL) at 0°C. After 1 hour at room temperature pour the mixture into ice-water (100 g), extract with dichloromethane (300 mL), wash extract with 5% aq. sodium bicarbonate (30 mL) and brine (200 mL), dry over sodium sulfate, and concentrate under reduced pressure to give the crude title compound as a white solid (35.0 g, 0.16 mol). The material is used for the next step of reaction without further purification. ^!H NMR (CDC1₃): δ 2.38 (s, 3H), 4.52 (s, 2H), 7.13-7.35 (m, 3H).

Alternative synthesis of 4-bromo-l-chloromethyl-2-methyl -benzene. Methanesulfonyl chloride (6.83 mL, 88.3 mmol) is added slowly to a solution of (4-bromo-2-methyl-phenyl)methanol (16.14 g, 80.27 mmol) and triethylamine (16.78 mL; 120.4 mmol) in dichloromethane (80.7 mL) cooled in ice/water. The mixture is allowed to slowly warm to ambient temperature and is stirred for 16 hours. Further

methanesulfonyl chloride (1.24 mL; 16.1 mmol) is added and the mixture is stirred at ambient temperature for 2 hours. Water (80mL) is added and the phases are separated. The organic layer is washed with hydrochloric acid (IN; 80 mL) then saturated aqueous sodium hydrogen carbonate solution (80 mL), then water (80 mL), and is dried over Na₂S0₄. Filtration and concentration under reduced pressure gives a residue which is purified by flash chromatography (eluting with hexane) to give the title compound (14.2 g; 80.5% yield). ^!H NMR (300.11 MHz, CDC1₃): δ 7.36-7.30 (m, 2H), 7.18 (d, J= 8.1 Hz, 1H), 4.55 (s, 2H), 2.41 (s, 3H).

Preparation 3

4- [(4-bromo-2-methyl-phenyl)methyl] -5 -isopropyl- lH-pyrazol-3 -ol

Scheme 1, step C: Add sodium hydride (8.29 g, 0.21 mol, 60% dispersion in oil) to a solution of methyl 4-methyl-3-oxovalerate (27.1 mL, 0.19 mol) in tetrahydrofuran at 0°C. After 30 min at room temperature, add a solution of 4-bromo-l-chloromethyl-2- methyl-benzene (35.0 g, 0.16 mol) in tetrahydrofuran (50 mL). Heat the resulting mixture at 70 °C overnight (18 hours). Add 1.0 M HC1 (20 mL) to quench the reaction. Extract with ethyl acetate (200 mL), wash extract with water (200 mL) and brine (200 mL), dry over Na₂S0₄, filter and concentrate under reduced pressure. Dissolve the resulting residue in toluene (200 mL) and add hydrazine monohydrate (23.3 mL, 0.48 mol). Heat the mixture at 120 °C for 2 hours with a Dean-Stark apparatus to remove water. Cool and remove the solvent under the reduced pressure, dissolve the residue with dichloromethane (50 mL) and methanol (50 mL). Pour this solution slowly to a beaker with water (250 mL). Collect the resulting precipitated product by vacuum filtration. Dry in vacuo in an oven overnight at 40 °C to yield the title compound as a solid (48.0 g, 0.16 mol). MS (m/z): 311.0 (M+l), 309.0 (M-l). Alternative synthesis of 4-[(4-bromo-2-methyl-phenyl)methyl] -5 -isopropyl- lH-pyrazol-

3-ol.

A solution of 4-bromo-l-chloromethyl-2-methyl-benzene (13.16 g, 59.95 mmoles) in acetonitrile (65.8 mL) is prepared. Potassium carbonate (24.86 g, 179.9 mmol), potassium iodide (11.94 g, 71.94 mmol) and methyl 4-methyl-3-oxovalerate (8.96 mL; 62.95 mmol) are added. The resulting mixture is stirred at ambient temperature for 20 hours. Hydrochloric acid (2N) is added to give pH 3. The solution is extracted with ethyl acetate (100 ml), the organic phase is washed with brine (100 ml) and dried over Na₂S0₄. The mixture is filtered and concentrated under reduced pressure. The residue is dissolved in toluene (65.8 mL) and hydrazine monohydrate (13.7 mL, 0.180 mol) is added. The resulting mixture is heated to reflux and water is removed using a Dean and Stark apparatus. After 3 hours the mixture is cooled to 90 °C and additional hydrazine monohydrate (13.7 mL; 0.180 mol) is added and the mixture is heated to reflux for 1 hour. The mixture is cooled and concentrated under reduced pressure. The resulting solid is triturated with water (200 mL), filtered and dried in a vacuum oven over P₂Os at 60°C. The solid is triturated in iso-hexane (200 mL) and filtered to give the title compound (14.3 g; 77.1% yield). MS (m/z): 309/311 (M+l).

Preparation 4

4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl- beta-D-glucopyranoside

Scheme 1, step D: To a 1L flask, add 4-[(4-bromo-2-methyl-phenyl)methyl]-5- isopropyl-lH-pyrazol-3-ol (20 g, 64.7 mmol), alpha-D-glucopyranosyl bromide tetrabenzoate (50 g, 76 mmol), benzyltributylammonium chloride (6 g, 19.4 mmol), dichloromethane (500 mL), potassium carbonate (44.7 g, 323 mmol) and water (100 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (500mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography to yield the title compound (37 g, 64 mmol). MS (m/z): 889.2 (M+l), 887.2 (M-l).

Preparation 5

4- {4- [(lis)-4-hydroxybut- 1 -en- 1 -yl] -2-methylbenzyl } -5 -(propan-2-yl)- lH-pyrazol-3-yl

2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside

Scheme 1, step E: Add 3-buten-l-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4- bromo-2-methylbenzyl)-5 -(propan-2-yl)- lH-pyrazol-3 -yl 2,3 ,4,6-tetra-O-benzoyl-beta-D- glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90 °C for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+l).

Preparation 6

4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside

Scheme 1, step F: Add 3,3,3-triacetoxy-3-iodophthalide (134 mg, 0.96 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (280 mg, 0.32 mmol) and sodium bicarbonate (133.8 mg, 1.6 mmol) in dichloromethane (20 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (270 mg, 0.31 mmol). MS (m/z): 876.5 (M+l), 874.5 (M-l).

Preparation 7

tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-benzoyl-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate

Scheme 1, step G: Add sodium triacetoxyborohydride (98 mg, 0.46 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (270 mg, 0.31 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (179 mg, 0.62 mmol) in 1,2- dichloroethane (5 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (10 mL). Extract with dichloromethane (30 mL). Wash extract with water (30 mL) and brine (40 mL), dry organic phase over sodium sulfate, filter and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (275 mg, 0.25 mmol).

MS (m/z): 1115.6 (M+l).

Preparation 8

4- {4- [( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan- 2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride

Scheme 1, step H: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 0.6 mL, 2.4 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3- [(2,3,4,6-tetra-0-benzoyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4- yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (275 mg, 0.25 mmol) in dichloromethane (5 mL). After overnight (18 hours) at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (258 mg, 0.24 mmol). MS (m/z): 1015.6 (M+l).

Preparation 9

4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl- beta-D-glucopyranoside.

Scheme 2, step A: To a 1 L flask, add 4-[(4-bromo-2-methyl-phenyl)mefhyl]-5- isopropyl-lH-pyrazol-3-ol (24 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D- glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (5 g, 15.5 mmol), dichloromethane (250 mL), potassium carbonate (32 g, 323 mmol) and water (120 mL). Stir the reaction mixture overnight at room temperature. Extract with dichloromethane (450 mL). Wash extract with water (300 mL) and brine (500 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (36.5 g, 57 mmol). MS (m/z): 638.5 (M+l), 636.5 (M-l).

Alternative synthesis of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside.

Reagents 4-[(4-bromo-2-methyl-phenyl)methyl]-5-isopropyl-lH-pyrazol-3-ol (24.0 g, 77.6 mmol), 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide (50.4 g, 116 mmol), benzyltributylammonium chloride (4.94 g, 15.52 mmol), potassium carbonate (32.18 g, 232.9 mmol), dichloromethane (250 mL) and water (120 mL) are combined and the mixture is stirred at ambient temperature for 18 hours. The mixture is partitioned between dichloromethane (250 mL) and water (250 mL). The organic phase is washed with brine (250 mL), dried over Na₂S0₄, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (eluting with 10% ethyl acetate in dichloromethane to 70% ethyl acetate in dichloromethane) to give the title compound (36.5 g, 74% yield). MS (m/z): 639/641 (M+l). Preparation 10

4- {4- [(lis)-4-hydroxybut- 1 -en- 1 -yl] -2-methylbenzyl } -5 -(propan-2-yl)- lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

Scheme 2, step B: Add 3-buten-l-ol (6.1 mL, 70 mmol) to a solution of 4-(4- bromo-2-methylbenzyl)-5 -(propan-2-yl)- 1 H-pyrazol-3 -yl 2,3 ,4,6-tetra-O-acetyl-beta-D- glucopyranoside (15 g, 23.5 mmol) in acetonitrile (200 mL) and triethylamine (50 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (1.43 g, 4.7 mmol) and palladium acetate (526 mg, 2.35 mmol). After refluxing at 90 °C for 2 hours, cool, and concentrate to remove the solvent under the reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (7.5 g, 11.9 mmol) MS (m/z): 631.2 (M+l), 629.2 (M-l).

Preparation 11

4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol-3-yl

2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside

Scheme 2, step C: Add 3,3,3-triacetoxy-3-iodophthalide (2.1g, 4.76 mmol) to a solution of 4-{4-[(l£)-4-hydroxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH- pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside ( 1.5 g, 2.38 mmol) and sodium bicarbonate (2 g, 23.8 mmol) in dichloromethane (50 mL) at 0 °C. After 15 minutes at room temperature, quench the reaction with saturated aqueous sodium thiosulfate (10 mL). Extract with dichloromethane (30 mL), wash extract with water (30 mL) and brine (40 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (0.95 g, 1.51 mmol). MS (m/z): 628.8(M+1), 626.8 (M-l).

Preparation 12a

tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)oxy] -lH-pyrazol-4-yl}methyl)phenyl]but-3-en- 1 -yl} -2,9- diazaspiro[5.5]undecane-9-carboxylate

Scheme 2, Step D: Add sodium triacetoxyborohydride (303 mg, 1.4 mmol) to a solution of 4-{4-[(l£)-4-oxybut-l-en-l-yl]-2-methylbenzyl}-5-(propan-2-yl)-lH-pyrazol- 3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (600 mg, 0.95 mmol) and tert-butyl 2,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (333 mg, 1.2 mmol) in 1,2- dichloroethane (30 mL). After 30 minutes at room temperature, quench the reaction with saturated aqueous sodium bicarbonate (15 mL). Extract with dichloromethane (60 mL). Wash extract with water (30 mL) and brine (60 mL). Dry organic phase over sodium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue by flash chromatography to yield the title compound (500 mg, 0.58 mmol).

MS (m/z): 866.8, 867.8 (M+l), 864.8, 865.8 (M-l).

Preparation 13

4- {4- [( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan- 2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride

Scheme 2, step E: Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 1.5 mL, 5.8 mmol) to a solution of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6- tetra-0-acetyl-beta-D-glucopyranosyl)oxy] – lH-pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 – yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 0.58 mmol) in dichloromethane (20 mL). After 2 hours at room temperature, concentrate to remove the solvent under reduced pressure to yield the title compound as a solid (480 mg, 0.57 mmol).

MS (m/z): 767.4 (M+l).

Scheme 3

Preparation 14

tert-butyl 4-but-3-ynyl-4,9-diazas iro[5.5]undecane-9-carboxylate

Scheme 3, step A: Cesium carbonate (46.66 g, 143.21 mmol) is added to a suspension of tert-butyl 4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (16.66 g, 57.28 mmoles) in acetonitrile (167 mL). The mixture is stirred for 10 minutes at ambient temperature then 4-bromobutyne (6.45 mL, 68.74 mmol) is added. The reaction is heated to reflux and stirred for 18 hours. The mixture is cooled and concentrated under reduced pressure. The residue is partitioned between water (200 mL) and ethyl acetate (150 mL). The phases are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are washed with water (200 mL), then brine (150 mL), dried over MgS0₄, filtered, and concentrated under reduced pressure to give the title compound (17.2 g, 98% yield). ^lH NMR (300.11 MHz, CDC1₃): δ 3.43-3.31 (m, 4H), 2.53-2.48 (m, 2H), 2.37-2.29 (m, 4H), 2.20 (s, 2H), 1.94 (t, J= 2.6 Hz, 1H), 1.44 (s, 17H).

Preparation 15

tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)but-3-enyl]-4,9- diazaspiro[5.5]undecane-9-carboxylate

Scheme 3, step B: Triethylamine (5.62 mmoles; 0.783 mL), 4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (8.56 mL, 59.0 mmol) and zirconocene chloride (1.45 g, 5.62 mmoles) are added to tert-butyl 4-but-3-ynyl-4,9-diazaspiro[5.5]undecane-9-carboxylate (17.21 g, 56.16 mmoles). The resulting mixture is heated to 65 °C for 3.5 hours. The mixture is cooled and dissolved in dichloromethane (150 mL). The resulting solution is passed through a ~4cm thick pad of silica gel, eluting with dichloromethane (2 x 200 mL). The filtrate is concentrated under reduced pressure to give the title compound (21.2 g, 87% yield). 1H NMR (300.11 MHz, CDCI3): δ 6.65-6.55 (m, 1H), 5.49-5.43 (m, 1H), 3.42-3.29 (m, 4H), 2.40-2.27 (m, 6H), 2.25-2.08 (m, 2H), 1.70 – 1.13 (m, 29H).

Preparation 16

tert-butyl 2-{(3£’)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D-glucopyranosyl)oxy]-lH- pyrazol-4-yl} methyl)phenyl]but-3 -en- 1 -yl} -2,9-diazaspiro [5.5]undecane-9-carboxylate

Scheme 3, step C: A solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)- lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (20 g, 31.3 mmol), tert- butyl 4-[(£)-4-(4,4,5 ,5 -tetramethyl- 1 ,3,2-dioxaborolan-2-yl)but-3 -enyl] -4,9- diazaspiro[5.5]undecane-9-carboxylate (16.3 g, 37.5 mmol) and potassium carbonate (12.97 g, 93.82 mmol) in tetrahydrofuran (200 mL) and water (40 mL) is degassed for 15 min by bubbling nitrogen gas through it. Pd(OAc)₂ (140 mg, 625 μιηοΐ) and 2- dicyclohexylphosphino-2′,4′,6′-tri-i -propyl- Ι, -biphenyl (0.596 g, 1.25 mmol) are added and the reaction is heated to reflux for 16 h. The solution is cooled to ambient temperature and methanol (200 mL) is added. After 30 minutes the solvent is removed under reduced pressure. The mixture is partitioned between ethyl acetate (500 mL) and brine (500 ml) adding aqueous MgS0₄ (1M; 500 ml) to aid the phase separation. The layers are separated and the organic layer is dried over MgS0₄ and filtered through a 10 cm pad of silica gel, eluting with ethyl acetate (-1.5 L). The filtrate is discarded and the silica pad is flushed with 5% MeOH in THF (2 L). The methanolic filtrate is concentrated under reduced pressure to give the title compound (20. lg, 92%).

MS (m/z): 699 (M+l).

Preparation 17

tert-butyl 4- [(E)-4- [4- [(3 -hydroxy-5-isopropyl- 1 H-pyrazol-4-yl)methyl] -3 -methyl- phenyl]but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate

Scheme 4, step A: Add tert-butyl 4-[(£)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)but-3-enyl]-4,9-diazaspiro[5.5]undecane-9-carboxylate (35.8 kg, 82.4 mol) in methanol (130 L) to a solution of (4-[(4-bromo-2-methyl-phenyl)methyl]-5- isopropyl-lH-pyrazol-3-ol (23.9 kg, 77.3 mol) in methanol (440 L) at room temperature. Add water (590 L) and tripotassium phosphate (100 kg, 471.7 mol) and place the reaction under nitrogen atmosphere. To the stirring solution, add a suspension of

tris(dibenzylideneacetone) dipalladium (1.42 kg, 1.55 mol) and di-tert- butylmethylphosphonium tetrafluoroborate (775 g, 3.12 mol) in methanol (15 L). The resulting mixture is heated at 75 °C for 2 hours. Cool the mixture and filter over diatomaceous earth. Rinse the the filter cake with methanol (60 L), and concentrate the filtrate under reduced pressure. Add ethyl acetate (300 L), separate the layers, and wash the organic layer with 15% brine (3 x 120 L). Concentrate the organic layer under reduced pressure, add ethyl acetate (300 L), and stir the mixture for 18 to 20 hours. Add heptane (300 L), cool the mixture to 10 °C, and stir the mixture for an additional 18 to 20 hours. Collect the resulting solids by filtration, rinse the cake with ethyl acetate/heptane (2:3, 2 x 90 L), and dry under vacuum at 40°C to give the title compound (29.3 kg, 70.6% yield) as a white solid. ^lH NMR (400 MHz, CD₃OD): δ 7.14 (s, 1H), 7.07 (d, J= 8.0 Hz, 1H), 6.92 (d, J= 7.6 Hz, 1H), 6.39 (d, J= 16.0 Hz, 1H), 6.25-6.12 (m, 1H), 3.63 (s, 2H), 3.45-3.38 (bs, 3H), 3.34 (s, 3 H), 3.33 (s, 3H), 2.85-2.75 (m, 1H), 2.49-2.40 (m, 5 H), 2.33 (s, 3H), 1.68-1.62 (m, 2H), 1.60-1.36 (m, 15H), 1.11 (s, 3H), 1.10 (s, 3H).

Preparation 12b

Alterternative preparation of tert-butyl 2-{(3£)-4-[3-methyl-4-({5-(propan-2-yl)-3- [(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but- 3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate.

Scheme 4, step B: Combine tert-butyl 4-[(E)-4-[4-[(3-hydroxy-5-isopropyl-lH- pyrazol-4-yl)methyl] -3-methyl-phenyl]but-3 -enyl] -4,9-diazaspiro [5.5]undecane-9- carboxylate (17.83 kg, 33.2 moles), acetonitrile (180 L), and benzyltributylammonium chloride (1.52 kg, 4.87 moles) at room temperature. Slowly add potassium carbonate (27.6 kg, 199.7 moles) and stir the mixture for 2 hours. Add 2,3,4,6-tetra-O-acetyl-alpha- D-glucopyranosyl bromide (24.9 kg, 60.55 mol), warm the reaction mixture to 30°C and stir for 18 hours. Concentrate the mixture under reduced pressure and add ethyl acetate (180 L), followed by water (90 L). Separate the layers, wash the organic phase with 15% brine (3 x 90 L), concentrate the mixture, and purify using column chromatography over silica gel (63 kg, ethyl acetate/heptanes as eluent (1 :2→1 :0)) to provide the title compound (19.8 kg, 94% purity, 68.8% yield) as a yellow foam, !H NMR (400 MHz, CDC1₃): δ 7.13 (s, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 16.0,

1H), 6.25-6.13 (m, 1H), 5.64 (d, J= 8.0 Hz, 1H), 5.45-5.25 (m, 2H), 5.13-4.95 (m, 2H), 4.84-4.76 (m, 1H), 4.25-4.13 (m, 2H), 4.10-4.00 (m, 2H), 3.90-3.86 (m, 1H), 3.58-3.50 (m, 2H), 3.40-3.22 (m, 4H), 2.89-2.79 (m, 1H), 2.10-1.90 (m, 18 H), 1.82 (s, 3H), 1.62- 0.82 (m, 22H).

Preparation 18

2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-0-acetyl-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl} -2,9- diazaspiro[5.5]undecane

Scheme 4, step C: Combine tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)- 3-[(2,3,4,6-tetra-0-acetyl-beta-D-glucopyranosyl)oxy]-lH-pyrazol-4- yl}methyl)phenyl]but-3-en-l-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (19.6 kg, 22.6 moles) with dichloromethane (120 L) and cool to 0°C. Slowly add trifluoroacetic acid (34.6 L, 51.6 kg, 452 moles) and stir for 9 hours. Quench the reaction with ice water (80 L), and add ammonium hydroxide (85-90 L) to adjust the reaction mixture to pH (8- 9). Add dichloromethane (120 L), warm the reaction mixture to room temperature, and separate the layers. Wash the organic layer with water (75 L), brine, and concentrate under reduced pressure to provide the title compound (16.2 kg, 95.0% purity, 93% yield) as a yellow solid. ^lH NMR (400 MHz, CDC1₃): δ 7.08 (s, IH), 6.99 (d, J= 8.0 Hz, IH),

6.76 (d, J= 7.6 Hz, IH), 6.38 (d, J=15.6 Hz, IH), 6.00-5.83 (m, IH), 5.31 (d, J= 7.6 Hz, IH), 5.25-5.13 (m, 4H), 4.32 (dd, J= 12.8, 9.2 Hz, IH), 4.14 (d, J= 11.2 Hz, IH), 3.90 (d, J= 10.0 Hz, IH), 3.75-3.50 (m, 3H), 3.30-3.00 (m, 5 H), 2.85-2.75 (m, IH), 2.70-2.48 (m, 3H), 2.25 (s, IH), 2.13-1.63 (m, 19H), 1.32-1.21 (m, IH), 1.14 (s, 3H), 1.13 (s, 3H), 1.12 (s, 3H), 1.10 (s, 3H).

Example 1

Hydrated crystalline 4- {4-[(l£)-4-(2,9-diazaspiro[5.5]undec-2-yl)but- 1 -en- 1 -yl]-2- methylbenzyl} -5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside acetate

First alternative preparation of 4-{4-[(l£’)-4-(2.9-diazaspiro[5.5]undec-2-yl)but-l-en-l- yl]-2-methylbenzyl| -5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside (free base).

Scheme 1, step I: Add sodium hydroxide (0.5 mL, 0.5 mmol, 1.0 M solution) to a solution of 4- {4-[( l£)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} – 5-(propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside dihydrochloride (258 mg, 0.24 mmol) in methanol (2 mL). After 2 hours at 40°C, concentrate to remove the solvent under reduced pressure to give a residue, which is purified by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 μιη C18XBridge ODB column, solvent A – H.0 with NH₄HCO₃ @ pH 10, solvent B – MeCN to yield the title compound (free base) as a solid (46 mg, 0.08 mmol). MS (m/z): 598.8 (M+l), 596.8 (M-l).

Second alternative preparation of 4-{4-r(l-£’)-4-(2.9-diazaspiror5.51undec-2-yl)but-l-en- 1 -yl] -2-methylbenzyl I -5 -(propan-2-yl)- lH-pyrazol-3 -yl beta-D-glucopyranoside (free base^“).

Scheme 2, step F: Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4- {4-[( l_JE)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl } -5 – (propan-2-yl)-lH-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (480 mg, 0.24 mmol). After 18 hours (overnight) at room temperature, concentrate to dryness under reduced pressure. Purify the resulting residue by preparative HPLC method: high pH, 25% B for 4 min, 25-40 B % for 4 min @ 85 mL/min using a 30 x 75 mm, 5 μιη C18XBridge ODB column, solvent A – H₂0 with NH₄HCO₃ @ pH 10, solvent B – MeCN to yield the title compound (free base) as a solid (50 mg, 0.08 mmol).

MS (m/z): 598.8 (M+l), 596.8 (M-l). 1H NMR (400.31 MHz, CD3OD): δ 7.11 (d, J=1.3

Hz, 1H), 7.04 (dd, J=l .3,8.0 Hz, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.36 (d, J= 15.8 Hz, 1H), 6.16 (dt, J= 15.8, 6.3 Hz, 1H), 5.02 (m, 1H), 3.81 (d, J= 11.7 Hz, 1H), 3.72 (d, J= 16.8 Hz, 1H), 3.68 (d, J= 16.8 Hz, 1H) , 3.64 (m, 1H), 3.37-3.29 (m, 4H), 2.79 (m, 1H), 2.72 (t, J= 5.8 Hz, 4H), 2.44-2.33 (m, 6H), 2.30 (s, 3H), 2.26 ( broad s, 2H), 1.59 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.36 (m, 2H), 1.11 (d, J= 7.0 Hz, 3H), 1.10 (d, J= 7.0 Hz, 3H).

Third alternative preparation of 4-{4-[(l£^,)-4-(2,9-diazaspiro[5.51undec-2-yl)but-l-en-l- yll-2-methylbenzyl|-5-(propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside.

Scheme 3, step D: Trifluoroacetic acid (32.2 mL; 0.426 mol) is added to a solution of tert-butyl 2-{(3_JE)-4-[3-methyl-4-({5-(propan-2-yl)-3-beta-D- glucopyranosyl)oxy]-lH-pyrazol-4-yl}methyl)phenyl]but-3-en-l-yl}-2,9- diazaspiro[5.5]undecane-9-carboxylate (14.87 g; 21.28 mmol) in dichloromethane (149 mL) cooled in iced water. The solution is allowed to warm to room temperature. After 30 minutes, the mixture is slowly added to ammonia in MeOH (2M; 300 mL), applying cooling as necessary to maintain a constant temperature. The solution is stirred at room temperature for 15 min. The mixture is concentrated under reduced pressure and the residue is purified using SCX-2 resin. The basic filtrate is concentrated under reduced pressure and the residue is triturated/sonicated in ethyl acetate, filtered and dried. The resulting solid is dissolved in MeOH (200mL) and concentrated in vacuo. This is repeated several times to give the title compound (free base) (12.22 g, yield 96%). MS (m/z): 599 (M+l); [a]_D ²0 = -12 ° (C=0.2, MeOH).

Preparation of final title compound, hydrated crystalline 4-{4-|YlE)-4-(2.9- diazaspiro [5.5^“|undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl I -5-(propan-2-vD- 1 H-pyrazol-3 – yl beta-D-glucopyranoside acetate.

4- {4- [(1 E)-4-(2,9-diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl } -5 – (propan-2-yl)-lH-pyrazol-3-yl beta-D-glucopyranoside (902 mg) is placed in a round bottom flask (100 mL) and treated with wet ethyl acetate (18 mL). [Note – wet ethyl acetate is prepared by mixing ethyl acetate (100 mL) and dionized water (100 mL). After mixing, the layers are allowed to separate, and the top wet ethyl acetate layer is removed for use. Acetic acid is a hydrolysis product of ethyl acetate and is present in wet ethyl acetate.] The compound dissolves, although not completely as wet ethyl acetate is added. After several minutes, a white precipitate forms. An additional amount of wet ethyl acetate (2 mL) is added to dissolve remaining compound. The solution is allowed to stir uncovered overnight at room temperature during which time the solvent partially evaporates. The remaining solvent from the product slurry is removed under vacuum, and the resulting solid is dried under a stream of nitrogen to provide the final title compound as a crystalline solid. A small amount of amorphous material is identified in the product by solid-state NMR. This crystalline final title compound may be used as seed crystals to prepare additional crystalline final title compound.

Alternative preparation of final title compound, hvdrated crystalline 4-{4-[(lE)-4-(2.,9- diazaspiro [5.5]undec-2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl I -5-(propan-2-yl)- 1 H-pyrazol-3 – yl beta-D-glucopyranoside acetate.

Under a nitrogen atmosphere combine of 4-{4-[(lE)-4-(2,9-diazaspiro[5.5]undec- 2-yl)but- 1 -en- 1 -yl] -2-methylbenzyl} -5-(propan-2-yl)- 1 H-pyrazol-3-yl 2,3,4,6-tetra-O- acetyl-beta-D-glucopyranoside (2.1 kg, 2.74 mol), methanol (4.4 L), tetrahydrofuran (4.2 L), and water (210 mL). Add potassium carbonate (460 g, 3.33 moles) and stir for four to six hours, then filter the reaction mixture to remove the solids. Concentrate the filtrate under reduced pressure, then add ethanol (9.0 L) followed by acetic acid (237 mL, 4.13 mol) and stir at room temperature for one hour. To the stirring solution add wet ethyl acetate (10 L, containing approx. 3 w/w% water) slowly over five hours, followed by water (500 mL). Stir the suspension for twelve hours and add wet ethyl acetate (4.95 L, containing approx. 3 w/w% water) over a period of eight hours. Stir the suspension for twelve hours and add additional wet ethyl acetate (11.5 L, containing approx. 3 w/w% water) slowly over sixteen hours. Stir the suspension for twelve hours, collect the solids by filtration and rinse the solids with wet ethyl acetate (3.3 L, containing approx. 3 w/w% water). Dry in an oven under reduced pressure below 30°C to give the title compound as an off-white crystalline solid (1.55 kg, 2.35 mol, 96.7% purity, 72.4 w/w% potency, 68.0% yield based on potency). HRMS (m/z): 599.3798 (M+l).

PATENT

CN105705509

https://patentscope.wipo.int/search/en/detail.jsf?docId=CN175101669&tab=PCTDESCRIPTION

The present invention is in the field of treatment of diabetes and other diseases and conditions associated with hyperglycemia. Diabetes is a group of diseases characterized by high blood sugar levels. It affects approximately 25 million people in the United States, and according to the 2011 National Diabetes Bulletin, it is also the seventh leading cause of death in the United States (US Department of Health and Human Resources Services, Centers for Disease Control and Prevention). Sodium-coupled glucose cotransporters (SGLT’s) are one of the transporters known to be responsible for the uptake of carbohydrates such as glucose. More specifically, SGLT1 is responsible for transporting glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 can result in a decrease in glucose absorption in the small intestine, thus providing a useful method of treating diabetes.

Alternative medicines and treatments for diabetes are needed. The present invention provides an acetate salt of a pyrazole compound which is an SGLT1 inhibitor, and thus it is suitable for treating certain conditions such as diabetes.

U.S. Patent No. 7,655,632 discloses certain pyrazole derivatives having human SGLT1 inhibitory activity, which are also disclosed for use in the prevention or treatment of diseases associated with hyperglycemia, such as diabetes. Moreover, WO 2011/039338 discloses certain pyrazole derivatives having SGLT1/SGLT2 inhibitor activity, which are also disclosed for use in the treatment of bone diseases such as osteoporosis.

PATENT

WO-2019141209

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019141209&tab=FULLTEXT&_cid=P10-JYNZF2-05384-1

Diabetes is a group of lifelong metabolic diseases characterized by multiple causes of chronic hyperglycemia. Long-term increase in blood glucose can cause damage to large blood vessels and microvessels and endanger the heart, brain, kidney, peripheral nerves, eyes, feet and so on. According to the statistics of the World Health Organization, there are more than 100 complications of diabetes, which is the most common complication, and the incidence rate is also on the rise. The kidney plays a very important role in the body’s sugar metabolism. Glucose does not pass through the lipid bilayer of the cell membrane in the body, and must rely on the glucose transporter on the cell membrane. Sodium-coupled glucose co-transporters (SGLTs) are one of the transporters known to be responsible for the uptake of carbohydrates such as glucose. More specifically, SGLT1 is responsible for transporting glucose across the brush border membrane of the small intestine. Inhibition of SGLT1 results in a decrease in glucose absorption in the small intestine and can therefore be used in the treatment of diabetes.

Ellerelli has developed a novel SGLTs inhibitor for alternative drugs and treatments for diabetes. CN105705509 discloses the SGLTs inhibitor-pyrazole compound, which has the structure shown in the following formula (1):

It is well known for drug production process has strict requirements, the purity of pharmaceutical active ingredients will directly affect the safety and effectiveness of drug quality. Simplified synthetic route optimization, and strictly control the purity of the intermediates has a very important role in improving drug production, quality control and optimization of the dosage form development.

CN105705509 discloses a method for synthesizing a compound of the formula (1), wherein the intermediate compound 2-{(3E)-4-[3-methyl4-({5-(propyl-2-yl)) is obtained by the step B in Scheme 4. -3-[(2,3,4,6-tetra-acetyl-β-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3- Tert-butyl-1-enyl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (Compound obtained in Preparation Example 12b) was obtained as a yellow foam, yield 68.6%, purity 94 %, this step involves silica gel column purification, low production efficiency, high cost, and poor quality controllability; the intermediate 2-{(3E)-4-[3-methyl 4-({5- (prop-2-yl)-3-[(2,3,4,6-tetra-acetyl-β-D-glucopyranosyl)oxy)-1H-pyrazol-4-yl}methyl) Phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane (Compound obtained in Preparation Example 18) as a yellow solid with a purity of 95.0%; The resulting intermediate compounds were all of low purity. Moreover, CN105705509 produces a compound of formula (1) having a purity of 96.7% as described in the publications of the publications 0141 and 0142. The resulting final compound is not of high purity and is not conducive to subsequent drug preparation.

Process for preparing pyranoglucose-substituted pyrazole compound, used as a pharmaceutical intermediate in SGLT inhibitor for treating diabetes.

Example 1

626 g of the compound of the formula (16), 6 L of acetonitrile, 840 g of cesium carbonate and 1770 g of 2,3,4,6-tetra-O-pivaloyl-α-D-glucosyl bromide (formula (17) The compound is sequentially added to the reaction vessel, heated to 40 ° C to 45 ° C, and reacted for 4 to 5 hours, then cooled to 20 to 25 ° C, filtered, and the obtained solid is rinsed once with acetonitrile; the filter cake is dissolved with 8 L of ethyl acetate and 10 L of water. After the liquid separation, the organic phase was concentrated to about 3 L, 10 L of acetonitrile was added, and the mixture was stirred for 12 h to precipitate a solid, which was filtered. The filter cake was rinsed with acetonitrile and dried under vacuum at 60 ° C for 24 h to give white crystals, 652 g of compound of formula (9c). The yield was 61%, the HPLC purity was 98.52%, and the melting point was 180.0-182.1 °C. ¹ H NMR (400 MHz, MeOD) (see Figure 1): δ 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.39 (d, J=15.6,1H), 6.19-6.12 (m,1H), 5.59 (d, J=8.4 Hz, 1H), 5.40-5.35 (t, J=9.6 Hz, 1H), 5.17-5.06 (m, 2H) , 4.18-4.14 (dd, J = 12.4 Hz, 4.4 Hz, 1H), 4.10-4.06 (dd, J = 12.4 Hz, 1.6 Hz, 1H), 3.92-3.89 (dd, J = 10 Hz, 2.4 Hz, 1H) , 3.64-3.54 (dd, J=20 Hz, 16.8 Hz, 2H), 3.31-3.30 (m, 4H), 2.86-2.79 (m, 1H), 2.37-2.29 (m, 11H), 1.63-1.38 (m, 17H), 1.15-1.05 (m, 42H). MS (m/z): 1035.7 (M+H).

640 g of the compound of the formula (9c) and 6.4 L of ethyl acetate were successively added to the reaction vessel, and the temperature was lowered to 15 ° C to 20 ° C. 1176 g of p-toluenesulfonic acid monohydrate was added in portions for 2 to 3 hours; after the reaction was over, 3.5 L of a 9% potassium hydroxide aqueous solution was added, and the mixture was stirred for 10 minutes, and the aqueous phase was discarded. The organic phase was washed successively with 3.5 L of 9% and 3.5 L of 3% aqueous potassium hydroxide and concentrated to 2.5 L. 21L of n-heptane was added to the residue, and the mixture was stirred for 12 hours; filtered, and the filter cake was rinsed with n-heptane; the filter cake was dried under vacuum at 60 ° C for 24 h to obtain white crystals, p-toluene of the compound of formula (10c). The sulfonate salt was 550 g, the yield was 80%, the purity was 97.59%, and the melting point was 168.0-169.2 °C. ¹ H NMR (400 MHz, MeOD) (see Figure 2): δ 7.72 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.10 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.39 (d, J = 15.6, 1H), 6.19-6.12 (m, 1H), 5.60 (d, J = 8.0 Hz, 1H) ), 5.41-5.37 (t, J = 9.6 Hz, 1H), 5.17-5.06 (m, 2H), 4.18-4.14 (dd, J = 12.4 Hz, 4.0 Hz, 1H), 4.10-4.07 (d, J = 11.6Hz, 1H), 3.94-3.91 (dd, J=7.2Hz, 2.8Hz, 1H), 3.64-3.54 (dd, J=20.0Hz, 16.8Hz, 2H), 3.31-3.30 (m, 4H), 2.86 -2.79 (m, 1H), 2.49-2.29 (m, 14H), 1.78-1.44 (m, 8H), 1.15-1.05 (m, 42H). MS (m/z): 935.7 (M+H).

82.6 g of potassium hydroxide, 5.5 L of absolute ethanol and 550 g of the p-toluenesulfonate of the compound of the formula (10c) were sequentially added to the reaction vessel, and stirred at 45 to 50 ° C for about 4 hours. The temperature was lowered to 20 to 25 ° C, filtered, and the solid was rinsed with ethanol. The filtrate and the eluent were combined, and 65 g of acetic acid was added thereto, followed by stirring for 15 min. The reaction solution was concentrated under reduced pressure to about 1.5 L, and then 52 g of acetic acid was added. After stirring for 20 min, 4.5 L of ethyl acetate containing 3% water and 160 mL of purified water were added dropwise. After the dropwise addition, continue stirring for 3 to 4 hours. Filter and filter cake was rinsed with ethyl acetate containing 3% water. The solid was transferred to a reaction kettle, 500 mL of water was added and stirred for 18 h. After filtration, the filter cake was washed successively with water and an ethanol/ethyl acetate mixed solvent. The filter cake was dried under vacuum at 35 to 40 ° C for 4 hours to obtain a white solid, 245 g of compound of formula (1), yield 75%, purity 99.55%. ¹ H NMR (400 MHz, MeOD) (see Figure 3): δ 7.11 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.39 (d, J=16.0,1H), 6.20-6.13 (dt, J=15.6 Hz, 6.8 Hz, 1H), 5.03-5.01 (m, 1H), 3.83 (d, J=11.2, 1H), 3.71-3.59 (m, 3H), 3.35-3.30 (m, 4H), 3.09-3.06 (t, J = 6 Hz, 4H), 2.87-2.77 (m, 1H), 2.49-2.31 (m, 6H), 2.30 (s, 3H), 2.26(s, 2H), 1.90 (s, 3H), 1.78 (m, 2H), 1.68 (m, 2H), 1.65 (m, 2H), 1.44-1.43 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), MS (m/z): 599.5 (M+H).

Example 2

5.00 kg of the maleate salt of the compound of the formula (16), 40 L of tetrahydrofuran, 5.47 kg of potassium phosphate and 11.67 kg of 2,3,4,6-tetra-O-pivaloyl-α-D-glucosyl bromide The compound (formula (17)) is sequentially added to the reaction vessel, heated to 40 to 45 ° C, and reacted for 4 to 5 hours, then cooled to 15 to 25 ° C, filtered, and the solid was rinsed once with tetrahydrofuran. The filter cake was dissolved in 36 L of ethyl acetate and 20 L of water and then separated. The organic phase was concentrated to ca. 18 L, 64 L acetonitrile was added and stirred for 15 h. Filtration, the filter cake was rinsed with acetonitrile, and dried under vacuum at 60 ° C for 24 h to give white crystals of the compound of formula (9c), 4.50 kg, yield 57%, HPLC purity 99.19%.

4.45 kg of the compound of the formula (9c) and 45 L of butyl acetate were sequentially added to the reaction vessel, and the temperature was lowered to 15 ° C to 20 ° C. 4.13 kg of methanesulfonic acid was added in portions and the reaction was carried out for 2 to 3 hours. 22 L of a 9% aqueous potassium hydroxide solution was added, stirred for 10 min, and the liquid phase was discarded. The organic phase was washed successively with 10 L of 9%, 4.5 L of 10% and 2 L of 2.5% aqueous potassium hydroxide and concentrated to 15 L. 68 L of n-heptane was added to the residue, and the mixture was stirred for further 12 h. Filtered and the filter cake was rinsed once with n-heptane. The solid was dried under vacuum at 60 ° C for 24 h to obtain white crystals. The methanesulfonic acid salt of the compound of formula (10c) was 4.37 kg, yield 99%, purity 97.94%.

0.73 kg of potassium hydroxide, 43 L of methanol and 4.30 kg of the compound of the formula (10c) were sequentially added to the reaction vessel, and stirred at 45 to 50 ° C for 4 hours. The temperature was lowered to 20 to 25 ° C, filtered, and 0.56 kg of acetic acid was added to the filtrate, and the mixture was stirred for 15 minutes. The reaction solution was concentrated to about 15 L under reduced pressure, and 0.40 g of acetic acid was added. After stirring for 10 min, 39 L of 3% water in ethyl acetate and 1.3 L of purified water were added dropwise. After the dropwise addition, stirring was continued for about 2 hours. Filter and filter cake was rinsed once with ethyl acetate containing 3% water. The solid was transferred to a reaction kettle, and 3.5 L of water was added and stirred for 18 h. After filtration, the filter cake was washed successively with water and an ethanol/ethyl acetate mixed solvent. The cake was vacuum dried at 35 to 40 ° C to give a white solid. Compound (1) (1), 1.84 g, yield 67%, purity 99.65%.

Patent ID	Title	Submitted Date	Granted Date
US9573970	4–5-(PROPAN-2-YL)-1H-PYRAZOL-3-YL BETA-D GLUCOPYRANOSIDE ACETATE	2014-10-30	2016-07-28

/////////////SY-008 , SY 008 , SY008, ELI LILY, PHASE 1, GLT1 inhibitor, type 2 diabetes, Yabao Pharmaceutical, CHINA, DIABETES

CC(=O)O.Cc5cc(\C=C\CCN2CCCC1(CCNCC1)C2)ccc5Cc3c(nnc3C(C)C)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O

Cc5cc(\C=C\CCN2CCCC1(CCNCC1)C2)ccc5Cc3c(nnc3C(C)C)O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4
O

Fasoracetam

July 29, 2019 10:05 am / Leave a comment

Image result for fasoracetam

Fasoracetam

Molecular FormulaC₁₀H₁₆N₂O₂
Average mass196.246 Da

(5R)-5-(1-Piperidinylcarbonyl)-2-pyrrolidinone

(5R)-5-(Piperidin-1-ylcarbonyl)pyrrolidin-2-one

110958-19-5 [RN]

2-Pyrrolidinone, 5-(1-piperidinylcarbonyl)-, (5R)-

7708, UNII: 42O8UF5CJB

NS 105

N-(5-Oxo-D-prolyl)piperidine

(+)-1-(((R)-5-Oxo-2-pyrrolidinyl)carbonyl)piperidine

AEVI GENOMIC MEDICINE, INC. [US/US]; 435 Devon Park Drive, Suite 715 Wayne, Pennsylvania 19087, US

Fasoracetam is a research chemical of the racetam family.^[3] It is a putative nootropic that failed to show sufficient efficacy in clinical trials for vascular dementia. It is currently being studied for its potential use for attention deficit hyperactivity disorder.^[2]^[4]

Fasoracetam appears to agonize all three groups of metabotropic glutamate receptors and has improved cognitive function in rodent studies.^[5] It is orally bioavailable and is excreted mostly unchanged via the urine.^[6]

Fasoracetam was discovered by scientists at the Japanese pharmaceutical company Nippon Shinyaku, which brought it through Phase 3 clinical trials for vascular dementia, and abandoned it due to lack of efficacy.^[5]^[7]

Scientists at Children’s Hospital of Philadelphia led by Hakon Hakonarson have studied fasoracetam’s potential use in attention deficit hyperactivity disorder.^[5] Hakonarson started a company called neuroFix Therapeutics to try to bring the drug to market for this use; neuroFix acquired Nippon Shinyaku’s clinical data as part of its efforts.^[7]^[8] neuroFix was acquired by Medgenics in 2015.^[8] Medgenics changed its name to Aevi Genomic Medicine in 2016.^[9] Clinical trials in adolescents with ADHD who also have mGluR mutations started in 2016.^[8]

Image result for fasoracetam

Image result for Fasoracetam SYNTHESIS

SYN

Chemistry – A European Journal, 24(27), 7033-7043; 2018

PAPER

Chemistry – A European Journal (2018), 24, (27), 7033-7043

https://onlinelibrary.wiley.com/doi/full/10.1002/chem.201800372

Amidation of unprotected amino acids has been investigated using a variety of ‘classical“ coupling reagents, stoichiometric or catalytic group(IV) metal salts, and boron Lewis acids. The scope of the reaction was explored through the attempted synthesis of amides derived from twenty natural, and several unnatural, amino acids, as well as a wide selection of primary and secondary amines. The study also examines the synthesis of medicinally relevant compounds, and the scalability of this direct amidation approach. Finally, we provide insight into the chemoselectivity observed in these reactions.

Patent

WO-2019143829

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019143829&tab=PCTDESCRIPTION&_cid=P10-JYNTFB-68856-1

Novel crystalline forms of fasoracetam , processes for their preparation and compositions comprising them are claimed.

PATENT

WO2019143824

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019143824&_cid=P10-JYNTH3-69052-1

Novel crystalline and cocrystal forms of fasoracetam (R-fasoracetam) and a co-former, processes for their preparation and compositions comprising them are claimed. Also claims are novel crystalline forms of fasoracetam and 4-aminobenzoic acid or trimesic acid or R- ibuprofen or phloroglucinol or methyl-3,4-5-trihydroxybenzoate or ethyl gallate or phthalic acid or 6-hydroxy-2-napthoic acid or 4-nitrobenzoic acid or 2-indole-3-acetic acid or urea and their monohydrate and dihydrate (designated as Form B).

PATENT

WO2018195184

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018195184&_cid=P10-JYNTI8-69210-1

claiming methods for diagnosing and treating ADHD in biomarker positive subjects, assigned to Aevi Genomics Medicine, Inc and The Childrens Hospital of Philadelphia , naming different teams.

PAPER

https://advances.sciencemag.org/content/3/9/e1701028

Image result for Fasoracetam SYNTHESIS

References

^ FDA/NIH Substance registration system. Page accessed March 21, 2016
^ Jump up to:^a ^b “Drug Profile Fasoracetam”.
^ “5-oxo-D-prolinepiperidinamide monohydrate – Compound Summary”. Retrieved 21 July 2013.
^ “Recommended INN List 40” (PDF). WHO Drug Information. 12 (2). 1998.
^ Jump up to:^a ^b ^c Connolly, J; Glessner, J; Kao, C; Elia, J; Hakonarson, H. “ADHD & Pharmacotherapy: Past, Present and Future: A Review of the Changing Landscape of Drug Therapy for Attention Deficit Hyperactivity Disorder”. Ther Innov Regul Sci. 49 (5): 632–642. doi:10.1177/2168479015599811. PMC 4564067. PMID 26366330.
^ Malykh, AG; Sadaie, MR (12 February 2010). “Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders”. Drugs. 70 (3): 287–312. doi:10.2165/11319230-000000000-00000. PMID 20166767.
^ Jump up to:^a ^b Moskowitz, D. H. (2017). Finding the Genetic Cause and Therapy for ADHD, Autism and 22q. BookBaby (self published). ISBN 9781483590981.
^ Jump up to:^a ^b ^c Sharma, B. “Medgenics: NFC-1 Could Be A Key Future Revenue Driver”.
^ “Press Release: Medgenics, Inc. Announces Name Change to Aevi Genomic Medicine, Inc”. Aevi via MarketWired. 16 December 2016.

Fasoracetam

Names

IUPAC name

(5R)-5-(Piperidine-1-carbonyl)pyrrolidin-2-one

Other names

(5R)-5-Oxo-D-prolinepiperidinamide monohydrate, NS-105, AEVI-001, LAM 105, MDGN-001, NFC 1^[1]^[2]

Identifiers

CAS Number

110958-19-5

3D model (JSmol)

Interactive image

ChEMBL

ChEMBL2106179

ChemSpider

171980

KEGG

C13311

PubChem CID

198695

CompTox Dashboard (EPA)

DTXSID9048855

Properties

C₁₀H₁₆N₂O₂

196.250 g·mol⁻¹

Pharmacology

Routes of
administration

Oral

Legal status

US: Not FDA approved

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////Fasoracetam, attention deficit hyperactivity disorder, NS 105, Phase 3, vascular dementia

C1CCN(CC1)C(=O)[C@H]2CCC(=O)N2

BQ-788

July 26, 2019 10:04 am / Leave a comment

ChemSpider 2D Image | BQ-788 | C34H50N5NaO7

Image result for bq-788

BQ-788

Molecular FormulaC₃₄H₅₀N₅NaO₇
Average mass663.780 Da

SP ROT +3.8 ° Conc: 1.032 g/100mL; methanol; Wavlenght: 589.3 nm, Development of an efficient strategy for the synthesis of the ETB receptor antagonist BQ-788 and some related analogues
Peptides (New York, NY, United States) (2005), 26, (8), 1441-1453., https://doi.org/10.1016/j.peptides.2005.03.022

FOR FREE FORM +19.6 °, Conc: 0.998 g/100mL; : N,N-dimethylformamide; 589.3 nm

CAS 156161-89-6 [RN]

CAS 173326-37-9 FREE ACID

2,6-Dimethylpiperidinecarbonyl-γ-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ 788 sodium salt

BQ788

D-Norleucine, N-(((2R,6S)-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt

D-Norleucine, N-((cis-2,6-dimethyl-1-piperidinyl)carbonyl)-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, monosodium salt

D-Norleucine, N-[[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-, sodium salt (1:1)

MFCD00797882

N-[N-[N-[(2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt

Sodium N-{[(2R,6S)-2,6-dimethylpiperidin-1-yl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide

2,6-Dimethylpiperidinecarbonyl-Î³-Methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle

BQ-788 is a selective ET_B antagonist.^[1]

presumed to be under license from Banyu , was investigating BQ-788, a selective endothelin receptor B (ETRB) antagonist, for treating metastatic melanoma. By December 2009, the drug was in validation.

Also claimed is their use as an ETBR antagonist and for treating cancers, such as brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma and squamous cell carcinoma. Represent a first filing from ENB Therapeutics Inc and the inventors on these deuterated forms of BQ-788. Melcure SarL ,

SYN

By Brosseau, Jean-Philippe et alFrom Peptides (New York, NY, United States), 26(8), 1441-1453; 2005

CONTD…………

PAPER

https://pubs.acs.org/doi/pdf/10.1021/jo00130a028

N-(cw-2,6-Dimethylpiperidinocarbonyl)-y-methylleucylD-l-(methoxycarbonyl)tryptophanyl-D-norleucine Sodium Salt (1, BQ-788). To a solution of 15 (3.5 g, 5.5 mmol) in methanol (50 mL) was slowly added 5% aqueous NaHCOs (300 mL) over a period of 30 min. The solution was stirred until clarity was achieved (30 min, 23 °C). The solution was diluted with water (200 mL), and the resulting solution was passed through a C18 (60 mL) cartridge preequilbrated in water. BQ-788 (1) was eluted with methanol (2 x 50 mL), concentrated under reduced pressure, resuspended in water (50 mL), and lyophilized to quantitatively yield compound 1 as a white powder:

HPLC £r = 16.4 (gradient A, > 99%);

NMR (400 MHz, DMSO-d6) ó 0.80 (s, 9H), 0.74-0.85 (m, 3H), 1.00 (d, 3H), 1.02 (d, 3H), 1.10-1.25 (m, 6H), 1.30-1.55 (m, 6H), 1.60-1.75 (m, 2H), 2.92 (dd, 1H), 3.12 (dd, 1H), 3.78 (m, 1H), 3.95 (s, 3H), 4.08 (m, 1H), 4.13 (m, 1H), 4.29 (m, 1H), 4.50 (m, 1H), 5.98 (d, 1H), 7.22 (t, 1H), 7.32 (t, 1H), 7.50 (s, 1H), 7.58 (br d, 1H), 7.65 (d, 1H), 8.05 (d, 1H), 8.15 (br d, 1H) ESMS m/z 640.6 (M).

PATENT

WO-2019140324

Novel deuterated analogs of a substituted heterocyclic compound, particularly BQ-788 , processes for their preparation and compositions and combinations comprising them are claimed.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019140324&tab=PCTDESCRIPTION&_cid=P22-JYJK98-13819-1

PAPER

https://www.sciencedirect.com/science/article/abs/pii/S0196978105001415

Image result for bq-788

PAPER

By He, John X.; Cody, Wayne L.; Doherty, Annette M., From Journal of Organic Chemistry (1995), 60(25), 8262-6

Journal of medicinal chemistry (1996), 39(12), 2313-30.

References

^ Okada, M; Nishikibe, M (Winter 2002). “BQ-788, a selective endothelin ET(B) receptor antagonist”. Cardiovascular drug reviews. 20 (1): 53–66. PMID 12070534.

BQ-788
Names

Systematic IUPAC name Sodium N-{[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-(methoxycarbonyl)-D-tryptophanamide
Identifiers
CAS Number	156161-89-6
3D model (JSmol)	Interactive image
ChemSpider	4470569
PubChem CID	5311031
CompTox Dashboard (EPA)	DTXSID40166053
InChI [show]
SMILES [show]
Properties
Chemical formula	C₃₄H₅₀N₅NaO₇
Molar mass	663.792 g·mol⁻¹
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////BQ-788, BQ 788, BQ788, ETBR antagonist, cancers, brain cancer, pancreas cancer, colon cancer, breast cancer, ovary cancer, prostate cancer, glioblastoma, solid tumor, melanoma, squamous cell carcinoma, PEPTIDE

CCCC[C@H](C(=O)O)NC(=O)[C@@H](Cc1cn(c2c1cccc2)C(=O)OC)NC(=O)[C@H](CC(C)(C)C)NC(=O)N3[C@@H](CCC[C@@H]3C)C

Fluazolepali, 氟唑帕利 , Fluzoparib

July 25, 2019 1:31 pm / Leave a comment

Fluazolepali

CAS 2170504-09-1

Fluzoparib; SHR-3162, (HS10160)

HS 10160
SHR 3162

An orally available inhibitor of poly(ADP-ribose) polymerase 1 and 2 (PARP-1/2) for treatment of solid tumors (Jiangsu Hengrui Medicine Co. Ltd., Lianyungang, China)

Fluazolepali, developed by Hengrui and Howson, is intended for the treatment of recurrent ovarian cancer, triple-negative breast cancer, advanced gastric cancer and other advanced solid tumors. Currently, the drug has been introduced into China for recurrent ovarian cancer. Clinical stage.

In February 2019, a randomized, double-blind, controlled, multicenter, phase III clinical study (CTR20190294) of flazopril capsule versus placebo for maintenance of recurrent ovarian cancer was initiated in China and was sponsored by Hengrui Medicine.

Jiangsu Hansoh Pharmaceutical , in collaboration with Jiangsu Hengrui Medicine , is developing an oral capsule formulation of fluazolepali (fluzoparib; SHR-3162), a small molecule inhibitor to PARP-1 and PARP-2, for the treatment of solid tumors including epithelial ovarian, fallopian tube or primary peritoneal, breast and gastric cancer.

Originator Jiangsu Hengrui Medicine Co.
Class Antineoplastics
Mechanism of Action Poly(ADP-ribose) polymerase 1 inhibitors; Poly(ADP-ribose) polymerase 2 inhibitors

Phase II Ovarian cancer

Phase I Breast cancer; Fallopian tube cancer; Gastric cancer; Peritoneal cancer; Solid tumours

09 Jul 2019 Jiangsu HengRui Medicine initiates a phase I trial in Solid tumors in China (NCT04013048) [14C]-Fluzoparib
01 Jul 2019 Jiangsu HengRui Medicine plans a phase I drug-drug interaction trial (In volunteers) in China (PO) (NCT04011124)
12 Jun 2019 Jiangsu HengRui Medicine completes a phase I trial in Gastric cancer (Combination therapy, Recurrent, Metastatic disease, Second-line therapy or greater, Late-stage disease) in China (PO) (NCT03026881)

Fluzoparib (SHR 3162) is a selective poly [ADP-ribose] polymerase 1 (PARP1) and poly [ADP-ribose] polymerase 2 inhibitor (PARP2), being developed by Jiangsu HengRui Medicine, for the treatment of cancer. PARP enzymes play a vital role in repair of DNA damage and maintaining genomic stability. Fluzoparib inhibits PARP enzymes and induces DNA-double strands breaks, G₂/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Clinical development for ovarian cancer, breast cancer, fallopian tube cancer, peritoneal cancer, gastric cancer and solid tumours is underway in China and Australia.

An orally available inhibitor of poly (ADP-ribose) polymerase (PARP) types 1 and 2, with potential antineoplastic activity. Upon oral administration, fluzoparib inhibits PARP 1 and 2 activity, which inhibits PARP-mediated repair of damaged DNA via the base excision repair (BER) pathway, enhances the accumulation of DNA strand breaks, promotes genomic instability, and leads to an induction of apoptosis. The PARP family of proteins catalyze post-translational ADP-ribosylation of nuclear proteins, which then transduce signals to recruit other proteins to repair damaged DNA. PARP inhibition may enhance the cytotoxicity of DNA-damaging agents and may reverse tumor cell chemoresistance and radioresistance. Check for active clinical trials using this agent. (NCI Thesaurus)

PATENT

WO-2019137358

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019137358&tab=FULLTEXT&_cid=P20-JYI5A2-54836-1

Process for preparing heterocyclic compounds (presumed to be fluazolepali ) and its intermediates as PARP inhibitors useful for treating cancer.

Example 1

The compound and 5.0kg of 10% palladium on carbon 250g, 80L of methanol was added to the kettle at 0.4MPa, 24h 25 ℃ hydrogenation reaction. The palladium carbon was removed by filtration, the filter cake was washed with methanol, and the filtrate was collected, evaporated to dryness under reduced pressure, and ethyl acetate (20 L) was added to the concentrate, and the mixture was stirred and evaporated, and then cooled to 0° C. ～3, stirring, filtration, filter cake and then adding 20 L of ethyl acetate, pulping at room temperature for 3 to 4 h, filtration, vacuum drying at 45 ° C for 6-8 h to obtain 5.5 kg of compound 3 solid, yield 91.7%, HPLC purity 99.69%.

Example 2

According to the method of Example 19 of CN102686591A, 2 g of the compound 3 and 2.79 g of the compound 4 were charged to obtain 3.6 g of the compound of the formula I in a yield of 87.8%.

Example 3

At room temperature, 2.0 g of compound 2 (prepared according to the method disclosed in WO2009025784) was dissolved in 30 mL of isopropanol, and concentrated sulfuric acid was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 150 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the sulfate solid of Compound 2 could not be obtained.

Example 4

1. At room temperature, 1.11 g of compound 2 was dissolved in 10 mL of isopropanol, and 15% phosphoric acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried under vacuum. Compound 2 phosphate solid 1.46 g, yield 87.1%, HPLC purity 99.72%.

Example 5

At room temperature, 1.28 g of compound 2 was dissolved in 10 mL of isopropanol, and 20% acetic acid/isopropanol solution was added dropwise with stirring to adjust the pH to 3, and stirred at room temperature without solid precipitation; the reaction solution was poured into 100 mL of n-hexane, and continued. After stirring at room temperature, no solid precipitated, and the acetate solid of Compound 2 could not be obtained.

Example 6

1.05g of compound 2 was dissolved in 10mL of isopropanol at room temperature, and the pH was adjusted to 3 by adding 15% citric acid/isopropanol solution while stirring. At room temperature, no solid precipitated; the reaction solution was poured into 100 mL of n-hexane. After stirring at room temperature, no solid precipitated, and the citrate solid of Compound 2 could not be obtained.

Example 7

1.12 g of compound 2 was dissolved in 10 mL of isopropanol at room temperature, and 0.74 g of maleic acid was added thereto with stirring. The mixture was stirred at room temperature, filtered, and the filter cake was washed with isopropyl alcohol and dried in vacuo to obtain the maleate salt of compound 2. 1.51 g, yield 84.6%.

PATENT

WO2019109938

claiming synergistic combination comprising PARP inhibitor fluazolepali and apatinib mesylate .

PATENT

WO 2018005818

WO 2018129553

WO 2018129559

WO 2018208968

WO 2018213732

WO 2018191277

WO 2018201096

WO 2018085469

WO 2018085468

WO 2019090227

WO 2019133697

WO 2019067978

WO 2019071123

WO 2019090141

///////////Fluazolepali, Jiangsu Hansoh Pharmaceutical, Jiangsu Hengrui Medicine, fluzoparib, SHR-3162, 氟唑帕利 , Phase II, Ovarian cancer, HS10160, CHINA, HS 10160

https://med.sina.com/article_detail_103_2_64751.html

WXFL-10203614

July 23, 2019 12:56 pm / Leave a comment

(7R)-7-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile.png

WXFL-10203614

CAS 2054932-34-0 R isomer, (S isomer 2054932-33-9 )

C₁₅ H₁₅ N_7, 293.33

(7R)-7-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carbonitrile

(7R)-5,6,7,8-Tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)imidazo[1,2-a]pyridine-2-carbonitrile
Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-

Wuxi Fortune Pharmaceutical Co Ltd

Jak1 tyrosine kinase inhibitor

Wuxi Fuxin Pharmaceutical Research and Development , in collaboration with Wuxi Apptec , is investigating a tablet formulation of WXFL-10203614 , a JAK1 tyrosine kinase inhibitor, for the oral treatment of rheumatoid arthritis. In January 2019, a phase I trial was planned.

Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-, 4-methylbenzenesulfonate, hydrate (1:1:1)
cas 2226936-85-0

Imidazo[1,2-a]pyridine-2-carbonitrile, 5,6,7,8-tetrahydro-7-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-, (7R)-, 2,2,2-trifluoroacetate (1:1)
cas 2226936-87-2

syn

PATENT

WO2018095345 claiming novel crystalline salt forms of similar compound

PATENT

WO 2016192563

PATENT

US-20190218231

https://patentscope.wipo.int/search/en/detail.jsf?docId=US248874703&tab=PCTDESCRIPTION&_cid=P11-JYF9EY-53753-1

Novel crystalline forms of 7h-pyrrolo[2,3-D]pyrimidine compounds (designated as forms A to E) useful as JAK1 and JAK2 inhibitors for treating arthritis, inflammation and autoimmune diseases.

JAK belongs to the family of tyrosine kinases involved in inflammation, autoimmune diseases, proliferative diseases, transplant rejection, impaired cartilage turnover-related diseases, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6. The present invention also provides a method for preparing the compound or a pharmaceutical composition comprising the compound, and a method for preventing and/or treating inflammation, autoimmune diseases, proliferative diseases, transplant rejection, impaired cartilage turnover-related diseases, congenital cartilage malformations, and/or diseases associated with excessive secretion of IL6 by administrating the compound of the present invention.

Janus kinase (JAK) is a cytoplasmic tyrosine kinase that transduces a cytokine signal from a membrane receptor to an STAT transcription factor. The prior art has described four members of the JAK family: JAK1, JAK2, JAK3 and TYK2. When cytokines bind to their receptors, JAK family members are auto-phosphorylated and/or trans-phosphorylated from each other, followed by STATs phosphorylation, and then are migrated into the cell nucleus to regulate the transcription. JAK-STAT intracellular signal transduction is suitable for interferons, most interleukins, as well as various cytokines and endocrine factors, such as EPO, TPO, GH, OSM, LIF, CNTF, GM-CSF and PRL (Vainchenker W. et al. (2008)).

A combinatorial study of a genetic model and a small molecule JAK inhibitor has revealed the therapeutic potential of several JAKs. It has been confirmed by mouse and human genetics that JAK3 is an immunosuppressive target (O’Shea J. et al. (2004)). A JAK3 inhibitor has been successfully used in clinical development. At first, it was used in organ transplant rejection, and later also used in other immunoinflammatory indications such as rheumatoid arthritis (RA), psoriasis and Crohn’s disease (http://clinicaltrials.gov/). It has been confirmed by human genetics and mouse knockout studies that TYK2 is a potential target for immunoinflammatory diseases (Levy D. and Loomis C. (2007)). JAK1 is a new target in the field of immunoinflammatory diseases. The heterodimerization of JAK1 and other JAKs arouses a transduction of cytokine-driven pro-inflammatory signaling. Thus, it is expected that inhibition of JAK1 and/or other JAKs has a therapeutic benefit for a series of inflammatory diseases and other diseases driven by JAK-mediated signal transduction.

transduction.

Example 1: Preparation of Compound 1

Step 1: 2-chloro-4-nitro-1-oxo-pyridin-1-ium (40.0 g, 229.2 mmol) and (4-methoxyphenyl)methylamine (63 g, 458.4 mmol) were dissolved in EtOH (400 mL), and the resulting solution was stirred at reflux for 5 hours. TLC (PE:EA=2:1) showed that the reaction was complete. The EtOH was concentrated to half of its volume and was cooled in an ice bath for 2-3 hours. The resulting cold mixture was filtered, and the isolated solid was washed with PE (60 mL*3) and ice water (60 mL*3), respectively. Drying in vacuum given an orange solid, N-[(4-methoxyphenyl)methyl]-4-nitro-1-oxo-pyridin-1-ium-2-amine (2) (38.6 g, 140.2 mmol, with a yield of 61.2%). MS (ESI) calcd. For r C ₁₃H ₁₃N ₃O ₄[M+H] ⁺275, found 276.

Step 2: to a solution of N-[(4-methoxyphenyl)methyl]-4-nitro-1-oxo-pyridin-1-ium-2-amine (5.0 g, 18.16 mmol) in CHCI ₃(50 mL) was dropwise added PCI ₃(8.4 g, 60.8 mmol) at 0° C. After the addition, the reaction mixture was heated to 25° C. and stirred vigorously for 16 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The reaction mixture was filtered, and the resulting solid was washed with PE (30 mL*3) to give a yellow solid compound, N-[(4-methoxyphenyl)methyl]-4-nitro-pyridin-2-amine (3) (4.2 g, a crude product) which was directly used in the next step without further purification. MS (ESI) calcd. For C ₁₅H ₁₈N ₆[M+H] ⁺259, found 260.

Step 3: to a solution of N-[(4-methoxyphenyl)methyl]-4-nitro-pyridin-2-amine (4.2 g, 16.2 mmol) in toluene (10 mL) was dropwise added TFA (5.0 mL) at atmospheric temperature. Then, the mixture was stirred at 80° C. for 2 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H ₂O (50 mL), and its pH was adjusted to be neutral with solid NaHCO ₃. The aqueous phase was extracted with EA (50 mLE*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1/0-1:1) to obtain an orange solid compound, 4-nitropyridine-2-amine (4) (700 mg, 5.0 mmol, with a yield of 31.1%). MS (ESI) calcd. For C ₅H ₅N ₃O ₂[M+H] ⁺139, found 140.

Step 4: to a solution of 4-nitropyridine-2-amine (200 mg, 1.4 mmol) in DME (5 mL) was added 3-bromo-2-oxo-propanoate (280 mg, 1.4 mmol) at atmospheric temperature. The resulting mixture was stirred at 25° C. for 1 hour, and then was concentrated under reduced pressure to remove the solvent. The residue was dissolved with EtOH (10 mL); and then was refluxed for 3 hours. TLC showed that the reaction was complete. The reaction solution was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was basified with saturated NaHCO ₃aqueous solution (25 mL). The aqueous phase was extracted with DCM (15 mL*3); and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (EA:PE=10-60%) to obtain a light yellow solid compound, ethyl 7-nitroimidazo[1,2-]pyridin-2-carboxylate (5) (302 mg, with a yield of 88.9%). MS (ESI) calcd. For C ₁₀H ₉N ₃O ₄[M+H] ⁺235, found 236.

Step 5: a solution of ethyl 7-nitroimidazo[1,2-a]pyridin-2-carboxylate (150 mg, 637.8 mmol) in ethanol (20 mL) was added HCl (7 mg, 0.2 mmol) and PtO ₂(15 mg, 0.6 mmol) at atmospheric temperature. The reaction system was repeatedly vacuumed and filled with N ₂for three times, then filled with H ₂(50 psi), and was stirred at 50° C. for 16 hours. TLC (PE:EA=1:1) showed that the reaction was complete. The reaction mixture was concentrated to half of its volume, and filtered to obtain a white solid compound, ethyl 7-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate hydrochloride (6) (120 mg, a crude product). MS (ESI) calcd. For C ₁₀H ₁₅N ₃O ₂[M+H] ⁺209, found 210.

Step 6: ethyl 7-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate hydrochloride (100 mg, 0.4 mmol) and 4-chloro-7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidine (137 mg, 0.4 mmol) were dissolved in n-BuOH (5 mL), and DIEA (158 mg, 1.2 mmol) were added to the above solution. The resulting mixture was stirred under reflux for 16 hours. LC-MS showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with H ₂O (10 mL). The aqueous phase was extracted with EA (20 mL*3); and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (PE:EA=0:1) to obtain a light yellow solid compound, ethyl 7-[[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl] amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxylate (7) (55 mg, 0.11 mmol, with a yield of 28.1%). MS (ESI) calcd. For C ₂₃H ₂₄N ₆O ₄S [M+H] ⁺480, found 481.

Step 7: to a solution of ethyl 7-[[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxylate (3.0 g, 6.2 mmol) in THF (150 mL) was added NaH (499 mg, 12.5 mmol) in portions under N ₂atmosphere at 0° C. The mixture was stirred at that temperature for 1 hour, and then was dropwise added MeI (7.1 g, 50.2 mmol). After the addition, the mixture was stirred at atmospheric temperature for 1 hour. TLC showed that the reaction was complete. The reaction was quenched by the addition of saturated NH ₄Cl (10 mL), and then was diluted by the addition of ice water (50 mL). The aqueous phase was extracted with a mixed solvent of DCM/MeOH (3:1, 50 mL*3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (DCM:MeOH=10:1) to obtain a light yellow solid, ethyl 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate (8) (1.5 g, with a yield of 45%). MS (ESI) calcd. For C ₂₄H ₂₆N ₆O ₄S [M+H] ⁺494, found 495.

Step 8: to a solution of 7-[methyl-[7-(p-toluenesulfonyl) pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxylate (4.0 g, 8.1 mmol) in THF (40 mL) and H ₂O (8 mL) was added LiOH.H ₂O (509 mg, 12.1 mmol), and the mixture was stirred at 20° C. for 10 hours. TLC showed that the reactants were completely consumed. THF in the reaction mixture was removed under reduced pressure; and the pH of the residue was adjusted to 2-3 with 2M HCl (4 mL) to form a white solid. The solid was filtered out, and was concentrated under reduced pressure to obtain 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxylic acid (9) as a white solid (3.6 g, with a yield of 95.4%). MS (ESI) calcd. For C ₂₂H ₂₂N ₆O ₄S [M+H] ⁺466, found 467.

Step 9: to a solution of 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxylic acid (1.8 g, 3.9 mmol) in DMF (20 mL) was added CDI (751 mg, 4.6 mmol) at 0° C. The reaction solution was heated to 25° C. and stirred for 2 hours, and after that, solid ammonium chloride (2.1 g, 38.6 mmol) was added, and then the reaction was kept overnight at atmospheric temperature. LC-MS showed that the reactants were completely consumed. The reaction mixture was poured into ice water (50 mL), and a white solid was precipitated. The solid was filtered out, washed with water (20 mL), and was dried under reduced pressure in a rotating manner to obtain 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxamide (10) as a white solid (2.5 g, a crude product) which product was directly used in the next step. MS (ESI) calcd. For C ₂₂H ₂₃N ₇O ₃S [M+H] ⁺465, found 466.

Step 10: 7-[methyl-[7-(p-toluenesulfonyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1, 2-a]pyridin-2-carboxamide (2.5 g, 5.4 mmol) was dissolved in a mixture of THF (20 mL), MeOH (10 mL) and H ₂O (6 mL), and NaOH (429.6 mg, 10.7 mmol) was added. The mixture was heated to 60° C. and stirred for 30 minutes. LC-MS showed that the reactants were completely consumed. The reaction mixture was concentrated under reduced pressure to obtain 7-[methyl-[heptahydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-α]pyridin-2-carboxamide (11) as a white solid (2.5 g, a crude product) which was directly used in the next step. MS (ESI) calcd. For C ₁₅H ₁₇N ₇O [M+H] ⁺311, found 312.

Step 11: to a solution of 7-[methyl-[heptahydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-carboxamide (2.0 g, 6.4 mmol) and triethylamine (3.9 g, 38.5 mmol) in THF (20 mL) was dropwise added TFAA (4.1 g, 19.3 mmol) at 0° C. After the addition, the reaction solution was stirred at atmospheric temperature for 30 minutes. LC-MS showed the starting materials were completely consumed. The reaction mixture was poured into ice water (20 mL), and extracted with DCM/MeOH (5:1, 100 mL*2). The combined organic layer was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (DCM/MeOH=40/1 to 20:1) to obtain 7-[methyl-[7-hydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-nitrile (12,378 mg, with a yield of 19.8%). MS (ESI) calcd. For C ₁₅H ₁₅N ₇[M+H] ⁺293, found 294. 1H NMR (400 MHz, DMSO-d6) 11.44-11.71 (m, 1H), 7.99-8.17 (m, 2H), 7.11-7.20 (m, 1H), 6.63 (dd, J=1.76, 3.26 Hz, 1H), 5.33 (br. s., 1H), 4.21-4.21-4.31 (m, 1H), 4.13 (dt, J=4.14, 12.49 Hz, 1H), 3.27 (s, 3H), 2.91-3.11 (m, 2H), 2.31-2.44 (m, 1H), 2.07 (d, J=11.54 Hz, 1H).

Step 12: racemic 7-[methyl-[7-hydropyrrolo[2,3-d]pyrimidin-4-yl]amino]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-nitrile (30 mg, 102.3 umol) was separated by a chiral column to obtain the compound 1 (10 mg, with a yield of 32.8%).

Compound 1: retention time 6.407 min; MS (ESI) calcd. For C ₁₅H ₁₅N ₇[293, found 294 M+H]+. Purity 98.8%, e.e. was 98.9%; [α] _D ²⁰=+78.4° (c=0.6, DMSO). MS ESI calcd. For C ₁₅H ₁₅N ₇[M+H] ⁺294, found 294. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.02-2.15 (m, 1H) 2.39 (qd, J=12.42, 5.90 Hz, 1H) 2.92-3.12 (m, 2H) 3.28 (s, 3H) 4.05-4.36 (m, 2H) 5.20-5.45 (m, 1H) 6.64 (dd, J=3.39, 1.88 Hz, 1H) 7.17 (dd, J=3.26, 2.51 Hz, 1H) 8.02-8.17 (m, 2H) 11.69 (br s, 1H).

//////////WXFL-10203614, WXFL 10203614 , WXFL10203614, Wuxi Fuxin, arthritis, inflammation, autoimmune diseases, Wuxi Apptec, JAK1, JAK2 inhibitors

N#Cc1cn2CC[C@H](Cc2n1)N(C)c4ncnc3nccc34

Tanzisertib

July 22, 2019 1:30 pm / 1 Comment on Tanzisertib

ChemSpider 2D Image | Tanzisertib | C21H23F3N6O2

Tanzisertib

CAS 899805-25-5

trans-4-((9-((3S)-Tetrahydrofuran-3-yl)-8-((2,4,6-trifluorophenyl)amino)-9H-purin-2-yl)amino)cyclohexanol

4-[[9-[(3S)-oxolan-3-yl]-8-(2,4,6-trifluoroanilino)purin-2-yl]amino]cyclohexan-1-ol

C21-H23-F3-N6-O2, 448.4467

9557

Cyclohexanol, 4-[[9-[(3S)-tetrahydro-3-furanyl]-8-[(2,4,6-trifluorophenyl)amino]-9H-purin-2-yl]amino]-, trans-

CC 930
CC-930
Tanzisertib
UNII-M5O06306UO
A c-Jun amino-terminal kinase inhibitor.UNII, M5O06306UO

Treatment of Idiopathic Pulmonary Fibrosis (IPF)

Originator Celgene Corporation
Class Antifibrotics; Small molecules
Mechanism of ActionJ NK mitogen-activated protein kinase inhibitors

Orphan Drug Status Yes – Idiopathic pulmonary fibrosis

Discontinued Discoid lupus erythematosus; Idiopathic pulmonary fibrosis

16 Jul 2012 Celgene Corporation terminates a phase II trial in Discoid lupus erythematosus in USA (NCT01466725)
23 Feb 2012 Celgene initiates enrolment in a phase II trial for Discoid lupus erythematosus in the USA (NCT01466725)
08 Nov 2011The Committee for Orphan Medicinal Products (COMP) recommends orphan drug designation for tanzisertib in European Union for Idiopathic pulmonary fibrosis

Tanzisertib has been granted orphan drug status by the FDA for the treatment of idiopathic pulmonary fibrosis. A positive opinion has been received from the EU Committee for Orphan Medicinal Products (COMP

Tanzisertib has been used in trials studying the treatment of Fibrosis, Discoid Lupus, Pulmonary Fibrosis, Interstitial Lung Disease, and Lung Diseases, Interstitial, among others.

PATENT

https://patents.google.com/patent/US20090048275A1/de

Image result for US 20090048275

PATENT

WO 2006076595

US 20070060598

WO 2008057252

US 20080021048

US 20140094456

WO 2014055548

PATENT

WO 2015153683

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015153683

/////////Tanzisertib, CC 930, Idiopathic Pulmonary Fibrosis, Orphan Drug, phase II, CELGENE

c1c(c(c(cc1F)F)Nc2n(c3nc(ncc3n2)N[C@H]4CC[C@@H](CC4)O)[C@@H]5COCC5)F

CC-90009

July 22, 2019 1:27 pm / Leave a comment

2-(4-Chlorophenyl)-N-[[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl]-2,2-difluoroacetamide.png

CC-90009

CC-90009-AML-001

CAS 1860875-51-9

461.8 g/mol, C₂₂H₁₈ClF₂N₃O₄

2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide

4-Chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluorobenzeneacetamide
Benzeneacetamide, 4-chloro-N-[[2-(2,6-dioxo-3-piperidinyl)-2,3-dihydro-1-oxo-1H-isoindol-5-yl]methyl]-α,α-difluoro-

Phase 1 Clinical, Acute myelogenous leukemia, Protein cereblon modulator

Useful for treating chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia or acute myeloid leukemia.

Celgene is developing CC-90009, a cereblon E3 ligase modulator, for treating AML; in January 2019, data from a phase I trial were expected later that year.

0iginator Celgene Corporation
Class Antineoplastics
Mechanism of Action CRBN protein modulators; Ubiquitin protein ligase complex modulators

Phase I Acute myeloid leukaemia

28 Mar 2019 No recent reports of development identified for clinical-Phase-Unknown development in Acute-myeloid-leukaemia in USA (IV)
01 Sep 2016 Phase-I clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) in Canada (IV) (NCT02848001)
04 Aug 2016 Celgene plans a phase I trial for Acute Myeloid Leukaemia in USA and Canada (NCT02848001)

In September 2016, Celgene initiated a phase I dose-finding trial of CC 90009 in patients with relapsed or refractory acute myeloid leukaemia (NCT02848001; CC-90009-AML-001). The open-label study intends to enrol 60 patients in the US and Canada

CC-90009 is a cereblon modulator. CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. .

Development Overview

cereblon modulator CC-90009A modulator of cereblon (CRBN), which is part of the cullin 4-RING E3 ubiquitin ligase complex (CRL4-CRBN E3 ubiquitin ligase; CUL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and pro-apoptotic activities. Upon administration, CC-90009 specifically binds to CRBN, thereby affecting the activity of the ubiquitin E3 ligase complex. This leads to the ubiquitination of certain substrate proteins and induces the proteasome-mediated degradation of certain transcription factors, including Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T-cells. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which may include the activation of T-lymphocytes. In addition, this downregulates the expression of other proteins, including interferon regulatory factor 4 (IRF4) and c-myc, which plays a key role in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays a key role in the ubiquitination of certain proteins. Check for active clinical trials using this agent. (NCI Thesaurus)

WO 2017120446,

PATENT

WO2016007848

US 20170348298

WO 2017120415

WO 2017120446

WO 2017120437

PATENT

WO2017214014

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017214014&tab=PCTDESCRIPTION

Provided herein are methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy with 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of

stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Further provided is a compound for use in methods of treating, preventing, managing, and/or ameliorating a hematologic malignancy, wherein the compound is 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide or a stereoisomer or a mixture of stereoisomers, an isotopologue, pharmaceutically acceptable salt, tautomer, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.

The term Compound 1 refers to”2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide” having the structure:

and its stereoisomers or mixture of stereoisomers, isotopologues, pharmaceutically acceptable salts, tautomers, solvates, hydrates, co-crystals, clathrates, or polymorphs thereof. In certain embodiments, Compound 1 refers to 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide and its tautomers. In certain embodiments, Compound 1 refers to a polymorph of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-

oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In certain embodiments, Compound 1 refers to polymorph Form C of 2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide. In one embodiment, the stereoisomer is an enantiomer.

PATENT

WO-2019136016

Novel isotopologs of the compound presumed to be CC-90009 , processes for their preparation and compositions comprising them are claimed.

Patent ID	Title	Submitted Date
US2017199193	METHODS FOR TREATING CANCER AND THE USE OF BIOMARKERS AS A PREDICTOR OF CLINICAL SENSITIVITY TO THERAPIES	2017-01-06
US2018224435	METHODS FOR MEASURING SMALL MOLECULE AFFINITY TO CEREBLON	2018-02-02
US2018353496	FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE	2018-07-19
US2017196847	FORMULATIONS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE	2017-01-06
US2017348298	TREATMENT OF A HEMATOLOGIC MALIGNANCY WITH 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE	2017-06-05

Patent ID	Title	Submitted Date	Granted Date
US2018221361	ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF	2018-04-09
US9968596	Antiproliferative compounds and methods of use thereof	2017-10-02	2018-05-15
US2017197934	SOLID FORMS OF 2-(4-CHLOROPHENYL)-N-((2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXOISOINDOLIN-5-YL)METHYL)-2,2-DIFLUOROACETAMIDE, AND THEIR PHARMACEUTICAL COMPOSITIONS AND USES	2017-01-06
US9499514	ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF	2015-07-09	2016-01-14
US9808451	ANTIPROLIFERATIVE COMPOUNDS AND METHODS OF USE THEREOF	2016-09-23

////////CC-90009 , CC 90009 , CC90009, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, phase I, CANCER, CC-90009-AML-001

Clc1ccc(cc1)C(F)(F)C(=O)NCc2ccc3C(=O)N(Cc3c2)C4CCC(=O)NC4=O

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1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate (1·TsOH)

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