New Drug Approvals

Home » Posts tagged 'ELI LILY'

Tag Archives: ELI LILY

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,623,499 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,416 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,416 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

SY-008


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 7th 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 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). 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.

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 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- {(3JE)-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.

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

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-{(3JE)-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-{(3JE)-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- {(3JE)-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 7th 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:

Figure imgf000003_0001

or hydrate thereof.

Figure imgf000008_0001

Preparation 1

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

Figure imgf000009_0001

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

Figure imgf000009_0002

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

Figure imgf000010_0001

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

Figure imgf000012_0001

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

Figure imgf000012_0002

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

Figure imgf000013_0001

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-{(3JE)-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

Figure imgf000014_0001

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

Figure imgf000014_0002

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).

Figure imgf000016_0001

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.

Figure imgf000017_0001

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

Figure imgf000018_0001

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

Figure imgf000018_0002

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-{(3JE)-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

Figure imgf000019_0001

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

Figure imgf000020_0001

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

Figure imgf000021_0001

Preparation 14

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

Figure imgf000021_0002

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

Figure imgf000022_0001

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

Figure imgf000023_0001

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).

Figure imgf000024_0001
Figure imgf000024_0002

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

Figure imgf000024_0003

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.

Figure imgf000025_0001

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-{(3JE)-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

Figure imgf000026_0001

Scheme 4, step C: Combine tert-butyl 2-{(3JE)-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).

Figure imgf000027_0001

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).

Figure imgf000028_0001

Scheme 2, step F: Add methanol (5 mL), triethylamine (3 mL), and water (3 mL) to 4- {4-[( lJE)-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-{(3JE)-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.

Figure imgf000029_0001

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):
str1
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

Advertisements

SELPERCATINIB


img

Selpercatinib.png

SELPERCATINIB

LOXO 292

CAS: 2152628-33-4
Chemical Formula: C29H31N7O3
Molecular Weight: 525.613

CEGM9YBNGD

UNII-CEGM9YBNGD

 6-(2-hydroxy-2-methylpropoxy)-4-(6-{6-[(6-methoxypyridin- 3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3- yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

Selpercatinib is a tyrosine kinase inhibitor with antineoplastic properties.

A phase I/II trial is also under way in pediatric patients and young adults with activating RET alterations and advanced solid or primary CNS tumors.

Loxo Oncology (a wholly-owned subsidiary of Eli Lilly ), under license from Array , is developing selpercatinib, a lead from a program of RET kinase inhibitors, for treating cancer, including non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma and soft tissue sarcoma

In 2018, the compound was granted orphan drug designation in the U.S. for the treatment of pancreatic cancer and in the E.U. for the treatment of medullary thyroid carcinoma.

Trk is a high affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophic factor (NT). The Trk receptor family has three members, namely TrkA, TrkB and TrkC. Among the neurotrophic factors are (1) nerve growth factor (NGF) which activates TrkA, (2) brain-derived neurotrophic factor (BDNF) and NT4/5 which activate TrkB, and (3) NT3 which activates TrkC. Trk is widely expressed in neuronal tissues and is involved in the maintenance, signaling and survival of neuronal cells.
The literature also shows that Trk overexpression, activation, amplification and/or mutations are associated with many cancers including neuroblastoma, ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, multiple myeloma, astrocytoma. And medulloblastoma, glioma, melanoma, thyroid cancer, pancreatic cancer, large cell neuroendocrine tumor and colorectal cancer. In addition, inhibitors of the Trk/neurotrophin pathway have been shown to be effective in a variety of preclinical animal models for the treatment of pain and inflammatory diseases.
The neurotrophin/Trk pathway, particularly the BDNF/TrkB pathway, has also been implicated in the pathogenesis of neurodegenerative diseases, including multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease. The modulating neurotrophic factor/Trk pathway can be used to treat these and related diseases.
It is believed that the TrkA receptor is critical for the disease process in the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts. Therefore, TrkA inhibitors can be used to treat Chagas disease and related protozoal infections.
Trk inhibitors can also be used to treat diseases associated with imbalances in bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastasis. Bone metastases are a common complication of cancer, up to 70% in patients with advanced breast or prostate cancer and about 15 in patients with lung, colon, stomach, bladder, uterine, rectal, thyroid or kidney cancer Up to 30%. Osteolytic metastases can cause severe pain, pathological fractures, life-threatening hypercalcemia, spinal cord compression, and other neurostress syndromes. For these reasons, bone metastases are a serious cancer complication that is costly. Therefore, an agent that can induce apoptosis of proliferating bone cells is very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, almost all osteoblast apoptosis agents are very advantageous. Expression of the TrkA receptor and TrkC receptor has been observed in the osteogenic region of the fractured mouse model. In addition, localization of NGF was observed in almost all osteoblasts. Recently, it was demonstrated that pan-Trk inhibitors in human hFOB osteoblasts inhibit tyrosine signaling activated by neurotrophic factors that bind to all three Trk receptors. This data supports the theory of using Trk inhibitors to treat bone remodeling diseases, such as bone metastases in cancer patients.
Developed by Loxo Oncology, Larotrectinib (LOXO-101) is a broad-spectrum antineoplastic agent for all tumor patients expressing Trk, rather than tumors at an anatomical location. LOXO-101 chemical name is (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)pyrazolo[1,5-a] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the structural formula is as follows. LOXO-101 began treatment of the first patient in March 2015; on July 13, 2016, the FDA granted a breakthrough drug qualification for the inoperable removal or metastatic solid tumor of adults and children with positive Trk fusion gene mutations; Key entry was completed in February 2017; in November 2018, the FDA approved the listing under the trade name Vitrakvi.
Poor absorption, distribution, metabolism, and/or excretion (ADME) properties are known to be the primary cause of clinical trial failure in many drug candidates. Many of the drugs currently on the market also limit their range of applications due to poor ADME properties. The rapid metabolism of drugs can lead to the inability of many drugs that could be effectively treated to treat diseases because they are too quickly removed from the body. Frequent or high-dose medications may solve the problem of rapid drug clearance, but this approach can lead to problems such as poor patient compliance, side effects caused by high-dose medications, and increased treatment costs. In addition, rapidly metabolizing drugs may also expose patients to undesirable toxic or reactive metabolites.
Although LOXO-101 is effective as a Trk inhibitor in the treatment of a variety of cancers and the like, it has been found that a novel compound having a good oral bioavailability and a drug-forming property for treating a cancer or the like is a challenging task. Thus, there remains a need in the art to develop compounds having selective inhibitory activity or better pharmacodynamics/pharmacokinetics for Trk kinase mediated diseases useful as therapeutic agents, and the present invention provides such compounds.
SYN
WO 2018071447

PATENT

WO2018071447

PATENT

US 20190106438

PATENT

WO 2019075108

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019075108&tab=PCTDESCRIPTION

Compounds of Formula I-IV, 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-1-yl)pyridin-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula I); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula II); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula III); and 6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (Formula IV) are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases, including cancers.

[0007] Accordingly, provided herein is a compound of Formula I-IV:

and pharmaceutically acceptable salts, amorphous, and polymorph forms thereof.

PATENT

WO 2019075114

PATENT

WO-2019120194

Novel deuterated analogs of pyrazolo[1,5-a]pyrimidine compounds, particularly selpercatinib , processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating pain, inflammation, cancer and certain infectious diseases.

Example 2(S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl-2,3,3-d 3)-pyrazolo[ 1,5-a] pyrimidin-3-yl) -3-hydroxypyrazole prepared pyrrolidine-1-carboxamide (compound L-2) a.

[0163]

[0164]
Use the following route for synthesis:

[0165]
Patent ID Title Submitted Date Granted Date
US10137124 Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors 2018-01-03
US10172851 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2018-01-03
US10112942 Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors 2017-12-29

/////////////SELPERCATINIB, non-small-cell lung cancer, medullary thyroid cancer, colon cancer, breast cancer, pancreatic cancer, papillary thyroid cancer, other solid tumors, infantile myofibromatosis, infantile fibrosarcoma, soft tissue sarcoma, LOXO, ELI LILY,  ARRAY, LOXO 292, orphan drug designation

N#CC1=C2C(C3=CC=C(N4CC(C5)N(CC6=CC=C(OC)N=C6)C5C4)N=C3)=CC(OCC(C)(O)C)=CN2N=C1

Eli Lilly’s Profit Slides, Gets Priority Review for Ramucirumab


Eli Lilly’s third-quarter earnings fell 9 percent compared with last year, when the maker of Cymbalta and Cialis booked a sizeable revenue-sharing payment from a former drug developer partner.

The Indianapolis company beat Wall Street expectations for the quarter and narrowed its earnings forecast for the year.

Lilly also said Wednesday that the U.S. Food and Drug Administration will give its stomach cancer treatment ramucirumab a priority review, which means the drugmaker will learn about its fate inside of eight months rather than a year, which is the norm.

read at

http://www.dddmag.com/news/2013/10/eli-lillys-profit-slides-gets-priority-review

cut paste old article

Eli Lilly and Co. announced that results from the Phase 3 REGARD trial of ramucirumab (IMC-1121B) as a single agent in patients with advanced gastric cancer who have had disease progression after initial chemotherapy were published today in The Lancet. REGARD is the first Phase 3 study with either a single-agent biologic or an anti-angiogenic therapy to show improved overall survival and progression-free survival in advanced gastric cancer patients.

READ ALL AT

http://www.dddmag.com/news/2013/10/ramucirumab-trial-shows-improved-os-gastric-cancer?et_cid=3516952&et_rid=523035093&type=cta

Ramucirumab (IMC-1121B)[1] is a fully human monoclonal antibody (IgG1) being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF inangiogenesis.

Ramucirumab is being tested in several phase III clinical trials for the treatment of metastatic gastric adenocarcinoma,[2] non-small cell lung cancer,[3] among other types of cancer. On September 26, 2013 Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.[4][5]

This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

  1.  Statement On A Nonproprietary Name Adopted By The USAN Council – RamucirumabAmerican Medical Association.
  2.  ClinicalTrials.gov NCT01170663 A Study of Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW)
  3.  ClinicalTrials.gov NCT01168973 A Study in Second Line Non Small Cell Lung Cancer
  4. ClinicalTrials.gov NCT00703326 Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer
  5.  Fierce Biotech. “In another stinging setback, Eli Lilly’s ramucirumab fails PhIII breast cancer study”. Retrieved 27 September 2013.

 

MAA, EU, Boehringer Ingelheim and Eli Lilly and Company announce acceptance of EMA application for investigational Type 2 Diabetes treatment empagliflozin


Empagliflozin

26 March 2013

Boehringer Ingelheim and Eli Lilly and Company today announced the European Medicines Agency (EMA) has accepted for review a marketing authorisation application (MAA) for the investigational sodium glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin, for the treatment of Type 2 Diabetes (T2D) in adults. The acceptance of the MAA marks the beginning of the review process in the European Union for this potential oral diabetes treatment.

 

A New Drug Application (NDA) for empagliflozin was recently submitted to the Food and Drug Administration (FDA) in the United States for the treatment of Type 2 Diabetes mellitus (T2D) in adults.

Empagliflozin is part of a class of drugs being investigated for the reduction of blood glucose levels in adults with T2D. In clinical trials to date, SGLT2 inhibitors have been shown to reduce blood glucose by removing excess glucose independently of beta cell function and insulin resistance.

* Empagliflozin is an investigational compound. Its safety and efficacy have not yet been fully established

About Diabetes

An estimated 371 million people worldwide have Type 1 and Type 2 Diabetes. Type 2 Diabetes is the most common type, accounting for an estimated 90% of all diabetes cases.Diabetes is a chronic condition that occurs when the body either does not properly produce, or use, the hormone insulin.

Empagliflozin is drug which is being investigated in clinical trials for the oral treatment of type 2 diabetes by Boehringer Ingelheim and Eli Lilly and Company.[1][2] It is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90 percent of glucose reabsorption into the blood. Blocking SGLT-2 causes blood glucose to be eliminated through the urine via the urethra.[3][4]

SGLT-2 inhibitors such as empagliflozin reduce blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine.[5]

  1. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P (January 2012). “Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors”. Diabetes Obes Metab 14 (1): 83–90. doi:10.1111/j.1463-1326.2011.01517.x. PMID 21985634.
  2.  “Empagliflozin”. clinicaltrials.gov. U.S. National Institutes of Health. Retrieved 22 September 2012.
  3.  Nair S, Wilding JP (January 2010). “Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus”. J. Clin. Endocrinol. Metab. 95 (1): 34–42. doi:10.1210/jc.2009-0473. PMID 19892839.
  4.  Bays H (March 2009). “From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus”. Curr Med Res Opin 25 (3): 671–81. doi:10.1185/03007990802710422. PMID 19232040.
  5.  Abdul-Ghani MA, DeFronzo RA (September 2008). “Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus”. Endocr Pract 14 (6): 782–90. PMID 18996802.

 

%d bloggers like this: