Tafluprost

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Oct 252015

isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate,

propan-2-yl (E)-7-[2-[(E)-3,3-difluoro-4-phenoxybut-1-enyl]-3,5-dihydroxycyclopentyl]hept-5-enoate

Molecular Formula: C₂₅H₃₄F₂O₅

Molecular Weight: 452.531266

Drug: Zioptan
Generic molecule: tafluprost
Company: Merck
Approval date: Feb. 10, 2012

The scoop: Merck says this is the first (get ready for a mouthful) preservative-free prostaglandin analog ophthalmic solution and is for treating elevated eye pressure in some patients with the most common form of glaucoma. Merck sells the ointment in the U.S. and most of Europe, while it licensed it to Japanese drugmaker Santen in Japan, Germany and northern Europe.

Tafluprost (trade names Taflotan, marketed by Santen Pharmaceutical Co. and Zioptan, by Merck (U.S.)) is a prostaglandin analogue used topically (as eye drops) to control the progression of glaucoma and in the management of ocular hypertension. It reduces http://en.wikipedia.org/wiki/Intraocular_pressure”; rel=”nofollow”>intraocular pressure by increasing the outflow of aqueous fluid from the eyes.^[1]^[2]

Taflotan contains 15 µg/ml Tafluprost. Taflotan sine is a preservative-free, single-dose formulation containing 0.3 ml per dose.^[3]

tafluprost_PG

Tafluprost
Systematic (IUPAC) name

isopropyl (5Z)-7-{(1R,2R,3R,5S)-2-[(1E)-3,3-difluoro-4-phenoxybut-1-en-1-yl]-3,5-dihydroxycyclopentyl}hept-5-enoate
Clinical data
Trade names	Saflutan, Taflotan, Tapros, Zioptan
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	C (US)
Legal status	℞-only (US)
Routes	Topical (eye drops)
Identifiers
CAS number	209860-87-7
ATC code	S01EE05
PubChem	CID 6433101
ChemSpider	8044182
UNII	1O6WQ6T7G3
ChEBI	CHEBI:66899
ChEMBL	CHEMBL1963683
Chemical data
Formula	C₂₅H₃₄F₂O₅
Mol. mass	452.531266 g/mol

Chemical structure for AC1O5FKL

Links

Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel 2008/2009
Santen Home Page
Gelbe Liste (in German)

Its synthesis from compound Corey aldehyde and HWE (Hormer-Wadsworth-Emmons) reagent 1 generates trans olefin 2 , 2 and fluorination reagent 3 hydrolysis reaction 4 , lactone 4 with DIBAL reduction to give the ring hemiacetal 5 , 5 and Wittig reagent 6 cis olefin reaction after esterification with isopropyl iodide Tafluprost.

……………………….

http://www.google.st/patents/WO2013118058A1?cl=en

European Patent No. 8509621 discloses a process for the preparation of tafluprost. In the first step, (3afl,4fl,5fl,6aS)-4-formyl-2-oxohexahydro-2 — cyclopenta[b]furan-5-ylbenzoate (CTAF 1 (i)) is condensed with dimethyl (2-oxo-3- phenoxypropyl)-phosphonate in the presence of lithium chloride and triethylamine, to provide (3aft,4F?,5F?,6aS)-2-oxo-4-((£)-3-oxo-4-phenoxybut-1 -en-1 -yl)hexahydro-2H- cyclopenta[b]-furan-5-ylbenzoate (CTAF1 ). In the second step, CTAF 1 is reacted with morpholinosulfurtrifluoride to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-2-oxohexahydro-2 –cyclopenta-[b]furan-5-yl benzoate (CTAF2). CTAF 2 is debenzoylated by potassium carbonate in methanol, to provide (3aH,4H,5H,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-5-hydroxyhexahydro-2H- cyclopenta[b]furan-2-one(CTAF 3), which is further reduced by diisobutyl aluminum hydride (DIBALH) to provide (3af?,4f?,5f?,6aS)-4-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 – yl) hexahydro-2H-cyclopenta[b]furan-2,5-diol (CTAF 4). CTAF 4 is then treated with (4- carboxybutyl)triphenylphosphonium bromide, in the presence of potassium bis(trimethylsilyl)amide in THF, to provide (Z)-7-((1 f?,2f?,3f?,5S)-2-((£)-3,3-difluoro-4- phenoxybut-1 -en-1 -yl)-3,5-dihydroxycyclopentyl)hept-5-enoic acid (“tafluprost free acid,” CTAF5), which is reacted with isopropyl iodide in the presence of DBU to provide (Z)- isopropyl 7-((1 F?,2F?,3F?,5S)-2-((£)-3,3-difluoro-4-phenoxybut-1 -en-1 -yl)-3,5-dihydroxy- cyclopentyl)hept-5-enoate (“tafluprost,” CTAF 6). The reaction sequence is summarized in Scheme 1 .

CTAF 1(i)

CTAF 1 CTAF 2

U.S. Patent Application Publication No. 2010/0105775A1 discloses amino acid salts of prostaglandins. The application also discloses a process for the preparation of prostaglandins, comprising forming an amino acid salt of a prostaglandin and converting the amino acid salt to the prostaglandin.

EXAMPLE 1 : Preparation of CTAF 1

CTAF1(i)

CTAF1

To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.217 g, 5.429 mmol) in THF (5 ml_) was added a solution of dimethyl (2-oxo-3- phenoxypropyl)phosphonate(1 .21 g, 4.705 mmol) in THF (2 ml_), over 15 minutes at 0- 5°C under a nitrogen atmosphere. The mixture was warmed to 25-35 , 0.5 M zinc chloride solution in THF (9.4 ml_, 4.705 mmol) was added over 10 minutes, and then the mixture was stirred for 15 minutes at 25-35^<€. CTAF1 (i) (3af?,4F?,5F?,6aS)-4-formyl-2- oxohexahydro-2 –cyclopenta[b]furan-5-yl benzoate (1 g) in dichloromethane (10 ml_) was added over 5 minutes at 25-35 °C. The temperature was raised to 35-40 °C and the mixture was stirred for 2hours under a nitrogen atmosphere. The mixture was cooled to 15°C and the reaction was quenched by adding acetic acid (0.2 mL), followed by adding saturated ammonium chloride solution (10 mL), and further stirring for 15 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were evaporated under reduced pressure below 50°C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (0.9 g, 61 %yield).

EXAMPLE 2: Preparation of CTAF 2

CTAF1 CTAF2

To a stirred solution of CTAF1 (5 g, 0.0123 mol) in dichloromethane (100 mL) was added diethylaminosulfurtrifluoride (13 mL, 0.09841 mol) at 0-5 °C under a nitrogen atmosphere. The temperature was raised to 25-35 °C and maintained for 24 hours under a nitrogen atmosphere at the same temperature. The mass was slowly added into a saturated sodium bicarbonate solution (75 mL) at 0-5 °C. Temperature was raised to 25- 35 °C, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with water (25mL) and dried over sodium sulfate (5 g). The organic layer was evaporated to dryness under reduced pressure below 40 °C. The crude product was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane, to afford the title compound (4.2 g, 79% yield). EXAMPLE 3: Preparation of CTAF 4

CTAF 2 CTAF 4

CTAF 2 (2.30 g, 5.37 mmol) was dissolved in toluene (25 mL) and the solution was cooled to -65 °C under nitrogen. Diisobutyl aluminum hydride (1 .5 M in toluene, 1 1 .8 mL, 17.7mmol) was added over 15 minutes at -61 to -65 . The mixture was stirred for 3hours and then the reaction was quenched by adding methanol (1 .5 mL). Sulfuric acid (1 M, 25 mL) was added and the temperature rose to -20°C during the addition. Methyl t-butyl ether (MTBE) (10 mL) was added and the mixture was allowed to warm to room temperature. The organic phase was separated and the aqueous phase was extracted with MTBE (2x 10 mL). The combined organic phase was washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL), and then brine (10 mL). The washes were back-extracted with MTBE (10 mL). The combined organic phases were dried with magnesium sulfate, filtered, and evaporated to give a colourless oil (2.20 g). The crude product was chromatographed on silica (60 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), and then with ethyl acetate, to give CTAF 4 as a colourless oil (1 .71 g, 97% yield).

EXAMPLE 4: Preparation of CTAF 2

CTAF1 CTAF2

To a stirred solution of CTAF1 (20 g, 0.0492 mol) in dichloromethane(400 mL) was added diethylaminosulfurtrifluoride (52 mL, 0.393 mol) at 0-10°C under a nitrogen atmosphere. The temperature was raised to 25-35 and maintained for 96hours under a nitrogen atmosphere at that temperature. The mass was slowly added to a saturated NaHCOs solution (600 mL) at 0-10°C. The mixture was heated to 25-35 ^<€ and filtered through aCelite bed. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layer was washed with 10% NaCI solution (100 mL) and evaporated to dryness under reduced pressure below 40°C. The residue was purified by column chromatography on silica gel (100-200 mesh) with 30% ethyl acetate in hexane.

Column purified material was dissolved in MTBE (80 mL) at 40°C and stirred for 30 minutes at that temperature. Diisopropyl ether (160 mL) was added at 35-40 and stirring continued for 30 minutes at 35-40 . Cooled the mass to 5-15°C and stirred for 30 minutes at that temperature. The solid was filtered, washed with a mixture of MTBE and diisopropyl ether (DIPE) (1 :2 by volume, 60 mL), and dried at 40°C under vacuum, to afford pure CTAF2 (12.0 g, 57% yield).

EXAMPLE 5: Preparation of CTAF 5

(4-Carboxybutyl)triphenylphosphonium bromide (10.32 g, 23.3 mmol, 4 eq) was suspended in THF (20 mL) under a nitrogen atmosphere and cooled to 5°C. NaHMDS solution (1 M in THF, 46.6 mL, 46.6 mmol, 8 eq) was added over 10 minutes. The red/orange mixture was stirred for 30 minutes. A solution of CTAF 4 (1 .90 g, 5.82 mmol) in THF (10 mL) was added over 30 minutes at 0-3 . The mixture was stirred for 1 .5hours and then the reaction was quenched by adding water (30 mL) and the masswas warmed to room temperature. The aqueous phase was separated and the organic phase was washed with water (20 mL). The combined aqueous phases were washed with MTBE (30 mL). The organic phases up to this point were discarded. The aqueous phase was acidified with 2M hydrochloric acid (14 mL, to pH 3-4) and extracted with ethyl acetate (2×30 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried with magnesium sulfate, filtered, and evaporated under reduced pressure to give CTAF 5 asa yellow oil (8.60 g).

A 2.96 g sample was removed and the remainder (5.64 g) was chromatographed on silica (30 g) eluting with ethyl acetate to give purified CTAF 5 (1 .41 g) asa yellow oil. NMR analysis showed approximately 90% purity, remainder triphenyl phosphine oxide.

EXAMPLE 6: Preparation of CTAF 5 DCHA salt

CTAF 5 CTAF 5 DCHA sa t

CTAF5 (1 1 .72 g, 90% purity, 25.7 mmol, containing 1 .4% trans isomer) was dissolved in acetone (60 mL). Dicyclohexylamine (4.66 g, 25.7 mmol) was added and the mixture was stirred at room temperature overnight. The solid was filtered and washed with acetone (6 mL), then dried to give the DCHA salt (12.93 g, 85% yield, 0.29% trans-isomer).

A sample (7.03 g) was further purified by recrystallisation. It was dissolved in hot acetone (30 mL) and cooled to room temperature with stirring. The mixture was stirred for 3 hours, filtered and the solid was washed with acetone (3 mL) and dried to give a white solid (6.41 g, 91 % recovery, 0.1 1 % trans-isomer).

A PXRD pattern of the product is shown as Fig. 1 , obtained using copper Ka radiation. In the drawing, the y-axis is intensity units and the x-axis is the 2-theta angle, in degrees. EXAMPLE 7: Pre aration of CTAF 6

CTAF 5 DCH A sa l ^ I AI- O

CTAF 5 DCHA salt (5.80 g, 9.80 mmol) was suspended in ethyl acetate (20 mL). Sulfuric acid (1 M, 20 mL) was added and the mixture was stirred until a clear solution was obtained. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried with magnesium sulfate, filtered, and evaporated. The residue was dissolved in acetone (40 mL) and charged into a jacketed vessel at 30°C. 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (8.95 g, 58.8 mmol) was added, then 2- iodopropane (10.0 g, 58.8 mmol) was added, and the mixture was stirred for 20hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and aqueous potassium dihydrogen orthophosphate (8 g) in water (50 mL). The organic phase was separated and the aqueous was extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (20 mL), dried with magnesium sulfate, filtered and evaporated to give a yellow oil (4.83 g). The crude product was chromatographed on silica (130 g), eluting with a mixture of ethyl acetate and heptane (2:1 by volume), to give CTAF 6 (3.98 g, 90% yield) as a colorless oil.

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

MAVATREP, JNJ 39439335,

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Oct 252015

Mavatrep; UNII-F197218T99; Mavatrep (USAN); JNJ-39439335; 956274-94-5;

2-(2-(2-(2-(4-trifluoromethylphenyl)vinyl)-1H-benzimidazol-5-yl)phenyl)propan-2-ol

(E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

Phase I Musculoskeletal pain; Pain

01 Mar 2013 Janssen Research and Development completes a phase I trial in Japanese and Caucasian adult male volunteers in the US (NCT01631487)
01 Mar 2013 Janssen completes enrolment in its phase I trial for Pain (in volunteers) in the USA (NCT01631487)
05 Feb 2013 Janssen Research and Development initiates enrolment in a phase I trial for Pain (Japanese and Caucasian volunteers) in USA (NCT01631487)

Originator Johnson & Johnson Pharmaceutical Research & Development
Developer Janssen Research & Development
Class Analgesics; Benzimidazoles; Small molecules
Mechanism of Action TRPV1 receptor antagonists

ChemSpider 2D Image | Mavatrep | C25H21F3N2O

PHASE 1 Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Public title:	A Clinical Study to Investigate the Effect on Pain Relief of a Single Dose of JNJ-39439335 in Patients With Chronic Osteoarthritis Pain of the Knee

http://clinicaltrials.gov/ct2/show/NCT01006304
http://apps.who.int/trialsearch/trial.aspx?trialid=NCT00933582

http://www.ama-assn.org/resources/doc/usan/mavatrep.pdf SEE STRUCTURE IN THIS FILE

MAVATREP IS JNJ-39439335
—

(E)-2-(2-(2-(4-(trifluoromethyl)styryl)-1H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol hydrochloride

956282-89-6 CAS NO OF HCl SALT

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00271, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00271

The process development of Mavatrep (1), a potent transient receptor potential vanilloid-1 (TRPV1) antagonist, is described. The two key synthetic transformations are the synthesis of (E)-6-bromo-2-(4-(trifluoromethyl)styryl)1H-benzo[d]imidazole (4) and the Suzuki coupling of 4 with 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (5). Compound 1a was prepared in four chemical steps in 63% overall yield.

http://www.google.st/patents/US20110190344

CLICK ON IMAGE FOR CLEAR VIEW

Example 10 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol(Cpd 18)

Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0278]

A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 μL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70° C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). ¹HNMR (400 MHz, DMSO-d₆) δ (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d, 1H, J=16.0 Hz), 6.70 (d, 1H, J=16.0 Hz).
[0000]

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0279]

A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and “3 drops” of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step.
[0280]

To a solution of 4-bromo-benzene-1,2-diamine (16.1 g, 86.7 mmol) in acetic acid (100 mL) was added dropwise a solution of Compound 10b (assumed 95.4 mmol) in acetic acid (100 mL). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, and a mixture of ethyl acetate and hexanes 3:7 (500 mL) was added. The mixture was triturated at room temperature for 3 h to give a precipitate. The solid was filtered, and dried in vacuo to give the title Compound 10c (23.2 g, 73%). ¹H NMR (400 MHz, DMSO-d₆/CDCl₃) δ (ppm): 8.45 (d, 1H, J=16.7 Hz), 7.84-7.90 (m, 1H), 7.74 (d, 2H, J=8.3
[0281]

Hz), 7.56-7.62 (m, 3H), 7.50-7.52 (m, 1H), 7.34 (d, 1H, 16.7 Hz).
[0000]

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0282]

To a solution of methyl 2-bromobenzoate (20.76 g, 96 mmol) in 120 mL of anhydrous ether under Argon at 0° C. was slowly added methylmagnesium bromide (77 mL, 3.26 M) at a rate that the internal temperature of the mixture was below 20° C. A white suspension resulted, and the mixture was stirred at room temperature for 2 h. The mixture was cooled in an ice-water bath. To the reaction mixture was very slowly added hydrochloric acid (400 mL, 0.5 M). The pH of the final mixture was adjusted to less than about 6 with few drops of 2M hydrochloric acid. The layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined and dried over magnesium sulfate. The organic fraction was filtered, and the filtrate was concentrated to yield the title compound as a pale yellow liquid, which was distilled under vacuum to afford the title Compound 10d as a colorless liquid (16.9 g, 82%, b.p. about 65-70° C./0.3 mmHg). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.67 (dd, 1H, J=1.7, 7.9 Hz), 7.58 (dd, 1H, J=1.3, 7.9 Hz), 7.30 (ddd, 1H, J=1.4, 7.4, 7.9 Hz), 7.10 (ddd, 1H, J=1.7, 7.4, 7.8 Hz), 2.77 (br s, 1H), 1.76 (s, 6H).
[0000]

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0283]

To a solution of n-BuLi (166 mL, 2.6 M, 432 mmol) in 200 mL of THF at −78° C. under argon was slowly added a solution of Compound 10d (42.2 g, 196 mmol) in 60 mL of THF at a rate that the internal temperature remained below −70° C. The mixture was stirred at −75° C. for 2 h. To the reaction mixture was then added triisopropylborate (59 mL, 255 mmol) in three portions. The mixture was allowed to warm slowly to room temperature overnight. The mixture was then cooled to 0° C., and was carefully quenched with dilute hydrochloric acid (250 mL, 2N). The mixture was then stirred at room temperature for 1 h. The pH of the mixture was checked and adjusted to acidic using additional 2N HCl if prophetic. The two layers were separated, and the aqueous layer was extracted twice with ether. The organic layers were combined, and dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a pale yellow oil. The residue was then diluted with ethyl acetate (400 mL) and, washed with 1N sodium hydroxide solution (150 mL×3). The basic aqueous layers were combined and acidified with 2N HCl. The clear solution turned cloudy when the acid was added. The mixture was extracted with ether (150 mL×3). The organic layers were combined and dried with magnesium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to yield the title Compound 10e as a colorless oil (26.2 g, 82%) which was used without further purification in the next step. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.00 (s, 1H), 7.66 (dm, 1H, J=7.3 Hz), 7.45 (dt, 1H, J=1.1, 7.7 Hz), 7.40 (dm, 1H, J=7.6 Hz), 7.31 (dt, 1H, J=1.2, 7.1 Hz), 1.44 (s, 6H).
[0000]

Step E. (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

[0284]

To a mixture of Compound 10e (11.7 g, 71 mmol), Compound 10c (19.9 g, 54 mmol), sodium carbonate (46 g, 435 mmol) and PdCl₂(dppf).CH₂Cl₂(8.9 g, 11 mmol) in a 1 L round bottom flask equipped with water condenser was added 400 mL of anhydrous DME and 200 mL of water. The mixture was evacuated and filled with Argon three times. The mixture was heated to 100° C. for 20 h. The mixture was then cooled to room temperature. The biphasic system was transferred to a 1 L separatory funnel and the two layers were separated. The organic layer was washed with brine (2×300 mL). The aqueous layers were combined and extracted with ethyl acetate once (about 300 mL). The organic layers were combined, dried with sodium sulfate, and filtered. The volume of the filtrate was reduced to about 170 mL under reduced pressure. The mixture was then filtered through a pad of silica gel and the pad was washed with ethyl acetate until the filtrate did not contain any product. After concentration, a light pink/beige solid was obtained. The solid was triturated with 50 mL ethyl acetate, and the mixture was heated to 85° C. for 5 min. The mixture was slowly cooled to r.t., then cooled at 0° C. for 0.5 h. The mixture was filtered, and the solid was washed with cold ethyl acetate twice, and dried under vacuum at 40° C. to yield the title Compound 18 as a light beige solid (7.58 g, 33%). RP-HPLC 95% pure.
¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.73 (m, 1H,), 7.90 (d, 2H, J=8.2 Hz), 7.85 (dd, 1H, J=8.0, 0.6 Hz), 7.78 (d, 2H, J=8.4 Hz), 7.74 (d, 1H, J=16.8 Hz), 7.59-7.47 (m, 1H), 7.41 (s, 1H), 7.37-7.32 (m, 2H), 7.21 (dt, 1H, J=1.2, 7.4 Hz), 7.06 (s, 1H), 7.02 (d, 1H, J=7.4 Hz), 4.85 (s, 1H), 1.21 (s, 6H).
Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3.
m.p. (uncorr.) 250-251° C.

Example 10.1 Scale Up Preparation of (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol (Cpd 18) Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid

[0286]

A 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40° C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (T_maxabout 42° C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60° C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40° C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60° C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.

Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazole

[0287]

To a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b (>100%) as a yellow oily solid.
[0288]

A 5-L 4-neck round bottom flask equipped with mechanical stirrer, thermocouple, air condenser with argon inlet, and a stopper was charged with 4-bromo-benzene-1,2-diamine (244 g, 1.27 mol) and acetic acid (2.13 L). To this solution was added a solution of Compound 10b (327 g, 1.39 mol) in toluene (237 mL). After this addition, the temperature spiked to 45° C. in about 30 seconds and then subsided. The reaction was then heated to 90° C. for 16 h (overnight). The reaction was cooled to 40° C., and poured into a mixed solution of EtOAc and heptane (about 1:3, 5.75 L) and a precipitate occurred. The resulting slurry was stirred for 3 h, and the solid was collected by filtration, washed with EtOAc:heptane (1:3, 3 L), and then dried in a vacuum oven (60° C.) to give 324.3 g (65%) of the title Compound 10c as a partial acetate salt.

Step C. 2-(2-bromo-phenyl)-propan-2-ol

[0289]

A 12-Liter 4-neck flask equipped with a thermocouple, condenser, septum, addition funnel and overhead mechanical stirrer under argon was charged with methyl-2-bromobenzoate (226.5 g, 1.05 mol) and THF (1.6 L, 19.66 mol). The mixture was cooled to a temperature between 2 and 5° C. with stirring and held for 30 min. To the solution was slowly added methyl magnesium bromide in diethyl ether (3M, 1.05 L; 3.15 mol) via the addition funnel at a rate to maintain the reaction temperature below 15° C. An exotherm was observed during the addition, the reaction temperature warmed from 3 to 15° C. The addition of 1.05 L Grignard was complete in 4 h (approximate feed rate was 4.17 mL/min). The reaction mixture appeared to be off-white/yellow slurry. The reaction was allowed to warm to room temperature and stirred overnight (15 h). The reaction was sampled by HPLC/TLC and showed no starting material present. The ice bath was again applied to the reaction flask and a 0.5 M HCl solution (4.5 L; 2.25 mol) was slowly added over a period of 2 h. The temperature increased dramatically from 0 to 15° C. After the quench was complete, the reaction was stirred at room temperature for 30 min. Additional 2 N HCl (500 mL; 1.00 mol) was slowly added to maintain a pH less than 6. MTBE (1 L) was added to help with the phase split. The reaction was stirred at room temperature for 1 to 2 h to dissolve the solid material into the aqueous phase (most likely Mg(OH)₂which is very basic). The pH must be checked and adjusted with additional acid when necessary. The phases were separated and the aqueous layer was washed with an additional 1 L MTBE (2×500 mL). The organic phases were combined, washed with NaHCO₃solution (2×300 mL), dried over MgSO₄, filtered and the filtrate was concentrated under vacuum to yield the title Compound 10d (220.83 g, 97.48% yield) as a clear yellow oil.

Step D. 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol

[0290]

A 12-Liter 4-neck round bottom flask equipped with a thermocouple, condenser, addition funnel and overhead mechanical stirrer under dry Argon was charged with anhydrous THF, (3 L) and chilled to −70 to −78° C. via a dry ice/acetone bath. n-Butyl lithium (2.5N in hexanes, 860 mL, 2.15 mol) was slowly added via addition funnel. An exotherm was observed as the temperature rose from −78 to −70° C. To the addition funnel was added a solution of Compound 10d (220 g, 979.97 mmol) in anhydrous THF (1 L). The 2-(2-bromophenyl)propan-2-ol solution was slowly added to the n-BuLi solution. The addition took 90 min in order to maintain a reaction temperature below −70° C. After the addition was complete, the reaction mixture was stirred at −70 to −75° C. for 30 min. The triethylborate (230 mL, 1.35 mol) was quickly added in 3 portions at −70° C. An exotherm was observed, the batch temperature rose from −70 to −64° C. The reaction was stirred at −70° C. and slowly warmed to room temperature over night. After the reaction was cooled to 0-5° C., the reaction was slowly quenched with 2 M HCl (1 L, 2.00 mol) added via the addition funnel while maintaining the batch temperature 0-5° C. The reaction mixture was stirred for 1 h. The aqueous phase pH was 9-10. The pH was then adjusted to acidic (4-5) with 2 M HCl (200 mL). The two phases were separated and the aqueous layer was extracted with MTBE (2×500 mL). The combined organic phases were dried with anhydrous magnesium sulfate. The solution was filtered and concentrated to yield a yellow oil. The yellow oil was diluted with MTBE (1.5 L) and washed with 1M NaOH (3×500 mL). The product containing basic aqueous phases were combined and acidified with 2 M HCl (800 mL) (the clear solution turns turbid with the addition of acid). After stirring the turbid solution for 15 min (pH=4-5) (Note 1), it was extracted with MTBE (2×500 mL). The organic phases were combined and dried over MgSO₄. The solution was filtered and the filtrate was concentrated to yield the title Compound 10e as a clear yellow oil (121.78 grams, 77% yield).

Step E. (E)-2-(2-{2-[2-(4-Trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol

A 5-L 4-neck flask equipped with a thermocouple controller, condenser, overhead mechanical stirrer, Firestone Valve® and a nitrogen inlet/outlet was charged with dimethoxyethane (2 L), DI water (1 L) and sodium carbonate (230.9 g, 2.18 mol). The solution was degassed and purged with N₂three times. Compound 10e (71.7 g, 0.35 mol) and Compound 10c (100.0 g, 0.27 mol) were added to the degassed solution. The solution was degassed and purged with N₂three times. PdCl₂(dppf) (44.48 g, 54.4 mmol) was added to the solution, and the solution was degassed and purged with N₂three times. The resulting two-phase suspension was heated to reflux for 18 h, and then cooled to room temperature. The reaction mixture was transferred to a 12-L separatory funnel, and the layers were separated. The organic layer was washed with brine (1 L). The two aqueous layers were combined and extracted with EtOAc (1 L). The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated to an oil. Two separate 100 g coupling reactions were combined and purified by chromatography in 10 successive chromatography runs on an ISCO preparative chromatography system (10×1.5 Kg SiO2, 5 column volumes of EtOAc, 250 mL/min flow rate). The combined fractions were transferred to two 22 L 4-neck round bottom flasks, and Silicycle Si-thiol functionalized silica gel (2 g) was added to each solution. The solutions were warmed to 40° C. and aged for 1 h. The solutions were filtered thru a medium glass funnel and washed with EtOAc (4 L) and combined. The filtrate was evaporated to a semi solid, which was transferred to a 2 L round bottom flask, to which EtOAc (0.4 L) was added. The resulting white precipitate slurry was cooled to −5° C. and stirred for 1 h. The slurry was filtered and washed twice with cold EtOAc (100 mL). The solids were dried in a vacuum oven at 40° C. for 40 h to afford 84.0 g (36.5% yield, 98.8 area % purity) of the title Compound 18 as a white solid. Anal. Calcd for C₂₅H₂₁N₂OF₃.0.04% H₂O.0.15 mol MeOH: C, 70.48; H, 5.14: N, 6.42; F, 13.06 Found: C, 70.54; H, 4.83: N, 6.18; F, 13.33

Example 10.2 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol monosodium salt (Cpd 18)

A 5-L 4-neck flask equipped with a thermocouple controller, an overhead mechanical stirrer, and a nitrogen inlet/outlet was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (125.0 g, 0.510 mol) and MeOH (1.25 L). A solution of sodium methoxide in methanol (0.5 M, 592 mL, 0.3 mol) was added. The reaction was heated to 65° C. for 30 min and all solids dissolved. The solution was cooled and evaporated to dryness. The foam was collected by scraping it out of the flask. The solids were placed in vacuum oven for 24 h at 40° C. to afford 139 g (about 100% isolated yield) of the title Compound 18 monosodium salt as a yellowish solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.80-7.84 (m, 3H), 7.74 (d, 2H, J=8.59 Hz), 7.65 (d, 1H, J=16.4 Hz), 7.40-7.44 (m, 2H), 7.25-7.37 (m, 2H), 7.16-7.20 (m, 1H), 7.01-7.05 (m, 1H), 6.84-6.87 (m, 1H), 1.23 (s, 6H). Mass Spectrum (LCMS, APCI pos.) Calcd. For C₂₅H₂₁F₃N₂O: 423.2 (M+H). Found 423.3. m.p. (uncorr.) 258-259° C.

Example 10.3 (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol hydrochloride salt (Cpd 18)

A 250-mL separatory funnel was charged with (E)-2-(2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-phenyl)-propan-2-ol. Compound 18 (1.0 g, 2.4 mmol) and EtOAc (20 mL). Aqueous HCl (1M, 20 mL) was added to the white slurry, and the separatory funnel was shaken. The solid product quickly dissolved, and a white precipitate started to form. The organic layer was transferred to a 100 mL round bottom flask equipped with a magnetic stir bar, and was stirred for 2 h. The thick slurry was filtered, rinsed with EtOAc (2×5 mL), and put into a vacuum oven at 40° C. for 36 h to afford 0.95 g (87.5%) of the title Compound 18 hydrochloride salt.

US7951829

Patent	Submitted	Granted
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190344]	2011-08-04
BENZIMIDAZOLE MODULATORS OF VR1 [US2011190364]	2011-08-04
Benzimidazole Modulators of VR1 [US7951829]	2007-11-08	2011-05-31

////////////Phase I, Musculoskeletal pain, Pain, Mavatrep, JNJ 39439335,

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Chemical synthesis of IL-10 cytokine 90% cheaper than bioproduction, Provepep

Uncategorized Comments Off

Oct 152015

Chemical synthesis of IL-10 cytokine 90% cheaper than bioproduction, Provepep

By Dan Stanton+, 08-Oct-2015

Chemical synthesis of peptides and proteins can be done at a tenth of the cost of bioproduction says French chemistry specialist Provepep.

http://www.in-pharmatechnologist.com/Product-Categories/APIs-active-pharmaceutical-ingredients/Chemical-synthesis-of-IL-10-90-cheaper-than-bioproduction-Provepep

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An introduction to the Prequalification of Active Pharmaceutical Ingredients

Uncategorized Comments Off

Sep 052015

An introduction to the Prequalification of Active Pharmaceutical Ingredients

The WHO Prequalification of Medicines Programme (PQP) facilitates access to quality medicines through assessment of products and inspection of manufacturing sites. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a pilot project to prequalify APIs.

WHO-prequalified APIs are listed on the WHO List of Prequalified Active Pharmaceutical Ingredients. The list provides United Nations agencies, national medicines regulatory authorities (NMRAs) and others with information on APIs that have been found to meet WHO-recommended quality standards. It is believed that identification of sources of good-quality APIs will facilitate the manufacture of good-quality finished pharmaceutical products (FPP) that are needed for procurement by UN agencies and disease treatment programmes.

Details of the API prequalification procedure are available in the WHO Technical Report Series TRS953, Annex 4. Key elements of this document are given below.

What is API prequalification?

API prequalification provides an assurance that the API concerned is of good quality and manufactured in accordance with WHO Good Manufacturing Practices (GMP).

API prequalification consists of a comprehensive evaluation procedure that has two components: assessment of the API master file (APIMF) to verify compliance with WHO norms and standards and assessment of the sites of API manufacture to verify compliance with WHO GMP requirements.

Prequalification of an API is made with specific reference to the manufacturing details and quality controls described in the APIMF submitted for assessment. Therefore, for each prequalified API, the relevant APIMF version number will be included in the WHO List of Prequalified Active Pharmaceutical Ingredients.

Steps in the process

The WHO prequalification procedure for medicines and active pharmaceutical ingredients

Steps API prequalification

Initially, an application is screened to determine whether it is covered by the relevant expression of interest (EOI). It is also screened for completeness; in particular, the formatting of the submitted APIMFs is reviewed. Once the application has been accepted, a WHO reference number is assigned to it.

A team of assessors then reviews the submitted APIMF, primarily at bimonthly meetings in Copenhagen. Invariably, assessors raise questions during assessment of the APIMF that require revision of the information submitted and/or provision of additional information, and/or replacementof certain sections within the APIMF. Applicants are contacted to resolve any issues raised by the assessors.

It is important that any prequalified API can be unambiguously identified with a specific APIMF. Therefore, once any and all issues regarding its production have been resolved, the applicant will be asked to submit an updated APIMF that incorporates any changes made during assessment. The version number of the revised and up-to-date APIMF will be included on the WHO List of Prequalified Active Pharmaceutical Ingredients, to serve as a reference regarding the production and quality control of that API.

For APIMFs that have already been accepted in conjunction with the prequalification of an FPP, full assessment is generally not required. Such APIMFs are reviewed only for key information and conformity with administrative requirements. Nonetheless, a request for further information may be made, to ensure that the APIMF meets all current norms and standards; PQP reserves the right to do so.

An assessment is also undertaken of WHO GMP compliance at the intended site(s) of API manufacture. Depending on the evidence of GMP supplied by the applicant, this may necessitate on-site inspection by WHO. If a WHO inspection is conducted and the site is found to be WHO GMP-compliant, the API will be recommended for prequalification. Additionally, a WHO Public Inspection Report (WHOPIR) will be published on the PQP web site.

When the APIMF and the standard of GMP at the intended manufacturing site(s) have each been found to be satisfactory, the API is prequalified and listed on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The successful applicant will also be issued a WHO Confirmation of Active Pharmaceutical Ingredient Prequalification document. This document contains the accepted active ingredient specifications and copies of the assay and related substances test methodology. This document may be provided by the API manufacturers to interested parties at their discretion.

Maintenance of API prequalification status

Applicants are required to communicate to WHO any changes that have been made to the production and control of a WHO-prequalified API. This can either be in the form of an amendment, or as a newly-issued version of the APIMF. It is the applicant’s responsibility to provide WHO with the appropriate documentation (referring to relevant parts of the dossier), to prove that any intended or implemented change will not have or has not had a negative impact on the quality of the prequalified API. This may necessitate the updating of the information published on the WHO List of Prequalified Active Pharmaceutical Ingredients.

The decision to prequalify an API is based upon information available to WHO at that time, i.e. information in the submitted APIMF, and on the status of GMP at the facilities used in the manufacture and control of the API. The decision to prequalify an API is subject to change, should new information become available to WHO. For example, if serious safety and/or quality concerns arise in relation to a prequalified API, WHO may suspend the API until the investigative results have been evaluated by WHO and the issues resolved, or delist the API in the case of issues that are not resolved to WHO’s satisfaction.

Who can participate?

Any manufacturer of any active pharmaceutical ingredient (API) that is included on an Invitation to Submit an Expression of Interest for Product Evaluation can submit an application for product evaluation.

If an applicant is acting on behalf of a manufacturer, the actual manufacturer(s) of the API and any contract manufacturers, must be clearly listed in the cover letter

To manufacturers of medicinal products

The vision of the WHO Prequalification of Medicines Programme (PQP) is of a world in which good-quality medicines are available to all those who need them. PQP facilitates access to good-quality medicines through assessment of products and inspection of manufacturing facilities. Since good-quality active pharmaceutical ingredients (APIs) are vital to the production of good-quality medicines, PQP has started a project to prequalify APIs.

APIs that meet assessment criteria will be added to the WHO List of Prequalified Active Pharmaceutical Ingredients. Manufacturers and National Regulatory Authorities (NRAs) can use the List to help them identify APIs of assured quality, while UN agencies and others can use the List to supplement the information found on the WHO List of Prequalified Medicines Products.

The issuing of an invitation to submit an expression of interest (EOI) is the first step in the prequalification process. Each invitation is developed in consultation with WHO disease programmes, other UN agencies (including UNAIDS and UNICEF) and UNITAID. The 1st Invitation to manufacturers of APIs to submit a request for an evaluation of an API was issued in October 2010.

The current EOI is:

8 ^th invitation to manufacturers of APIs to submit an EOI for product evaluation

In applying for evaluation of an API, manufacturers are requested to submit a covering letter, application form, API master file (APIMF), site master file (SMF), and evidence of current GMP certification to PQP. Thereafter, PQP will undertake a comprehensive evaluation of the APIMF and review the GMP status of the manufacturing site(s). In some cases, PQP will request additional information and may also inspect the manufacturing site(s).

Prequalification of Active Pharmaceutical Ingredients (APIs) – Procedural Guidance

Any applicant who is unclear over any aspect of the API prequalification procedure should contact PQT prior to submission, since incorrect submissions will be rejected.

read at

http://apps.who.int/prequal/

ASLAN Pharmaceuticals Gains Orphan Designation for Rare Cancer Drug ASLAN001 (varlitinib)

phase 2, Uncategorized Comments Off

Aug 242015

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

ASLAN001 , Varlitinib

C22H19ClN6O2S

Molecular Weight: 466.94

Elemental Analysis: C, 56.59; H, 4.10; Cl, 7.59; N, 18.00; O, 6.85; S, 6.87

CAS: 845272-21-1 (Varlitinib); 1146629-86-8 (Varlitinib tosylate).

ASLAN001; ASLAN-001; ASLAN 001; AR 00334543; ARRY-334543; ARRY334543; ARRY-543; ARRY543; ARRY 543.

(R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

(R)-4-[[3-Chloro-4-[(thiazol-2-yl)methoxy]phenyl]amino]-6-[(4-methyl-4,5-dihydrooxazol-2-yl)amino]quinazoline

4,6-Quinazolinediamine, N4-[3-chloro-4-(2-thiazolylmethoxy)phenyl]-N6-[(4R)-4,5-dihydro-4-methyl-2-oxazolyl]-

ASLAN Pharmaceuticals, a Singapore-based drugmaker, announced The Food and Drug Administration (FDA) gave an orphan drug designation on August 13 to its pan-HER inhibitor ASLAN001 (varlitinib), a drug candidate created to treat a destructive form of bile duct cancer called cholangiocarcinoma that has no known cure. ………http://www.dddmag.com/news/2015/08/aslan-pharmaceuticals-gains-orphan-designation-rare-cancer-drug

Current developer: Array Biopharma Inc,

Varlitinib, also known as ARRY-543 and ASLAN001, is an orally bioavailable inhibitor of the epidermal growth factor receptor family with potential antineoplastic activity.

Varlitinib (ASLAN-001) is an oncolytic drug in phase II clinical trials at ASLAN Pharmaceuticals for the treatment of gastric cancer and for the treatment of metastatic breast cancer in combination with capecitabine. Clinical development is also ongoing for the treatment of solid tumors in combination with cisplatin/FU and cisplatin/capecitabine. The product had been in phase I/II clinical trials at Array BioPharma for the treatment of patients with advanced pancreatic cancer. Phase II clinical trials had also been ongoing for the treatment of solid tumors. No recent development has been reported for this research

Varlitinib selectively and reversibly binds to both EGFR (ErbB-1) and Her-2/neu (ErbB-2) and prevents their phosphorylation and activation, which may result in inhibition of the associated signal transduction pathways, inhibition of cellular proliferation and cell death. EGFR and Her-2 play important roles in cell proliferation and differentiation and are upregulated in various human tumor cell types. Due to the dual inhibition of both EGFR and Her-2, this agent may be therapeutically more effective than agents that inhibit EGFR or Her-2 alone.

The drug is a dual inhibitor of the ErB-2 and EGFR receptor kinases, both of which have been shown to stimulate aberrant growth, prolong survival and promote differentiation of many tumor types. The compound behaves as a reversible ATP-competitive inhibitor with nanomolar potency both in vitro and in cell-based proliferation assays.

In 2011, the compound was licensed to Aslan Pharmaceuticals by Array BioPharma worldwide for the treatment of solid tumors, initially targeting patients with gastric cancer through a development program conducted in Asia.

In 2015, orphan drug designation was assigned to the compound in the U.S. for the treatment of cholangiocarcinoma.

SEE NMR ………….http://www.medkoo.com/Product-Data/Varlitinib/Varlitinib-QC-KB20121128web.pdf

……………..

https://www.google.co.in/patents/US20050043334

Example 52

(R)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (R)-2-aminopropan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 53

(S)-N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine

Prepared using (S)-2-amino-propan-1-o1. MS APCI (+) m/z 467, 469 (M+1, Cl pattern) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H), 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

………………

PATENT

http://www.google.co.in/patents/WO2005016346A1?cl=en

Example 52

R VN4-r3-Chloro-4-(^‘thiazol-2-v-metho-xy)-phenyll-N6-(4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoUne-4,6-diamine

[00194] Prepared using (R)-2-aminopropan- 1 -ol. MS APCI (+) m/z 467, 469

(M+l, CI pattern) detected; 1H NMR (400 mHz, DMSO-D6) δ 9.53 (s, IH), 8.47 (s, IH), 8.09 (s, IH), 7.86 (d, IH), 7.81 (d, IH), 7.77 (d, IH), 7.69 (m, 3H), 7.32 (d, IH), 7.02 (s, IH), 5.54 (s, 2H), 4.47 (m, IH), 3.99 (m, IH), 3.90 (m, IH), 1.18 (d, 3H). Example 53

(S)-N4-|^“3-Chloro-4- thiazol-2-ylmethoxy)-phenyll-N6-(^‘4-methyl-4,5-dihvdro-oxazol- 2-yl)-quinazoline-4,6-diamine [00195] Prepared using (S)-2-amino-propan- 1 -ol. MS APCI (+) m z 467, 469

………

CAUTION a very similar molecule but not same

NOTE……..METHYL NEXT TO OXYGEN ATOM

Design, Synthesis and Bioactivities Evaluation of Novel Quinazoline Analogs Containing Oxazole Units

Xuehui Hou¹,
Jingyu Zhang²,
Xuan Zhao²,
Liming Chang²,
Ping Hu^1,* and
Hongmin Liu^3,*

DOI: 10.1002/cjoc.201400271,…………http://onlinelibrary.wiley.com/doi/10.1002/cjoc.201400271/abstract;jsessionid=04211D7526D97240F44E4355C6C57F50.f01t01

http://onlinelibrary.wiley.com/store/10.1002/cjoc.201400271/asset/supinfo/cjoc_201400271_sm_suppl.pdf?v=1&s=8dd0bf6d7ee4d3d6bf8503fef49bafc69220c931

CAUTION …THIS IS NOT SAME

A novel type of quinazoline derivatives, which were designed by the combination of quinazoline as the backbone and oxazole scaffold as the substituent, have been synthesized and their biological activities were evaluated for anti-proliferative activities and EGFR inhibitory potency. Compound 12b demonstrated the most potent inhibitory activity (IC₅₀=0.95 µmol/L for EGFR), which could be optimized as a potential EGFR inhibitor in the further study. The structures of the synthesized quinazoline analogs and all intermediates were comfirmed by ¹H and ¹³C NMR, 2D NMR spectra, IR spectra and MS spectra.

12c: Employing the same method as above, compound 12c was prepared and the amino alcohol was (S)-2-amino-propan-1-ol. Yellow solid, yield 52 %. m.p. 243-244 °C; [α] 20D =﹢22.5 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.54 (s, 1 H), 8.46 (s, 1 H), 8.06 (s, 2 H), 7.85 (d, 2 H, J=3.3 Hz), 7.79 (d, 2 H, J=3.3 Hz), 7.75 (d, 1 H, J=8.9 Hz), 7.64 (d, 1 H, J=8.3 Hz), 7.30 (d, 1 H, J=9.0 Hz), 5.54 (s, 2 H), 4.76 (m, 1 H), 3.72 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.15 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.2 (M+H).

12d: Employing the same method as above, compound 12d was prepared and the amino alcohol was (R)-2-amino-propan-1-ol. Yellow solid, yield 60%. m.p. 242-243 °C; [α] 20D = ﹣22.3 ° (c 1.0, CH3CN); 1 H NMR (DMSO-D6): δ 9.52 (s, 1 H), 8.80 (s, 1 H), 8.52 (dd, 1 H, J=2.7 Hz, J=8.9 Hz), 8.45 (s, 1 H), 8.30 (s, 1 H), 8.07 (s, 1 H), 7.85 (d, 1 H, J=3.2 Hz), 7.79 (d, 1 H, J=3.2 Hz), 7.75 (s, 1 H), 7.63 (d, 1 H, J=8.2 Hz), 7.31 (d, 1 H, J=9.0 Hz), 5.53 (s, 2 H), 4.76 (m, 1 H), 3.81 (s, 1 H), 3.19 (s, 1 H), 1.34 (d, 3 H, J=6.2 Hz). 13C NMR (DMSO-D6) δ: 165.8, 156.9, 152.0, 148.8, 145.3, 142.6, 134.3, 128.7, 128.0, 123.5, 121.7, 121.3, 121.0, 115.6, 114.6, 72.5, 67.7, 63.0, 29.8, 29.0, 20.0, 13.9. IR (KBr) ν: 3439, 3278, 3101, 2925, 1660, 1631, 1601, 1557, 1500, 1428, 1404, 1384, 1329, 1291, 1257, 1225, 1052 cm-1. Anal. calcd for C22H19N6O2SCl: C 55.59, H 4.10, N 18.00, O 6.85; found C 55.55, H 4.13, N 18.02, O 6.78; MS (ESI) m/z: 467.20 (M+H).

The above paper allows you to synthesize the key amino int 11 ………N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

this can be applied to varlitinib till int 11

6-Nitro-4-hydroxyquinazoline (3)

2-amino-5-nitrobenzoic acid (5.46 g, 30 mmol) was added to a 250 mL flask equipped with a reflux condenser. Then 50 mL formamide was added. The mixture was heated with vigorous stirring at 160 °C for 3 h. After cooling the solution was poured in ice-water to give 3 in almost pure form (Yellow solid 4.70 g, yield 82.0%). m.p. 317-318 °C; 1 H NMR (DMSO-d6): δ 12.74 (1 H, s, OH, exchangeable), 8.78 (1 H, d, J=2.4 Hz), 8.53 (1 H, dd, J=2.6 Hz, 9.0 Hz), 8.30 (s, 1 H), 7.84 (1 H, d, J=9.0 Hz); 13C NMR (DMSO-d6) δ: 160.1, 152.9, 148.9, 145.0, 129.1, 128.3, 122.7, 121.9. IR (KBr) ν: 3172, 3046, 2879, 1674, 1615, 1577, 1514, 1491, 1469, 1343, 1289, 1242, 1167, 1112, 928, 920, 901, 803, 753, 630, 574, 531 cm-1. Anal. calcd for C8H5N3O3: C 50.27, H 2.64, N 21.98; found C 50.30, H 2.65, N 21.96; MS (ESI) m/z: 189.97 (M-H).

13C NMR OF 3 IN DMSOD6

4-chloro-6-Nitroquinazoline (4)

In a 100 mL flask equipped with a reflux condenser, 6-nitroquinazolin-4-one (2.86 g, 15 mmol) and thionyl chloride (SOCl2) 25 mL were added. The mixture was heated under reflux with vigorous stirring for 2 h. After the solution was clear, the reaction mixture was heated for another 2 h. Then, 150 mL of ice MeOH was dropped into it carefully, the mixture was extracted with CH2Cl2. The organic layer was S3 dried under MgSO4, filtered and the solvent removed to give 4-chloro-6-nitroquinazoline (4). Yellow solid 2.45 g, yield 78%. m.p. 134-135 °C; 1 H NMR (DMSO-d6): δ 8.80 (1 H, d, J=3.0 Hz), 8.54(1 H, dd, J=2.7 Hz, 9.0 Hz), 8.35(s, 1 H), 7.87 (1 H, d, J= 9.0 Hz); 13C NMR (DMSO-d6) δ: 160.0, 152.5, 149.1, 145.1, 128.7, 128.4, 122.7, 122.0. IR (KBr) ν: 3431, 3082, 3038, 2664, 2613, 2567, 1724, 1685, 1676, 1646, 1617, 1578, 1526, 1468, 1359, 1346, 1269 cm-1. Anal. calcd for C8H4N3O2Cl: C 45.84, H 1.92, N 20.05, O 15.27; found C 45.81, H 1.97, N 20.02, O 15.21; MS (ESI) m/z: 207.96 (M-H).

nmr1 4 nmr dmsod6

13C NMR OF4 IN DMSOD6

Thiazol-2-yl-methano1 (6)

Sodium borohydride (16.0 g, 140 mmol) was added to a stirred solution of thiazole-2-carbaldehyde (24.2 g, 214 mmol) in MeOH (400 mL) at 0 °C . The reaction mixture was warmed to room temperature. After 1 hour, the reaction mixture was quenched by the addition of water and the organics were removed by concentration. The resulting aqueous mixture was extracted with EtOAc. The combined organic extracts were dried under Na2SO4 and concentrated to give thiazol-2-yl-methano1 (23.39 g, 95%). bp:75-76 °C (0.2 mmHg) [lit.[19] bp:70-80 °C (0.2 mmHg)]; m. p. 63-64 °C. 1 H NMR (CDCl3) δ 4.91 (s, 2 H), 5.1(br, l H), 7.28(d, 1 H, J=3.2 Hz), 7.68 (d, 1 H, J=2.9 Hz). IR (KBr) ν: 3135, 3099, 3082, 2814, 1509, 1446, 1351, 1189, 1149, 1073, 1050, 977, 775, 745, 613, 603 cm-1. Anal. calcd for C4H5NOS: C 41.72, H 4.38, N 12.16; found C 41.74, H 4.33, N 12.18; MS (ESI) m/z: 116.11 (M+H).

nmr1 6 in dmsod6 1H NMR

2-((2-Chloro-4-nitrophenoxy)methyl)thiazole (8)

2-(2-chloro-4-nitro-phenoxymethy1)-thiazole was prepared by adding thiazol-2-yl-methanol (5.48 g, 47.65 mmol) to a slurry of sodium hydride (2.42 g of a 60% dispersion in oil, 60.5 mmol) in THF (50 ml) at 0 °C After several minutes, 2-chloro-1-fluoro- 4-nitro-benzene (7.58 g, 43.60 mmol) was added and the reaction mixture warmed to room temperature. The reaction mixture was stirred at room temperature for 3 h, and 60 °C for 16 h. After cooling to room temperature, the reaction mixture was poured into 300 mL water. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(2- chloro-4-nitrophenoxymethy1)-thiazole (11.06 g, 86%) which was used in next step without further purification. m.p. 170-171 °C; 1 H NMR (DMSO-d6): δ 8.35 (1 H, d, J=2.8 Hz), 8.25 (1 H, dd, J=2.8 Hz, 9.15 Hz), 7.87 (1 H, d, J=3.3 Hz), 7.83(1 H, d, J=3.3 Hz), 7.54 (1 H, d, J=9.2 Hz), 5.73(s, 1 H); 13C NMR (DMSO-d6) δ: 164.2, 158.5, 143.2, 141.7, 125.9, 124.9, 122.4, 122.2, 114.6, 68.4; IR (KBr) ν: 3112, 3009, 1587, 1509, 1500, 1354, 1319, 1284, 1255, 1154, 1125, 1054, 1006, 894, 780, 746, 728 cm-1. Anal. calcd for C10H7N2O3SCl: C 44.37, H 2.61, N 10.35, O 17.73; found C 44.31, H 2.67, N 10.29; MS (ESI) m/z: 268.89 (M-H).

1H NMR 8 DMSOD6

13C NMR OF 8 IN DMSOD6

3-Chloro-4-(thiazol-2-ylmethoxy)aniline (9)

In a flask equipped with a reflux condenser, the compound 8 15.00 g (55.6 mmol), reduced zinc powder 14.44 g (222.0 mmo1, 4 eq), saturated ammonia chloride (5 mL) and methanol (100 mL) were mixed. The mixture was stirred at a temperature of 40 °C for 1.5 h. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 13.21 g, yield 99%. m.p. 60-61 °C; 1 H NMR (DMSO-d6): δ 7.80 (1 H, d, J=3.3 Hz), 7.75 (1 H, d, J=3.3 Hz), 6.96 (1 H, d, J=8.8 Hz), 6.64(1 H, d, J=2.7 Hz), 6.46 (1 H, dd, J=2.7 Hz, J=8.7 Hz), 5.30 (s, 2 H), 5.04 (s, 2 H, NH2, exchangeable); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.80, 123.1, 121.5, 117.7, 115.2, 113.6, 69.1. IR (KBr) ν: 3322, 3192, 3112, 1607, 1499, 1457, 1436, 1291, 1274, 1221, 1191, 1144, 1057, 1027, 857, 797, 767, 733, 584 cm-1. Anal. calcd for C10H9N2OSCl: C 49.90, H 3.77, N 11.64, O 6.65; found C 49.95, H 3.76, N 11.66, O 6.60; MS (ESI) m/z: 239.01 (M-H).

1H NMR DMSOD6 OF 9

13C NMR OF 9 IN DMSOD6

N-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-6-nitro- quinazolin-4-amine（10）

In a flask equipped with a reflux condenser, 6-nitro-4-chloro- quinazoline 8.0 g (38.3 mmol) and 3-Chloro-4-(thiazol-2-ylmethoxy)aniline 8.9 g (37.0 mmol) were dissolved into 150 mL of THF, and the solution was refluxed for 3 h.Then a lot of yellow solid was deposited. Then it was filtered affording to yellow solid 12.8 g, yield 81%. m.p. 183-184 °C (decompose); 1 H NMR (DMSO-d6): δ 11.97(s, 1 H, exchangeable), 9.84 (s, 1 H), 9.00 (s, 1 H), 8.76 (1 H, d, J=9.1 Hz), 8.12-8.14 (m, 1 H), 7.94 (1 H, d, J=2.3 Hz), 7.87 (1 H, d, J=3.2 Hz), 7.81 (1 H, d, J=3.2 Hz), 7.44 (1 H, d, J=9.0 Hz), 7.69 (1 H, dd, J=2.5 Hz, J=8.9 Hz), 5.61 (s, 2 H); 13C NMR (DMSO-d6) δ: 166.8, 145.1, 144.1, 142.8, 123.1, 121.5, 117.7, 115.2, 113.7, 69.1. IR (KBr) ν: 3442, 3100, 1636, 1618, 1570, 1552, 1523, 1492, 1442, 1400, 1377, 1344, 1301, 1267, 1069, 805 cm-1. Anal. calcd for C18H12N5O3SCl: C 52.24, H 2.92, N 16.92, O 11.60; found C 52.26, H 2.93, N 16.96, O 11.58; MS (ESI) m/z: 412.84 (M-H).

1H NMR DMSOD6 OF 10

13C NMR OF 10 IN DMSOD6

N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)quinazoline-4,6-diamine (11)

In a flask equipped with a reflux condenser, the compound 10 5.00 g (12.1 mmol), reduced zinc powder 3.2 g (48.5 mmo1, 4 eq), saturated ammonia chloride (3 mL) and methanol (60 mL) were mixed. The mixture was stirred at room temperature for 30 min. Then the zinc powder was filtered off, the filtrate was concentrated to obtain yellow solid 4.58 g, yield 98%. m.p. 197-198 °C (decompose); 1 H S4 NMR (DMSO-d6): δ 9.33(s, 1 H, exchangeable), 8.31 (s, 1 H), 8.05 (d, 1 H, J=2.6 Hz), 7.85 (d, 1 H, J=3.3 Hz), 7.79 (1 H, d, J=3.3 Hz), 7.73 (1 H, dd, J=2.5 Hz, J=9.0 Hz), 7.51 (1 H, d, J=8.9 Hz), 7.30 (1 H, d, J=2.4 Hz), 7.29 (1 H, d, J=4.7 Hz), 7.23 (1 H, dd, J=2.3 Hz, J=8.9 Hz), 5.57 (s, 2 H, exchangeable), 5.52 (s, 2 H); 13C NMR (DMSO-d6) δ: 165.9, 155.8, 149.7, 148.5, 147.3, 142.6, 142.5, 134.6, 128.7, 123.6, 123.2, 121.4, 121.3, 121.1, 116.5, 114. 7, 100.9, 67.8. IR (KBr) ν: 3443, 3358, 3211, 3100, 1631, 1596, 1577, 1560, 1530, 1494, 1431, 1383, 1217, 910 cm-1. Anal. calcd for C18H14N5OSCl: C 56.32, H 3.68, N 18.24, O 4.17; found C 56.34, H 3.70, N 18.22, O 4.14; MS (ESI) m/z: 382.66 (M-H).

11 1HNMR DMSOD6

13C NMR OF 11 IN DMSOD6

Construction finally as per patent ……….US20050043334

Treatment of N4-[3-chloro-4-(thiazol-2-ylmethoxy)phenyl]quinazoline-4,6-diamine (11) with 1,1′-thiocarbonyldiimidazole , followed by condensation with 2(R)-amino-1-propanol in THF/CH2Cl2 affords thiourea derivative , which finally undergoes cyclization in the presence of TsCl and NaOH in THF/H2O to furnish varlitinib .

ASLAN Pharmaceuticals
Address: 10 Bukit Pasoh Rd, Singapore 089824

Phone:+65 6222 4235

Map of ASLAN Pharmaceuticals

carl fith

Mr Carl Firth, CEO, Aslan Pharmaceuticals, Singapore (left) and Mr Dan Devine, CEO, Patrys, Australia (right)

///////ASLAN001, varlitinib, ASLAN Pharmaceuticals, Orphan Designation, ARRY-534, ARRY-334543 , PHASE 2, ORPHAN DRUG DESIGNATION, array

Benzyl 3-deoxy-3-(3,4,5-trimethoxybenzylamino)-β-L-xylopyranoside

Uncategorized Comments Off

Aug 202015

The title compound was synthesized by opening the epoxide of benzyl 2,3-anhydro-β-L-ribopyranoside with 3,4,5-trimethoxybenzylamine (Scheme 1). The three broad peaks in the 1 H-NMR due to one –NH at δ 2.20 ppm, and two –OH at δ 5.00 ppm and 5.26 ppm, disappeared upon D2O exchange. The chemical shifts of the sugar hydrogens, along with COSY and HMBC were used to assign C7, C1″, C2″, C3″, C4″, C5″ and C7′ atoms. The coupling constant between H-1″ and H-2″ on the sugar ring was found to be 7.98 Hz, indicating that the protons at the 1- and 2-positions were in axial positions and that the molecule exists in solution in 1 C4 conformation (Scheme 1). The coupling constant was similar to related analogs [14,15]. The coupling constant between H-2” and H-3” was found to be 9.12 Hz. The coupling constant between the pro-R and pro-S hydrogens on C7 was found to be 12.24 Hz. The 13C had five pairs of atoms with the same chemical shift. There were three pairs of carbon atoms on the 3,4,5-trimethoxybenzyl ring ( two ortho- and two meta-, and two equivalent methoxy groups) that had similar chemical shifts. On the benzyl group, chemical shifts of two pairs of carbon atoms (two ortho- and two meta-) were observed.

PREPN

Benzyl 2,3-anhydro-β-L-ribopyranoside (1) was obtained from L-arabinose in five steps using a previously reported synthetic route [14]. To a mixture of benzyl 2,3-anhydro-β-L-ribopyranoside 1 (0.15 g, 0.68 mmol) and 3,4,5-trimethoxybenzylamine 2 (180 mL, 0.91 mmol) was added ethyl alcohol (3 mL). After refluxing the mixture for 16 h and cooling at room temperature for 12 h, white crystals (needles) formed. Recrystallization from hexane/ethyl acetate mixture (3:2, v/v) produced a pure compound (0.206 g, 72%,

m.p. 158–160 °C);

[α]D 26 +50° (c 1, CHCl3).

C22H29NO7 Calculated: C 62.99; H, 6.97; N, 3.34; O, 26.70 Found: C 62.89; H, 7.01; N, 3.29; O, 26.65

1 H-NMR (400 MHz, Me2SO-d6)

δ 2.20 (bs, 1H, –NH),

2.41 (t, J = 9.12, 7.98 Hz, 1H, H-3),

3.21 (m, 2H),

3.45 (bs, 1H),

3.65 (s, 3H, –OCH3),

3.75 (b, 1H),

3.80 (s, 6H, 2-OCH3),

3.97 (m, 2H),

4.31 (d, J = 7.98 Hz, 1H, H-1),

4.61 (d, J = 12.24 Hz, 1H, –OCH2Ar),

4.80 (d, J = 12.24 Hz, 1H, –OCH2Ar),

5.00 (bs, 1H, –OH), 5.26 (bs, 1H, –OH).

13C-NMR (100 MHz, Me2SO-d6),

δ 53.22 (C-7′),

56.61 (–OCH3),

60.81 (–OCH3),

65.11 (C-3″),

67.37 (C-5″),

70.14 (C-4″),

70.41 (C-7),

73.00 (C-2″),

103.90 (C-1″),

105.80, 128.23, 128.40, 129.00, 136.80, 138.23, 138.93, 153.52.

Nmr predict

Molbank 2013, 2013(1), M793; doi:10.3390/M793

Benzyl 3-deoxy-3-(3,4,5-trimethoxybenzylamino)-β-L-xylopyranoside

Fulgentius Nelson Lugemwa

Department of Chemistry, Pennsylvania State University-York, 1031 Edgecomb Avenue, York, PA 17403, USA

http://www.mdpi.com/1422-8599/2013/1/M793

//////epoxide ring-opening, 3,4,5-trimethoxybenzylamine, benzyl 2,3-anhydro-β-L-ribopyranoside

Lusutrombopag….Oral thrombopoietin (TPO) mimetic

Phase 3 drug, Uncategorized Comments Off

Aug 202015

Lusutrombopag

(E)-3-[2,6-dichloro-4-[[4-[3-[(1S)-1-hexoxyethyl]-2-methoxyphenyl]-1,3-thiazol-2-yl]carbamoyl]phenyl]-2-methylprop-2-enoic acid

(S)-(-)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid

(2E)-3-{2,6-Dichloro-4-[(4-{3-[(1S)-1-(hexyloxy)ethyl]-2-methoxyphenyl}-1,3-thiazol-2-yl)carbamoyl]phenyl}-2-methylacrylic acid

UNII 6LL5JFU42F, CAS 1110766-97-6,

D10476, MW591.546 , [US2010267783], MF C₂₉H₃₂Cl₂N₂O₅S, S-888711

Shionogi & Co., Ltd., 塩野義製薬株式会社 INNOVATOR

Optically active compound (C-3B) Melting point: 142-145°C…………….EP2184279B1

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)………….EP2184279B1

Optical rotation: -7.0 ± 0.5 degrees (CHCl₃, c = 1.040, 21°C), NMR (CDCl₃) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)………EP2184279B1

Thrombopoietin receptor agonist, Oral thrombopoietin (TPO) mimetic

24 Mar 2015 Shionogi plans a phase III trial in Thrombocytopenia (in patients with chronic liver disease) in USA (NCT02389621)
31 Dec 2014 Preregistration for Thrombocytopenia in Japan (PO)
08 Nov 2013 Phase II development is ongoing in the US and the Europe

Process for preparing intermediates of an optically active 1,3-thiazole containing thrombopoietin receptor agonist Also claims crystalline forms of lusutrombopag intermediates and a process for preparing lusutrombopag. Shionogi is developing lusutrombopag, a small-molecule thrombopoietin mimetic, as an oral tablet formulation for treating thrombocytopenia.

In December 2014, an NDA was submitted in Japan. In May 2015, the drug was listed as being in phase III development for thrombocytopenia in the US and Europe.

The lusutrombopag, a low molecular-human thrombopoietin receptor agonist, its chemical formula, “(E) -3- [2,6-Dichloro-4- [4- [3 – [(S) -1-hexyloxyethyl] – 2-methoxyphenyl] -thiazol- 2-ylcarbamoyl] -phenyl] is a -2-methylacrylic acid “. lusutrombopag is represented by the following chemical structural formula.

Eltrombopag is represented by the following chemical structural formula.

Avatrombopag is represented by the following chemical structural formula.

Totrombopag choline is represented by the following chemical structural formula.

https://www.google.co.in/patents/EP2184279B1?cl=en

C 3B IS THE COMPD OF ROT (-) AND S, E FORM

According to the same method as in Example 1, an optically active compound (C-3A) and an opticallly active compound (C-3B) were synthesized from (RS)-(E)-3-(2,6-dichloro-4-{4-[3-(1-hexyloxyethyl)-2-methyloxyphenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methylacrylic acid (B-3) obtained in Reference Example 3.

Optically active compound (C-3A)Melting point: 139-141°C UNDESIRED

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82 – 0.87 (m, 3H) Optical rotaion +4.5 degrees (DMSO, c = 1.001, 25°C)

Optically active compound (C-3B)Melting point: 142-145°C DESIRED

NMR (DMSO-d6) δ ppm: 12.97 (brs, 1H), 8.29 (s, 2H), 7.90 (dd, 1H, J = 1.8 Hz, 7.5 Hz), 7.72 (s, 1H), 7.35 – 7.40 (m, 2H), 7.26 (t, 1H, J = 7.5 Hz), 4.82 (q, 1H, J = 6.3 Hz), 3.62 (s, 3H), 3.16 – 3.37 (m, 2H), 1.69 (s, 3H), 1.18 – 1.51 (m, 11H), 0.82-0.87 (m, 3H) Optical rotation -4.5 degrees (DMSO, c = 1.001, 25°C)

First step: Synthesis of (S)-1-(3-bromo-2-methyloxyphenyl)ethane-1-ol (17)

Using the same method as that of the first step of Example 3, the compound (17) was obtained from the compound (16) at a yield 77%.
Optical rotation: -23.5 ± 0.6 degrees (CHCl₃, c = 1.050, 21°C)
NMR (CDCl₃) θ ppm: 1.49 (3H, d, J = 6.6 Hz), 2.33 (1H, brs), 3.88 (3H, s), 5.19 (1H, q, J = 6.4 Hz), 7.01 (1H, t, J = 7.9 Hz), 7.40 (1H, dd, J = 7.7 Hz, J = 1.1 Hz), 7.46 (1H, dd, J = 8.0 Hz, J = 1.4 Hz)

Second step: Synthesis of (S)-1-bromo-3-(1-hexyloxyethyl)-2-methyloxybenzene (18)

Using the same method as that of the second step of Example 3, the compound (18) was obtained from the compound (17) at a yield of 96%.
Optical rotation: -29.8 ± 0.6 degrees (CHCl₃, c = 1.055, 21°C)
NMR (CDCl₃) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.42 (3H, d, J = 6.5 Hz), 1.54 (2H, m), 3.29 (2H, m), 3.85 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 7.02 (1H, t, J = 7.9 Hz), 7.39 (1H, dd, J = 7.8 Hz, J = 1.7 Hz), 7.45 (1H, dd, J = 7.9 Hz, J = 1.7 Hz)

Third step and fourth step: Synthesis of (S)-4-(3-(1-hexyloxyethyl)-2-methyloxyphenyl)thiazole-2-amine (20)

Using the same method as that of the fourth step of Example 3, the compound (19) was obtained from the compound (18), subsequently according to the same method as that of the fourth step, the compound (20) was obtained.

Compound (19)

NMR (CDCl₃) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2-1.4 (6H, m), 1.45 (3H, d, J = 6.6 Hz), 1.55 (2H, m), 3.29 (2H, m), 3.78 (3H, s), 4.73 (2H, m), 4.80 (1H, q, J = 6.4 Hz), 7.24 (1H, t, J = 7.8Hz), 7.52 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.65 (1H, dd, J = 7.7 Hz, J = 1.8 Hz)

Compound (20)

Optical rotation: -4.2 ± 0.4 degrees (DMSO, c = 1.025, 21°C)
NMR (CDCl₃) δ ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, m), 1.35 (3H, d, J = 6.5 Hz), 1.48 (2H, m), 3.25 (2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz)

Using the same method as that of the fifth step of Example 3, the compound (21) was obtained from the compound (20) at a yield of 94%.
Optical rotation: +4.7 ± 0.4 degrees (CHCl₃, c = 1.07, 21°C)
NMR (CDCl₃ ) δ ppm: 0.87 (3H, t, J = 6.9 Hz), 1.2 – 1.35 (6H, m), 1.38 (3H, t, J = 7.1
Hz), 1.44 (3H, d, J = 6.4 Hz), 1.57 (2H, m), 1.77 (3H, d, J = 1.4 Hz), 3.30 (2H, m), 3.59 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 4.83 (1H, q, J = 6.4 Hz), 7.17 (1H, t, J = 7.7 Hz), 7.42 (1H, d, J = 1.7 Hz), 7.42 (1H, dd, J = 7.7 Hz, J = 1.8 Hz), 7.51 (1H, s), 7.67 (1H, dd, J = 7.6 Hz, J = 1.7 Hz), 7.89 (2H, s), 10.30 (1H, brs)

Sixth step: Synthesis of (S)-(E)-3-(2,6-dichloro-4-(4-(3-(1-hexyloxyethyl)-2-metyloxyphenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-3B)

Using the same method as that of the sixth step of Example 3, the compound (C-3B) was obtained from the compound (21) at a yield of 80%.

Optical rotation: -7.0 ± 0.5 degrees (CHCl₃, c = 1.040, 21°C)
NMR (CDCl₃) δ ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, m), 1.48 (3H, d, J = 6.4 Hz), 1.52 – 1.64 (2H, m), 1.86 (3H, d, J = 1.4Hz)), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs)
Results of powder X-ray deffraction are shown in Fig. 5.
Diffraction angle of main peak: 2θ = 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4 degrees

WO2005014561/EP1655291A1

https://www.google.co.in/patents/EP1655291A1?cl=en

WO2014003155, claiming a composition comprising lusutrombopag, useful for treating thrombocytopenia.

https://www.google.co.in/patents/US20150148385?cl=en

WO 2015093586

Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound

(Step 1) Synthesis of compound (VII ‘) 　under a nitrogen atmosphere, it was dissolved compound 1 (2.00kg) in 1,2-dimethoxyethane (28.0kg). 25% LDA tetrahydrofuran – heptane – ethyl benzene solution (13.20kg) was added dropwise over 1 hour at -55 ℃, and stirred for 30 minutes. It was added dropwise over 40 minutes to 1,2-dimethoxyethane (3.0kg) solution of N- formyl morpholine (3.74kg) at -55 ℃, and stirred for 1 hour. 1,2-dimethoxyethane (3.0kg) solution of 2-phosphono-propanoic acid triethyl (3.74kg) was added dropwise over 45 minutes at 0 ℃, and stirred for 2 hours. 35% aqueous solution of sulfuric acid (15.8kg) was added dropwise over 40 minutes to the reaction solution. Water (16.0kg) was added and extracted. The resulting organic layer was washed with water (8.0kg), and the solvent was evaporated under reduced pressure. Acetonitrile (16.0kg) was added, and the mixture was stirred for 1 hour at 25 ℃, and the mixture was stirred and cooled to 0 ℃ 5 hours and 30 minutes. The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (16.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Over 1 hour and then cooled to 30 ℃, and the mixture was stirred for 45 minutes. Over 40 minutes and then cooled to 5 ℃, and the mixture was stirred for 3 hours.The precipitated crystals were collected by filtration, and washed with 5 ℃ acetonitrile (3.2kg). The resulting crystals it was dissolved in acetonitrile (13.0kg) at 75 ℃. It was cooled to 60 ℃, and the mixture was stirred for 30 minutes. Furthermore, up to 30 ℃ over 1 hour and then cooled and stirred for 70 minutes. Over 30 minutes and then cooled to 5 ℃, and the mixture was stirred for 4 hours. I precipitated crystals were collected by filtration. Washed with 5 ℃ acetonitrile (3.2kg), and dried to give the compound (VII ‘) (1.63kg, 51.2% yield). NMR (CDCl ₃ ) delta ppm: 8.07 (s, 2H), 7.47 (s, 1H), 4.32 (Q, 2H, J = 7.0 Hz), 1.79 (s, 3H), 1.38 (t, 3H, J = 7.0 Hz) 　Results of powder X-ray diffraction and I shown in Figure 1 and Table 3. [Table 3] 　In the powder X-ray diffraction spectrum, diffraction angle (2θ): 8.1 ± 0.2 °, 16.3 ± 0.2 °, 19.2 ± 0.2 °, 20.0 ± 0. 2 °, the peak was observed at 24.8 ± 0.2 °, and 39.0 ± 0.2 ° degrees.

(Synthesis of Compound (XI ‘))

(Step 2) Synthesis of Compound 4 　under a nitrogen atmosphere over Compound 3 (3.00kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (11.40kg) 1 hour at 25 ℃ in The dropped, and stirred for 2 hours. 1mol / L isopropylmagnesium chloride in tetrahydrofuran solution (0.56kg) was added at 25 ℃, and stirred for 2 hours. To the reaction mixture N- methoxymethyl -N- methylacetamide the (1.45kg) was added dropwise over at 25 ℃ 40 minutes, and stirred for 80 minutes. 7% hydrochloric acid (9.7kg) was added to the reaction mixture, and the mixture was extracted with toluene (11.0kg). The resulting organic layer twice with water (each 7.5kg) washed, the solvent was evaporated under reduced pressure to give Compound 4 (2.63kg). NMR (CDCl ₃ ) delta ppm: 7.69 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.55 (dd, 1H, J = 7.7 Hz, J = 1.5 Hz), 7.05 (t, 1H, J = 7.7 Hz), 3.88 (s, 3H), 2.64 (s, 3H) ppm:

(Step 3) Synthesis of Compound 5 　Under a nitrogen atmosphere, chloro [(1S Compound 4 (2.63kg), 2S) -N- ( p- toluenesulfonyl) -1,2-diphenyl-ethane diamine] (p- cymene) ruthenium (II) (28.6g), it was added to tetrahydrofuran (1.3kg) and triethylamine (880.0g). Formic acid (570.0g) was added dropwise over 6 hours at 40 ℃, and stirred for 1 hour. In addition 3.5% hydrochloric acid (14.4kg) to the reaction mixture, and the mixture was extracted with toluene (13.0kg).The organic layer was washed with 3.5% hydrochloric acid (14.4kg) and water (7.5kg), the solvent was concentrated under reduced pressure to obtain a toluene solution of Compound 5 (4.44kg).

(Step 4) Synthesis of Compound 6 　under a nitrogen atmosphere, it was a potassium hydroxide (6.03kg) was dissolved in water (6.0kg). To the solution, it added tetrabutylammonium bromide (182.0g) and toluene solution of Compound 5 (4.44kg). 1-bromo-hexane (2.79kg) was added dropwise over 1 hour at 60 ℃, and the mixture was stirred for 4 hours. And extracted by adding water (4.4kg) to the reaction solution. The resulting organic layer was filtered through powdered cellulose and extracted with toluene (3.0kg) and water (7.6kg) to the filtrate. The solvent it was evaporated under reduced pressure from the organic layer. Toluene operation of evaporated under reduced pressure and the solvent by the addition of a (7.8kg) was repeated five times to obtain a toluene solution of Compound 6 (10.0kg).

(Step 5) Synthesis of Compound 7 　under a nitrogen atmosphere, magnesium powder (301.0g), in tetrahydrofuran (1.3kg), the compound in toluene (6.4kg) and 1mol / L isopropylmagnesium chloride in tetrahydrofuran (432.0g) 6 In addition of the toluene solution (0.50kg) at 30 ℃, and the mixture was stirred for 2 hours. Toluene solution of Compound 6 (9.50kg) was added dropwise over 3 hours at 50 ℃, and stirred for 2 hours. 1-bromo-hexane (746.0g) was added at 50 ℃, and the mixture was stirred for 1 hour. It was added dropwise over 1 hour at 5 ℃ toluene (5.3kg) solution of 2-chloro -N- methoxy -N- methyl-acetamide (1.78kg), and stirred for 1 hour. 3.7% hydrochloric acid (16.7kg) was added to the reaction mixture, and the mixture was extracted. The obtained organic layer was washed with water (15.0kg), and concentrated under reduced pressure to give a toluene solution of Compound 7 (8.25kg).

(Step 6) Synthesis of Compound (II ‘) 　under a nitrogen atmosphere, thiourea (1.03kg), in ethanol (1.2kg) and 65 ℃ toluene solution of compound 7 (8.25kg) in toluene (6.3kg) over 3 hours was added dropwise and stirred for 2 hours. The reaction solution was extracted by adding 0.7% hydrochloric acid (30.6kg), and washed twice with water (30.0kg). Ethanol in the organic layer (9.5kg), and extracted by addition of heptane (10.0kg) and 3.5% hydrochloric acid (5.9kg). The resulting aqueous layer with 4% hydrochloric acid (1.5kg) and ethanol (3.5kg) merged the aqueous layer was extracted from the organic layer, the ethanol was washed with heptane (10.0kg) (3.1kg) It was added. 8% aqueous sodium hydroxide (6.0kg) was added dropwise over at 5 ℃ 30 minutes, and stirred for 20 minutes. 8% aqueous sodium hydroxide (5.8kg) was added dropwise over a period at 5 ℃ 15 minutes.The precipitated crystals were collected by filtration, washed with 45% aqueous ethanol (10.9kg) and water (15.0kg) (crude crystals of Compound (II ‘)). The resulting crude crystals were dissolved in 50 ℃ in ethanol (8.1kg), over a period of 1 hour and then cooled to 10 ℃, and the mixture was stirred for 30 minutes. Water (10.0kg) over 2 hours was added dropwise and stirred for 30 minutes. The precipitated crystals were collected by filtration, washed with 50% aqueous ethanol (7.5kg) and water (10.0kg) (crystals of the compound after recrystallization from ethanol / water system (II ‘)). The resulting crystals were dissolved at 55 ℃ in toluene (1.6kg) and heptane (1.3kg), over 1 hour and cooled to 20 ℃, and stirred for 30 minutes. Heptane (6.3kg) over a period of 30 minutes was added dropwise and stirred for 15 minutes. The obtained crystals precipitated were collected by filtration, washed with a mixed solvent of toluene (0.3kg) and heptane (2.3kg), and dried to give compound (II ‘) (1.67kg, 44.5% yield) a (crystalline compound after recrystallization from toluene / heptane system (II ‘)).

NMR (CDCl ₃ ) delta ppm: 0.84 (3H, t, J = 7.0 Hz), 1.2 – 1.3 (6H, M), 1.35 (3H, D, J = 6.5 Hz), 1.48 (2H, M), 3.25 ( 2H, m), 3.61 (3H, s), 4.78 (1H, q, J = 6.4 Hz), 6.99 (2H, brs), 7.05 (1H, s), 7.16 (1H, t, J = 7.7 Hz), 7.27 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.81 (1H, dd, J = 7.6 Hz, J = 1.9 Hz) 　it is shown in Figure 2 and Table 4 the results of powder X-ray diffraction. [Table 4] 　In the powder X-ray diffraction spectrum, diffraction angle (2θ): 12.5 ± 0.2 °, 13.0 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0. 2 °, 23.0 ± 0.2 °, a peak was observed at 24.3 ± 0.2 ° degrees. 　Above, each of the compounds (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) crystallographic purity of the results of the , Fig. 3, I 4 and 5 as well as Table 5. [Table 5](HPLC was measured by the above method A.) 　As shown in the results of the above table, as compared to recrystallization from ethanol / water, recrystallized with toluene / heptane system, compounds having a high optical purity it is possible to manufacture a crystal of (II ‘). 　Next, the above-mentioned compound (II ‘) of the crude crystals, the ethanol / compound after recrystallization from water (II’) crystals and toluene / heptane compound after recrystallization from (II ‘) results of crystals of HPLC of the respectively, Fig. 6, I 7 and 8 and Table 6. [Table 6] (units, .N.D shows the peak area of the (%). is, .HPLC to indicate not detected was measured by the above method B.) 　As shown in the results of Table, with ethanol / water system Compared to recrystallization, recrystallization from toluene / heptane system is found to be efficiently remove organic impurities A and organic impurities B.

(Step 7) Compound ‘Synthesis of DMSO adduct of (VIII) 　Under a nitrogen atmosphere, the compound (II ‘) (1.50kg) and compound (VII’) (1.43kg) in ethyl acetate (17.6kg) and triethylamine (1.09kg) were sequentially added, was dissolved.Diphenyl phosphorochloridate the (1.46kg) was added dropwise over 1 hour at 50 ℃, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 25 ℃, after the addition of 2.6% hydrochloric acid (8.1kg), and extracted. The resulting organic layer to 6.3% aqueous solution of sodium hydroxide (3.2kg) and 14% aqueous sodium carbonate (5.2kg) was added and stirred for 20 minutes. Adjusted to pH7.5 with 8.3% hydrochloric acid and extracted. The organic layer it was washed with 4.8% sodium chloride aqueous solution (11.0kg). DMSO and (16.5kg) was added, and the mixture was concentrated under reduced pressure.DMSO and (5.8kg) was added, over a period at 40 ℃ 30 minutes was added dropwise water (0.9kg), and stirred for 1 hour. Over a period of 30 minutes, cooled to 25 ℃, and the mixture was stirred for 30 minutes. Over at 25 ℃ 30 minutes was added dropwise water (1.4kg), and the precipitated crystals were collected by filtration. After washing with 90% DMSO solution (10.0kg) and water (27.0kg), to obtain crystals of DMSO adduct and dried to Compound (VIII ‘) (2.98kg, 95.2% yield).

1H-NMR (CDCl ₃ ) delta: 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.34 (M, 6H), 1.37 (t, J = 7.1 Hz, 3H), 1.44 (D, J = 6.5 Hz , 3H), 1.52-1.59 (m, 2H), 1.77 (d, J = 1.3Hz, 3H), 2.62 (s, 6H), 3.28-3.34 (m, 2H), 3.59 (s, 3H), 4.31 ( q, J = 7.1Hz, 2H), 4.83 (q, J = 6.5Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.40-7.43 (m, 2H), 7.51 (s, 1H), 7.68 (dd, J = 7.7, 1.8Hz, 1H), 7.92 (d, J = 1.3Hz, 2H), 10.58 (s, 1H). 　The results of the powder X-ray diffraction and I are shown in Figure 9 and Table 7. [Table 7]

In the powder X-ray diffraction spectrum, diffraction angle (2θ): 5.2 ° ± 0.2 °, 7.0 ° ± 0.2 °, 8.7 ° ± 0.2 °, 10.5 ° ± 0.2 °, 12.3 ° ± 0.2 °, 14.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 19.3 ° ± 0.2 °, 22.5 ° peak was observed to ± 0.2 ° and 24.1 ° ± 0.2 °. 　TG / DTA analysis result it is shown in Figure 10. 　Then, each result of HPLC of concentrated dry solid and the above DMSO adduct crystals described in the following Reference Examples 1, 11 and 12, 13 and 14, and I are shown in Table 8. [Table 8] (unit, .HPLC showing peak areas of (%) was measured by the above methods C.) 　As shown in the results of the above Table, when compared with the extract, DMSO adduct of the compound (VIII ‘) The in the crystal, less residual organic impurities D, and it found to be about 56% removal.

(Step 8) 　under nitrogen atmosphere, DMSO adduct of the compound (VIII ‘) and (2.50kg) it was dissolved in ethanol (15.8kg). 24% sodium hydroxide aqueous solution (1.97kg) was added dropwise over a period at 45 ℃ 30 minutes to the solution and stirred for 3 hours. The reaction mixture was cooled to 25 ℃, water was added (20.0kg) and ethanol (7.8kg). 18% hydrochloric acid (2.61kg) was added dropwise over at 25 ℃ 30 minutes, followed by addition of seed crystals prepared according to the method described in Patent Document 23. After stirring for 3 hours and allowed to stand overnight. Thereafter, the precipitated crystals were collected by filtration, to give after washing with 50% aqueous ethanol solution (14.2kg), and dried to a compound (XI ‘) (1.99kg, 93.9% yield).

NMR (CDCl ₃ ) delta ppm: 0.87 (3H, t, J = 6.8 Hz), 1.2 – 1.4 (6H, M), 1.48 (3H, D, J = 6.4 Hz), 1.52 – 1.64 (2H, M), 1.86 (3H, d, J = 1.4Hz), 3.35 (2H, t, J = 6.7Hz), 3.55 (3H, s), 4.87 (1H, q, J = 6.3 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.41 (1H, s), 7.49 (1H, dd, J = 7.9 Hz, J = 1.6 Hz), 7.51 (1H, dd, J = 7.5 Hz, J = 1.8 Hz), 7.65 (1H, d, J = 1.4 Hz), 8.33 (2H, s), 13.4 (2H, brs) 　I is shown in Figure 15 the results of powder X-ray diffraction.

Patent Document 1: JP-A-10-72492 JP
Patent Document 2: WO 96/40750 pamphlet
Patent Document 3: JP-A-11-1477 JP
Patent Document 4: Japanese Unexamined Patent Publication No. 11-152276
Patent Document 5: International Publication No. 00/35446 pamphlet
Patent Document 6: JP-A-10-287634 JP
Patent Document 7: WO 01/07423 pamphlet
Patent Document 8: International Publication WO 01/53267 pamphlet
Patent Document 9: International Publication No. 02 / 059 099 pamphlet
Patent Document 10: International Publication No. 02/059100 pamphlet
Patent Document 11: International Publication No. 02/059100 pamphlet
Patent Document 12: International Publication No. 02/062775 pamphlet
Patent Document 13: International Publication No. 2003/062233 pamphlet
Patent Document 14: International Publication No. 2004/029049 pamphlet
Patent Document 15: International Publication No. 2005/007651 pamphlet
Patent Document 16: International Publication No. 2005/014561 pamphlet
Patent Document 17: JP 2005-47905 Japanese
patent Document 18: Japanese Patent Publication No. 2006-219480
Patent Document 19: Japanese Patent Publication No. 2006-219481
Patent Document 20: International Publication No. 2007/004038 pamphlet
Patent Document 21: International Publication No. 2007/036709 pamphlet
Patent Document 22: International Publication No. 2007/054783 pamphlet
Patent Document 23: International Publication No. 2009/017098 pamphlet

Non-Patent Document 1: Proceedings of the National Akademyi of Science of the United State of America (…. Proc Natl Acad Sci USA) 1992, Vol. 89, p 5640-5644.
Non-Patent Document 2: Journal of Organic (.. J. Org Chem) Chemistry 1984, Vol. 49, p 3856-3857.
Non-Patent Document 3: (.. J. Org Chem). Journal of Organic Chemistry, 1992, Vol. 57, p 6667-6669
Non-Patent Document 4:. Shinretto (Synlett) 2004 year Vol. 6, p 1092-1094

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CCCCCCOC(C)C1=CC=CC(=C1OC)C2=CSC(=N2)NC(=O)C3=CC(=C(C(=C3)Cl)C=C(C)C(=O)O)Cl

Gamendazole a novel drug candidate for male contraception.

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Aug 192015

Gamendazole

(E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid

trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)

(E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid

C₁₈H₁₁Cl₂F₃N₂O₂
mw415.193
RC-MC-110

Heat Shock Protein 90 (HSP90) Inhibitors

University of Kansas Innovator

Gamendazole is a novel drug candidate for male contraception. It is an indazole carboxylic acid derived from lonidamine (LND). Gamendazole produced 100% antispermatogenic effects at 25 mg/kg i.p. in rats, whereas 200 mg/kg was fatal for 60% of rats tested. Since gamendazole produced 100% efficacy, it was tested orally. At a dose of 6 mg/kg, 100% of rats were infertile 4 weeks after a single administration. Complete infertility was maintained for 2 weeks, followed by complete recovery in 4 of 7 rats. The other 3 never recovered fertility. Upon dosing 6 mg/kg orally for 7 days, it produced similar infertility results, but only 2 of 7 rats recovered fertility. There were no abnormalities in rates of conception or abnormal conception in rats who recovered fertility.

Pathology reports were conducted on gamendazole treated rats. At 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p., there were no remarkable findings, with no evidence of inflammation, necrosis, tumors, or hemorrhage. There was also a lack of observable behavioral effects at 25 mg/kg i.p., 6 mg/kg oral, and in animals that survived 200 mg/kg i.p. Gamendazole treatment had no effect on testosterone levels, and was reported to affect Sertoli cell function, leading to decreased levels of inhibin B. Low levels of inhibin B were correlated to the infertility of the rat

Female oral contraceptive drugs are widely available in the market by several trade names, including Altravera, Brevicon, Levora, and i-pill, whereas potentially safer, more convenient, and more effective oral male contraceptives are not yet commercially available. However, there are some experimental drugs.AF-2785 1, gamendazole 2, lonidamine 3, and adjudin 4 are most promising among the experimental

Experimental drugs.

Gamendazole was recently identified as an orally active antispermatogenic compound with antifertility effects. The cellular mechanism(s) through which these effects occur and the molecular target(s) of gamendazole action are currently unknown. Gamendazole was recently designed as a potent orally active antispermatogenic male contraceptive agent. Here, we report the identification of binding targets and propose a testable mechanism of action for this antispermatogenic agent. Both HSP90AB1 (previously known as HSP90beta [heat shock 90-kDa protein 1, beta]) and EEF1A1 (previously known as eEF1A [eukaryotic translation elongation factor 1 alpha 1]) were identified as binding targets by biotinylated gamendazole (BT-GMZ) affinity purification from testis, Sertoli cells, and ID8 ovarian cancer cells; identification was confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and Western blot analysis. BT-GMZ bound to purified yeast HSP82 (homologue to mammalian HSP90AB1) and EEF1A1, but not to TEF3 or HBS1, and was competed by unlabeled gamendazole. However, gamendazole did not inhibit nucleotide binding by EEF1A1.

Gamendazole binding to purified Saccharomyces cerevisiae HSP82 inhibited luciferase refolding and was not competed by the HSP90 drugs geldanamycin or novobiocin analogue, KU-1. Gamendazole elicited degradation of the HSP90-dependent client proteins AKT1 and ERBB2 and had an antiproliferative effect in MCF-7 cells without inducing HSP90. These data suggest that gamendazole may represent a new class of selective HSP90AB1 and EEF1A1 inhibitors. Testis gene microarray analysis from gamendazole-treated rats showed a marked, rapid increase in three interleukin 1 genes and Nfkbia (NF-kappaB inhibitor alpha) 4 h after oral administration. A spike in II1a transcription was confirmed by RT-PCR in primary Sertoli cells 60 min after exposure to 100 nM gamendazole, demonstrating that Sertoli cells are a target. AKT1, NFKB, and interleukin 1 are known regulators of the Sertoli cell-spermatid junctional complexes. A current model for gamendazole action posits that this pathway links interaction with HSP90AB1 and EEF1A1 to the loss of spermatids and resulting infertility.

Synthesis

…………………….

2-Halo benzoic acid is converted into aroyl chloride and then to aroyl cyanide in an overall yield of 82%. Aroyl cyanides 5 are converted to 2-halophenyl glyoxylate ester 7 via ketoamide 6 in 85% yields as shown in Scheme below. Direct conversion of aroyl cyanide 5 to ester 7 is also reported^[ U.S. Patent 4,596,885, 1986 .^] but with lesser yields.

Synthesis of 2-halophenylglyoxalate.

The 2-halophenylglyoxylate 7 esters are reacted with monosubstituted hydrazines 8 to give hydrazones 9. The monosubstituted hydrazones 9 are cyclized to give indazole esters 10. This cyclization is best conducted in the presence of DPPF · PdCl₂ in 94.54% yield as shown in Scheme below.

Synthesis of 1-substituted indazole-3-carboxylate.

The indazole-3-carboxylic esters 10 were reduced with sodium borohydride to alcohol 11 and were oxidized to aldehyde 12with MnO₂. The aldehyde is converted to acrylic acids with malonic acid (Knoevenagel condensation) to give 88–95.6% yield of the final compounds, as shown in Schemebelow.

Synthesis of AF-2785 and gamendazole.

Preparation of (E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid (R = CF₃) (Gamendazole) (2)

ChemSpider 2D Image | Gamendazole | C18H11Cl2F3N2O2

desired product 2 as a colorless solid (wt 5.32 g, yield 95.6%, HPLC purity 99.30%

DSC: 203.4 °C).

IR (KBr) (cm⁻¹): 3447, 1697, 1641, 1311, 1122, 872;

¹H NMR (400 MHz, DMSO): δ 5.90 (2H, s), 6.72 (1H, d,J = 16.22 Hz), 6.94 (1H, d, J = 8.34 Hz), 7.36–7.39 (1H, dd, J ₁ = 8.24 Hz, J ₂ = 1.42 Hz), 7.55 (1H, d, J = 8.56 Hz), 7.69 (1H, d,J = 1.46 Hz), 7.78 (1H, d, J = 16.22 Hz), 8.37 (1H, d, J = 8.63 Hz), 8.40 (1H, s), 12.61 (1H, s);

¹⁹F NMR (400 MHz, CDCl₃):δ − 59.97(CF₃);

¹³C NMR (100 MHz, DMSO): δ 50.05, 109.16, 118.73, 121.61, 122.76, 123.39, 123.98, 127.76, 128.11, 129.42, 131.26, 133.56, 133.65, 133.76, 134.10, 140.64, 140.70, 167.57.

MW for C₁₈H₁₁Cl₂F₃N₂O₂ calcd. 415.19; observed: 415.3 and 417.2. HRMS: calcd.: 415.0228, observed: 415.0225.

DOI:: 10.1080/00397911.2012.696306

Arava Veerareddy^a^*, Gogireddy Surendrareddy^a & P. K. Dubey^b

pages 2236-2241

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

Volume 43, Issue 16, 2013

http://www.tandfonline.com/doi/suppl/10.1080/00397911.2012.696306/suppl_file/lsyc_a_696306_sm3276.pdf

………………

http://www.google.com/patents/EP1786424A2?cl=en&dq=%22Gamendazole%22&source=uds

trans 3-[l- (l^-dichlorobenzy^-ό-trifluoromethyl-lH-indazol-S-ylj-acrylic acid (RC-MC-110) is provided.

EXAMPLE 2: Synthesis of a-ll-fl^-dichlorobenzyn-ό-trifluoromethyl-lH-indazol-S-yll-acrylic acid (RC-MC-110)

Step 1 : 2-(2-nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester.

Dimethyl malonate (59.7 g, 0.44 mol) was added dropwise to a stirred solution of potassium tert-butoxide (51 g, 0.44 mol) in dry t-butanol (500 mL). To the resultant suspension, a warm solution of 2-chloro-5-trifluoromethylnitrobenzene (50 g, 0.22 mol) in t-butanol (100 mL) was added and the mixture was refluxed for 6 h (reaction monitored by TLC). After completion of the reaction, most of the t-butanol was distilled off under vacuum, and chilled water was then added to the reaction mixture. The pH was adjusted to neutral with dilute hydrochloric acid, which resulted in the precipitation of the product. The mixture was stirred for 30 minutes and the product was filtered off (68 g, 95%). This material was used without further purification in the next step. A small amount was crystallized (EtOAc/hexane, 4:6) for analysis, to yield a yellow crystalline material, mp 65-67 ⁰C. ¹H NMR (CDCl₃) 8.30 (s, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 5.37 (s, 1 H), 3.80 (s, 6 H). MS (FAB) m/z: 322.1 (M⁺ + 1).

Step 2: (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester.

2-(2-Nitro-4-trifluoromethylphenyl)-malonic acid dimethyl ester (68 g, 0.21 mol) was dissolved in dimethyl sulfoxide (200 mL). Sodium chloride (34 g, 0.58 mol) and water (60 mL) were added and the mixture was stirred for 16-20 h at 120 ⁰C (reaction monitored by TLC). The reaction mixture was then cooled to room temperature and quenched into water, which caused precipitation of the product. After stirring for 30 minutes, the product (45 g, 80%) was isolated by filtration. The product was used without further purification in the next reaction. A small sample was crystallized (EtOAc/hexane, 2:8) for analysis, to yield yellow crystals, mp 104-105 ⁰C. ¹H

NMR (CDCl₃) 8.3 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 4.12 (s, 2 H), 3.60 (s, 3 H). MS (FAB) m/z: 275.2 (M⁺ + 1).

Step 3: (2-Acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester.

Hydrogenation and acetylation of (2-nitro-4-trifluoromethylphenyl)-acetic acid methyl ester (25 g, 0.095 mol) in the presence of 5% Pd-C (2.5 g, 50% wet) and acetic anhydride (38 g, 0.37 mol) in toluene (200 mL) was carried out under vigorous stirring at room temperature and atmospheric pressure for about 4-5 h (reaction monitored by TLC). The catalyst was removed by filtration and washed with toluene two times. The combined organics were evaporated in vacuo to yield the product (24.8 g, 95%), which was used without further purification in the next step. A small sample was crystallized from hexane to yield the product as a yellow solid, mp 92-94 ⁰C. H NMR (CDCl₃) 8.86 (s, 1 H), 8.21 (s, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1 H), 3.74 (s, 3 H), 3.68 (s, 2 H), 2.23 (s, 3 H). Step 4: ό-Trifluoromethyl-lH-indazole^-carboxylic acid methyl ester.

To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95 ⁰C. The mixture was then stirred for 0.5 h at 95 ⁰C, poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242 ⁰C. H NMR (DMSO-d-6) 8.25 (d, J = 8.5 Hz, 1 H), 8.04 (s, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 3.95 (s, 3 H). MS (FAB) m/z: 245.1 (M⁺ + 1).

Step 5: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester.

ό-Trifluoromethyl-lH-indazole-S-carboxylic acid methyl ester (2.75 g, 0.0112 mol) was dissolved in acetonitrile (50 mL), and potassium carbonate (1O g, 0.07 mol), 2,4-dichlorobenzyl chloride (2.42 g, 0.01239 mol) and tetrabutylammonium iodide (catalytic) were added. The reaction mixture was heated to reflux and refluxed for 2 h under good stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, potassium carbonate was filtered while hot and then washed with acetone. The combined solvents were distilled off under reduced pressure to afford the crude mixture of Nl and N2 benzylated products. The isomers were separated by column chromatography (silica gel, eluent started with hexane then changed to 8:2 hexane, ethyl acetate). l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester. Yield: 3.62 g (80%), white crystals mp 118-120 ⁰C. ‘ H NMR (CDCl₃) 8.39 (d, J = 8.4 Hz, 1 H) 7.74 (s, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 2.1 Hz, 1 H), 7.12 (dd, J = 8.4 and 2.1 Hz, 1 H), 6.78 (d, J = 8.4 Hz, 1 H), 5.82 (s, 2 H), 4.07 (s, 3 H). MS (FAB) m/z: 403 (M⁺ + 1).Z-^^-DichlorobenzylJ-δ-trifluoromethyl-ZH-indazole-S-carboxylic acid methyl ester. Yield: 680 mg (15%), white crystals mp 132-134 ⁰C. ‘ H NMR (DMSO-d-6) 8.27 (s, 1 H), 8.20 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.30 (dd, J = 8.3 and 1.8 Hz, 1 H), 6.78 (d, J = 8.3 Hz, 1 H), 6.17 (s, 2 H), 3.96 (s, 3 H).

Step 6: [l-(2.4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl1-methanol.

l -(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carboxylic acid methyl ester (3.0 g, 0.0075 mol) dissolved in CH₂Cl₂(50 mL) was cooled to -78 ⁰C. DIBAL-H (8.18 mL, 0.00818 mol) was added slowly dropwise via a syringe under an argon blanket over a period of 15 minutes. After the complete addition of DIBAL-H, the reaction mixture was stirred at -78°C for another 2 h (reaction monitored by TLC). The reaction was quenched carefully with methanol at -78 ⁰C. The reaction mixture was then carefully poured into water and the layers were separated. The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent yielded the crude alcohol (2.6 g, 93%), which was used without purification in the next step. The alcohol was a white solid, mp 137-139 ⁰C. ¹H NMR (CDCl₃) 7.97 (d, J = 8.4 Hz, 1 H), 7.66 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.12 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.65 (s, 2 H), 5.09 (s, 2 H). MS (FAB) m/z: 375 (M⁺ + 1).Step 7: l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehvde.

[l-(2,4-Difluorobenzyl)-6-trifluoromethyl-lH-indazol-3-yl]-methanol (3.75 g, 0.01 mol) was dissolved in CH₂Cl₂ (100 mL) and manganese(IV)oxide (8.7 g, 0.1 mol) was added and stirred for 2-3 h at room temperature (reaction monitored by TLC). The solids were removed by filtration and the removal of the CH₂Cl₂ in vacuo yielded the crude aldehyde. The aldehyde was used without further purification in the next step. The aldehyde (3.54 g, 95%) was a white solid, mp 97-98 ⁰C. ¹H NMR (CDCl₃) 10.25 (s, 1 H), 8.45 (d, J = 8.5 Hz, 1 H), 7.79 (s, 1 H), 7.60 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 2.0 Hz, 1 H), 7.20 (dd, J = 8.3 Hz and 2.0 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 5.79 (s, 2 H). MS (FAB) m/z: 373 (M⁺ + 1).

Step 8: 3-ri-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazol-3-yll-acrylic acid ethyl ester.

l-(2,4-Dichlorobenzyl)-6-trifluoromethyl-lH-indazole-3-carbaldehyde (2.0 g, 0.00536 mol) was dissolved in CH₂Cl₂ (50 niL) and Wittig reagent (carbethoxymethylene) triphenylphosphorane (1.06 g, 0.0536 mol) was added to the solution. The homogeneous reaction mixture was heated to reflux in an oil bath for 12 h. The reaction progress was monitored by TLC. The reaction mixture was cooled to room temperature and worked up by quenching into water and separating the organic layer. Removal of the CH₂Cl₂ yielded the crude product, which was purified by column chromatography to yield the pure product (2.25 g, 95%) as a white solid, mp 186-188 ⁰C. ¹H NMR (CDCl₃) 8.08 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 16.2 Hz, 1 H), 7.74 (s, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.16 (dd, J = 8.3 and 2.0 Hz, 1 H), 6.84 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 16.2 Hz, 1 H), 5.72 (s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H). MS (FAB) m/z: 443 (M⁺ + 1).It will be appreciated that the acrylic acid ethyl ester can be hydrogenated using 5% Pd-C in the presence of methanol, DCM at RT and 1 atm-pressure to give the propionic acid ester derivative. For example, treatment under such conditions yields 3-[l-(2,4-dichlorobenzyl)-6- trifluoromethyl-lH-indazol-3-yl]-propionic acid ethyl ester (JWS-2-70).

Step 9: l-(2,4-Dichlorobenzyl^‘)-3-r6-trifluoromethyl-lΗ-indazol-3-yll-acrvlic acid.

l-(2,4-Dichlorobenzyl)-3-[6-trifluoromethyl-lH-indazol-3-yl]-acrylic acid ethyl ester (2.0 g, 0.0045 mol) was dissolved in a mixture of tetrahydrofuran (50 mL) and methanol (25 mL). A lithium hydroxide solution (0.33 g, 0.013 mol lithium hydroxide in 7.5 mL water) was added slowly at room temperature under good stirring. The reaction mixture was then warmed to 40 ⁰C and held at that temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate in order to remove neutral impurities. The layers were separated and the aqueous layer was cooled to 0 ⁰C and then acidified with 20% sulfuric acid to pH 2. White solids precipitated and were filtered and dried to constant weight. The crude product was recrystallized from ethyl acetate and hexane (1 :1) to afford the pure product (1.68 g, 90%) as a white solid,

mp 186-188 ⁰C.

¹H NMR (DMSO-d-6) 8.39 (s, 1 H), 8.36 (d, J = 8.5 Hz, 1 H), 7.79 (d, J = 16.2 Hz, 1 H), 7.66 (d, J = 1.6 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1 H), 7.35 (dd, J = 8.3 and 1.6 Hz, 1 H), 6.93 (d, J = 8.3 Hz, 1 H), 6.76 (d, J = 16.2 Hz, 1 H), 5.89 (s, 2 H).

Anal, calcd. for C₁₈H_nCl₂F₃N₂O₂: C, 52.02; H, 2.65; N, 6.74. Found: C, 50.63; H, 2.63; N, 6.63.

HRMS (FAB +) m/z calcd. for C₁₈HnCl₂F₃N₂O₂ 415.01, found 415.0233.

MS (FAB) m/z: 415 (M⁺ + 1).

1H NMR

13C NMR

REFERENCES

1. Corsi , G. ; Palazzo , G. ; Germani , C. ; Barcellona , P. S. ; Silvestrini , B. 1-Halobenzyl-1H-indazole-3-carboxylic acids: A new class of antispermatogenic agents . J. Med. Chem. 1976 , 19 , 778
2. Palazzo , G. ; Corsi , G. ; Baiocchi , L. ; Silvestrini , B. Synthesis and pharmalogical properties of 1-substituted-3-dimethylaminoalkoxy-1H-indazoles . J. Med. Chem. 1966 , 9 , 38 – 41 .
3. Silvestrini , B. Basic and applied research in the study of indazole carboxylic acids . Chemotherapy 1981 , 27 ( Suppl.2 ), 9 – 20 .
4. Silvestrini , B. ; Palazzo , G. ; De Gregorio , M. D. 3-Lonidamine and related compounds . Progr. Med. Chem. 1985 , 21 , 111 – 135 .
5. Cheng , C. Y. ; Silvestrini , B. ; Grima , J. ; Mo , M. Y. ; Zhu , L. J. ; Johnsson , E. ; Saso , L. ; Leone , M. G. ; Palmery , M. ; Mruk , D. Two new male contraceptives exert their effects by depleting germ cells prematurely from the testes . Biol. Reprod. 2001 , 65 , 449 – 461 .
6. Xia , W. ; Mruk , D. D. ; Lee , W. M. ; Ceng , C. Y. Unraveling the molecular targets pertinent to junction restructuring events during spermatogenesis using the Adjudin-induced germ cell depletion model . J. Endocrinol. 2007 , 192 , 563 – 583 .
7. Cheng , C. Y. ; Mruk , D. D. ; Silvestrini , B. ; Bonanomi , M. ; Wong , C. H. ; Siu , M. K. Y. ; Lee , N. P. Y. ; Mo , M. Y. AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: A review of recent data . Contraception2005 , 72 , 251 – 261 .
8. Tash , J. S. ; Attardi , B. ; Hild , S. A. ; Chakrasali , R. ; Jakkarg , S. R. ; Georg , G. I. A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose . Biol. Reprod. 2008 , 78 , 1127 – 1138 .
9. Sarkar , O. ; Mathur , P. P. Adjudin-mediated germ cell depletion alters the anti-oxidant status of adult rat testes . Mol. Reprod. Dev. 2009 , 76 , 31 – 37 .
10. Mok , K.-W. ; Mruk , D. D. ; Lie , P. P. Y. ; Lui , W.-Y. ; Cheng , C. Y. Adjudin, a potential male contraceptive, exerts its effects locally in the seminiferous epithelium of mammalian testes. Reproduction. 2011, 141, 571–580.
11. Wang , H. ; Chen , X. X. ; Wang , L.-R. ; Mao , Y.-D. ; Zhou , Z. M. ; Sha , J.-H. AF-2364 is a prospective spermicide candidate .Asian J. Androl. 2010 , 12 , 322 – 335 .
1. “Gamendazole”. NextBio. www.nextbio.com. Retrieved 31 July 2011.
2. Tash, Joseph (July 2008). “A Novel Potent Indazole Carboxylic Acid Derivative Blocks Spermatogenesis and Is Contraceptive in Rats after a Single Oral Dose”. Biology of Reproduction 78 (6): 1127–1138. doi:10.1095/biolreprod.106.057810. PMID 18218612.

Chakrasali, R.; Jakkaraj, S.R.; Tash, J.S.; Hild, S.A.; Attardi, B.; Georg, G.I.
Design, synthesis and in vivo evaluation of Gamendazole(R), a novel orally active male contraceptive agent
228th Am Chem Soc (ACS) Natl Meet (August 22-26, Philadelphia) 2004, Abst MEDI 305

CHENG C.Y. ET AL: “Two New Male Contraceptives Exert Their Effects by Depleting Germ Cells Prematurely from the Testis” BIOLOGY OF REPRODUCTION, SOCIETY FOR THE STUDY OF REPRODUCTION, CHAMPAIGN, IL, US, vol. 65, no. 2, 1 August 2001 (2001-08-01), pages 449-461, XP002547492 ISSN: 0006-3363
2	*	GATTA F. ET AL: “Pyrazolo[3,4-d]pyrimidines. Related to Lonidamine” JOURNAL OF HETEROCYCLIC CHEMISTRY, HETEROCORPORATION. PROVO, US, vol. 26, no. 3, 1 March 1989 (1989-03-01), pages 613-618, XP002547493 ISSN: 0022-152X

US3895026 *	Feb 9, 1973	Jul 15, 1975	Acraf	Substituted 1-benzyl-1h-indazole-3-carboxylic acids and derivatives thereof
WO2003097063A1 *	May 5, 2003	Nov 27, 2003	Bayer Ag	Derivatives of 2-(1-benzyl-1h-pyrazolo (3, 4-b)pyridine-3yl) -5-(4-pyridinyl)-4-pyrimidine amine and the use thereof as guanylate cyclase stimulators
WO2006015263A2 *	Jul 29, 2005	Feb 9, 2006	Duan Jian-Xin	Lonidamine analogs

Gamendazole
Names


IUPAC name (E)-3-[1-[(2,4-Dichlorophenyl)methyl]-6-(trifluoromethyl)indazol-3-yl]prop-2-enoic acid^[1]
Other names trans-3-(1-Benzyl-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic acid)
Identifiers
CAS Registry Number	877773-32-5
ChemSpider	9387234
InChI [show]
Jmol-3D images	Image
PubChem	11212172
SMILES [show]
Properties
Chemical formula	C₁₈H₁₁Cl₂F₃N₂O₂
Molar mass	415.19 g·mol⁻¹

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FDA approves flibanserin first treatment for sexual desire disorder

Uncategorized Comments Off

Aug 192015

Flibanserin

BIMT-17

BIMT-17-BS

1,3-Dihydro-1-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-2H-benzimidazol-2-one

167933-07-5

FDA approves first treatment for sexual desire disorder
Addyi approved to treat premenopausal women

SEE FULL SYNTHESIS …CLICK HERE

The U.S. Food and Drug Administration today approved to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

August 18, 2015

Release

The U.S. Food and Drug Administration today approved Addyi (flibanserin) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Prior to Addyi’s approval, there were no FDA-approved treatments for sexual desire disorders in men or women.

“Today’s approval provides women distressed by their low sexual desire with an approved treatment option,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research (CDER). “The FDA strives to protect and advance the health of women, and we are committed to supporting the development of safe and effective treatments for female sexual dysfunction.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not due to a co-existing medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance. HSDD is acquired when it develops in a patient who previously had no problems with sexual desire. HSDD is generalized when it occurs regardless of the type of sexual activity, the situation or the sexual partner.

“Because of a potentially serious interaction with alcohol, treatment with Addyi will only be available through certified health care professionals and certified pharmacies,” continued Dr. Woodcock. “Patients and prescribers should fully understand the risks associated with the use of Addyi before considering treatment.”

Addyi can cause severely low blood pressure (hypotension) and loss of consciousness (syncope). These risks are increased and more severe when patients drink alcohol or take Addyi with certain medicines (known as moderate or strong CYP3A4 inhibitors) that interfere with the breakdown of Addyi in the body. Because of the alcohol interaction, the use of alcohol is contraindicated while taking Addyi. Health care professionals must assess the likelihood of the patient reliably abstaining from alcohol before prescribing Addyi.

Addyi is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). The FDA is requiring this REMS because of the increased risk of severe hypotension and syncope due to the interaction between Addyi and alcohol. The REMS requires that prescribers be certified with the REMS program by enrolling and completing training. Certified prescribers must counsel patients using a Patient-Provider Agreement Form about the increased risk of severe hypotension and syncope and about the importance of not drinking alcohol during treatment with Addyi. Additionally, pharmacies must be certified with the REMS program by enrolling and completing training. Certified pharmacies must only dispense Addyi to patients with a prescription from a certified prescriber. Additionally, pharmacists must counsel patients prior to dispensing not to drink alcohol during treatment with Addyi.

Addyi is also being approved with a Boxed Warning to highlight the risks of severe hypotension and syncope in patients who drink alcohol during treatment with Addyi, in those who also use moderate or strong CYP3A4 inhibitors, and in those who have liver impairment. Addyi is contraindicated in these patients. In addition, the FDA is requiring the company that owns Addyi to conduct three well-designed studies in women to better understand the known serious risks of the interaction between Addyi and alcohol.

Addyi is a serotonin 1A receptor agonist and a serotonin 2A receptor antagonist, but the mechanism by which the drug improves sexual desire and related distress is not known. Addyi is taken once daily. It is dosed at bedtime to help decrease the risk of adverse events occurring due to possible hypotension, syncope and central nervous system depression (such as sleepiness and sedation). Patients should discontinue treatment after eight weeks if they do not report an improvement in sexual desire and associated distress.

The effectiveness of the 100 mg bedtime dose of Addyi was evaluated in three 24-week randomized, double-blind, placebo-controlled trials in about 2,400 premenopausal women with acquired, generalized HSDD. The average age of the trial participants was 36 years, with an average duration of HSDD of approximately five years. In these trials, women counted the number of satisfying sexual events, reported sexual desire over the preceding four weeks (scored on a range of 1.2 to 6.0) and reported distress related to low sexual desire (on a range of 0 to 4). On average, treatment with Addyi increased the number of satisfying sexual events by 0.5 to one additional event per month over placebo increased the sexual desire score by 0.3 to 0.4 over placebo, and decreased the distress score related to sexual desire by 0.3 to 0.4 over placebo. Additional analyses explored whether the improvements with Addyi were meaningful to patients, taking into account the effects of treatment seen among those patients who reported feeling much improved or very much improved overall. Across the three trials, about 10 percent more Addyi-treated patients than placebo-treated patients reported meaningful improvements in satisfying sexual events, sexual desire or distress. Addyi has not been shown to enhance sexual performance.

The 100 mg bedtime dose of Addyi has been administered to about 3,000 generally healthy premenopausal women with acquired, generalized HSDD in clinical trials, of whom about 1,700 received treatment for at least six months and 850 received treatment for at least one year.

The most common adverse reactions associated with the use of Addyi are dizziness, somnolence (sleepiness), nausea, fatigue, insomnia and dry mouth.

The FDA has recognized for some time the challenges involved in developing treatments for female sexual dysfunction. The FDA held a public Patient-Focused Drug Development meeting and scientific workshop on female sexual dysfunction on October 27 and October 28, 2014, to solicit perspectives directly from patients about their condition and its impact on daily life, and to discuss the scientific challenges related to developing drugs to treat these disorders. The FDA continues to encourage drug development in this area.

Consumers and health care professionals are encouraged to report adverse reactions from the use of Addyi to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/MedWatch or by calling 1-800-FDA-1088.

Addyi is marketed by Sprout Pharmaceuticals, based in Raleigh, North Carolina.

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY PREDICT

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Addyi, flibanserin, fda 2015, sexual desire disorder

Filgotinib

Uncategorized Comments Off

Aug 182015

Filgotinib

C₂₁H₂₃N₅O₃S
MW425.504
Elemental Analysis: C, 59.28; H, 5.45; N, 16.46; O, 11.28; S, 7.54

1206161-97-8

Cyclopropanecarboxamide, N-[5-[4-[(1,1-dioxido-4-thiomorpholinyl)methyl]phenyl][1,2,4]triazolo[1,5-a]pyridin-2-yl]-

G146034

GLPG0634

N-(5-(4-((1,1-dioxidothiomorpholino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide

Galapagos Nv INNOVATOR

IL-6 antagonist; Jak1 tyrosine kinase inhibitor; Tyk2 tyrosine kinase inhibitor; Jak3 tyrosine kinase inhibitor; Jak2 tyrosine kinase inhibitor

Autoimmune disease; Cancer; Colitis; Crohns disease; Inflammatory disease; Neoplasm; Rheumatoid arthritis; Transplant rejection

Filgotinib (GLPG0634), by the Belgian biotech company Galápagos NV, is a drug which is currently under investigation for the treatment of rheumatoid arthritis and Crohn’s disease.

Filgotinib (GLPG0634) is an orally-available, selective inhibitor of JAK1 (Janus kinase 1) for the treatment of rheumatoid arthritis and potentially other inflammatory diseases. Filgotinib (GLPG0634) dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. The JAK1 selective inhibitor GLPG0634 (Filgotinib) is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases. Filgotinib (GLPG0634) is currently in a Phase 2 study in Crohn’s disease.

Mechanism of action

Filgotinib is a Janus kinase inhibitor with selectivity for subtype JAK1 of this enzyme. It is considered a promising agent as it inhibits JAK1 selectively. Less selective JAK inhibitors (e.g. tofacitinib) are already being marketed. They show long-term efficacy in the treatment of various inflammatory diseases. However, their lack of selectivity leads to dose-limiting side effects.^[1] It is thought that inhibition of all JAK isoenzymes is beneficial in rheumatoid arthritis. However, pan-JAK inhibition might also lead to unwanted side effects that might not outweigh its benefits. This is the rationale for the development of newer and more selective inhibitors like filgotinib.

The signal transmission of large numbers of proinflammatory cytokines is dependent on JAK1. Inhibition of JAK2 may also contribute to the efficacy against RA. Nonetheless it is thought that JAK2 inhibition might lead to anemia and thrombopenia by interference witherythropoietin and thrombopoietin and granulocyte-macrophage colony-stimulating factor. Therefore one might prefer to choose a more selective JAK1 inhibitor as a primary therapeutic option. Filgotinib exerts a 30-fold selectivity for JAK1 compared to JAK2.^[2] It is however still to be seen to what extent JAK2 inhibition should be avoided.

Novel crystalline forms of filgotinib salts, particularly hydrochloride salt, useful for treating JAK-mediated diseases eg inflammatory diseases, autoimmune diseases, proliferative diseases, allergy and transplant rejection. Galapagos and licensee AbbVie are developing filgotinib, a selective JAK-1 inhibitor, for treating rheumatoid arthritis (RA) and Crohn’s disease (CD). In August 2015, the drug was reported to be in phase 2 clinical development for treating RA and CD. The drug is also being investigated for the treatment of colitis and was discovered as part of the company’s arthritis alliance with GSK; however in August 2010 Galapagos reacquired the full rights. See WO2013189771, claiming use of filgotinib analog for treating inflammatory diseases. Also see WO2010010190 (co-assigned with GSK and Abbott) and WO2010149769 (assigned to Galapagos) claiming filgotinib, generically and specifically, respectively.

Clinical trials and approval

The efficacy of filgotinib is currently studied in a phase2b program (DARWIN trial 1, 2) with involvement of 886 rheumatoid arthritis patients and 180 Crohn’s disease patients.

Phase 1 study

It was shown in phase 1 studies that the pharmacokinetics of filgotinib metabolism is independent of hepatic CYP450 enzymatic degradation. The drug metabolism is however mediated by carboxylesterases. There is no interference reported with the metabolism of methotrexate nor with any of the investigated transport proteins.^[3]

Phase 2 study: Proof of concept (2011)

In november 2011 Galápagos released the results of their phase 2 study (identification: NCT01384422, Eudract: 2010-022953-40) in which 36 patients were treated who showed a suboptimal clinical response to methotrexate treatment. Three groups of twelve patients were treated either with 200 mg filgotinib in a single dose, 200 mg divided in two doses or placebo. The primary end-point was the ACR20 score, which monitors improvements in the symptomatology of the patient. After the scheduled 4 weeks of treatment, 83% of the respondents showed an improved ACR20-score. Half of the treated patients showed a complete (or near complete) remission of the disease. There were no reports ofanemia nor changes in lipidemia. The company stated in their press release that filgotinib is the first selective JAK1 inhibitor that shows clinical efficacy. As a result of this study, the company stated that “GLPG0634 shows one of the highest initial response rates ever reported for rheumatoid arthritis treatments”.^[4]

DARWIN 1 trial

The DARWIN 1 trial is a 24 week double blind placebo-controlled trial with 599 rheumatoid arthritis patients enrolled. All participants have moderate to severe RA and showed an insufficient response to standard methotrexate treatment. The trial compares three dosages of filgotinib as a once or twice per day regimen. During the trial all participants remain on their methotrexate treatment. According to the company, the results of this trial are expected in July 2015.^[5]

DARWIN 2 trial

The DARWIN 2 trial is a double blind placebo-controlled trial with 280 rheumatoid arthritis patients enrolled who show an insufficient response to standard methotrexate treatment. This trial, in contrast to the previous DARWIN 1 trial, methotrexate is discontinued. Therefore, this trial investigates filgotinib as a monotherapy.^[6] The recruitment of DARWIN trial 2b ended in november 2014.^[7] Preliminary results are expected in the second quarter of 2015 and a full completion of the study is expected in the third quarter of 2015.

DARWIN 3 trial

Patients who complete DARWIN 1 and 2 will be eligible for DARWIN 3.

Time line

june 2011: results of first phase 2 trial
november 2014: initiation of DARWIN 1 and 2 trials
april 2015: expected date of DARWIN 1 trial results
june 2015: expected date of DARWIN 2 trial results

CHEMIETEK

GLPG-0634, Current Lot, Certificate of Analysis

GLPG-0634, Current Lot, NMR

GLPG-0634, Current Lot, HPLC-MS

…………

PATENT

http://www.google.com/patents/WO2010149769A1?cl=en

Step 3:

[00131] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-

2-yl]-amide (leq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO^ Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

………..

PATENT

US2010/331319 A1, ; Page/Page column 13-14

http://www.google.com/patents/US20100331319

Synthetic Preparation of the Compound of the Invention and Comparative Examples

The compound of the invention and the comparative examples can be produced according to the following scheme.

wherein Ar represents phenyl-L1-heterocycloalkyl, where L1 is a bond, —CH₂— or —CO— and the heterocycloalkyl group is optionally substituted.

General 1.1.1 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2)

To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5° C. is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture is then allowed to warm to room temp. (20° C.) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea may be used as such for the next step without any purification. ¹H (400 MHz, CDCl₃) δ 12.03 (1H, br s, NH), 8.81 (1H, d, J=7.8 Hz, H-3), 8.15 (1H, br s, NH), 7.60 (1H, t, J=8.0 Hz, H-4), 7.32 (1H, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH₂), 1.35 (3H, t, J 7.1 Hz, CH₃).

1.1.2 5-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3)

To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1:1, 900 mL) is added N,N-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H₂S evolved). After 3 h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H₂O (250 mL) and filtration. The combined solids are washed successively with H₂O (250 mL), EtOH/MeOH (1:1, 250 mL) and Et₂O (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. ¹H (400 MHz, DMSO-d₆) δ 7.43-7.34 (2H, m, 2×aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1:1, M+H⁺, 100%).

1.1.3 General Procedure for Mono-Acylation to Afford Intermediate (4)

To a solution of the 2-amino-triazolopyridine (3) (7.10 g, 33.3 mmol) in dry CH₃CN (150 mL) at 5° C. is added Et₃N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material (3) is consumed. If required, further Et₃N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp. (for 1-16 h) to hydrolyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et₂O (50 mL). The solids are collected by filtration, washed with H₂O (2×50 mL), acetone (50 mL) and Et₂O (50 mL), then dried in vacuo to give the required bromo intermediate (4).

Method A Preparation of Compounds of the Invention Via Suzuki Coupling (5):

An appropriate boronic acid (2 eq.) is added to a solution of bromo intermediate (4) in 1,4-dioxane/water (5:1). K₂CO₃(2 eq.) and PdCl₂dppf (5%) are added to the solution. The resulting mixture is then heated in a microwave at 140° C. for 30 min (this reaction can also be carried out by traditional heating in an oil bath at 90° C. for 16 h under N₂). Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhyd. MgSO₄and evaporated in vacuo. The final compound is obtained after purification by flash chromatography or preparative HPLC. HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

Method B

B1. 4 4-[2-(Cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoyl chloride

2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N₂atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.

B2. Amide Formation (General Method)

An appropriate amine (1.1 eq) and Et₃N (5 eq) are dissolved in DCM under N₂atmosphere and cooled at 0° C. The acid chloride (B1, 1 eq) dissolved in DCM is added dropwise to this solution. The reaction is stirred at room temperature for 16 h. After this time, reaction is complete. The compound is extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO₄. Organic layers are filtered and evaporated. The final compound is isolated by preparative HPLC. Preparative HPLC: Waters XBridge Prep C18 5 μm ODB 19 mm ID×100 mm L (Part No. 186002978). All the methods are using MeCN/H₂O gradients. H₂O contains either 0.1% TFA or 0.1% NH₃.

…

Synthesis of the Compound of the Invention and Comparative Examples Compound 1 (the Compound of the Invention) Step 1:

2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂and thiomorpholine 1,1-dioxide (2 eq) was added portionwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhyd. MgSO₄. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

STEP 2: Suzuki coupling

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-1,1-dioxide (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K₂CO₃(2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO₄and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

Alternatively, after completion of the reaction, a palladium scavenger such as 1,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cooled down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HCl is added, and after stirring at RT, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at RT, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H₂O, treated with a palladium scavenger (e.g. SMOPEX 234) at 50° C., the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the title compound as a free base.

Alternative Route to Compound 1 (the Compound of the Invention): Step 1:

4-(Hydroxymethyl)phenylboronic acid (1.1 eq.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide in 1,4-dioxane/water (4:1). K₂CO₃(2 eq.) and PdCl₂dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. for 16 h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhyd. MgSO₄and evaporated in vacuo. The resulting mixture was used without further purification.

Step 2:

To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1.0 eq) in chloroform was slowly added phosphorus tribromide (1.0 equiv.). The reaction mixture was stirred at room temperature for 20 hours, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer was dried over anhyd. MgSO₄, filtered and concentrated to dryness. The resulting white residue was triturated in dichloromethane/diethyl ether 2:1 to afford the expected product as a white solid.

Step 3:

Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂and thiomorpholine 1,1-dioxide (1.1 eq) was added dropwise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was dissolved in DCM, washed with water and dried over anhyd. MgSO₄. Organic layers were filtered and evaporated. The final compound was isolated by column chromatography using EtOAc to afford the desired product.

…………………….

PATENT

WO 2015117981

Novel salts and pharmaceutical compositions thereof for the treatment of inflammatory disorders

Also claims a method for preparing filgotinib hydrochloride trihydrate. The present filing forms a pair with this week’s filing, WO2015117980, claiming a tablet composition comprising filgotinib hydrochloride.

The compound cyclopropanecarboxylic acid {5-[4-(l,l-dioxo-thiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5-a]pyridin-2-yl -amide (Compound 1), which has the chemical structure:

is disclosed in our earlier application WO 2010/149769 (Menet C. J., 2010) as being an inhibitor of JAK and as being useful in the treatment of inflammatory conditions, autoimmune diseases, proliferative diseases, allergy, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 or interferons. Hereafter this compound is named Compound 1. The data presented in WO 2010/149769 demonstrate that despite similar in vitro activities, Compound 1 has unexpectedly high in vivo potency compared with structurally similar compounds.

Example 1. Preparation of Compound 1

1.1. Route 1

1.1.1. 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide

[00205] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (2 eq) is added portionwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated without further purification.

1.1.2. Cyclopropanecarboxylic acid (5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-yl)-amide

1.1.2.1. Step i): l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea

[00206] To a solution of 2-amino-6-bromopyridine (1) (253.8 g, 1.467 mol) in DCM (2.5 L) cooled to 5°C is added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction

mixture is then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gives a solid which may be collected by filtration, thoroughly washed with petrol (3 x 600 niL) and air-dried to afford the desired product. The thiourea may be used as such for the next step without any purification. ^lH (400 MHz, CDC1₃) δ 12.03 (1H, br s), 8.81 (1H, d), 8.15 (1H, br s), 7.60 (1H, t), 7.32 (1H, dd), 4.31 (2H, q), 1.35 (3H, t).

1.1.2.2. Step ii): 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine

[00207] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) is added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture is stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) is then added and the mixture slowly heated to reflux (Note: bleach scrubber is required to quench H₂S evolved). After 3h at reflux, the mixture is allowed to cool and filtered to collect the precipitated solid. Further product is collected by evaporation in vacuo of the filtrate, addition of H₂0 (250 mL) and filtration. The combined solids are washed successively with H₂0 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et₂0 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound may be used as such for the next step without any purification. ^lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1 : 1, M+H⁺, 100%).

1.1.2.3. Step Hi): Cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide

[00208] To a solution of the 2-amino-triazolopyridine obtained in the previous step (7.10 g, 33.3 mmol) in dry MeCN (150 mL) at 5°C is added Et₃N (11.6 mL, 83.3 mmol) followed by cyclopropanecarbonyl chloride (83.3 mmol). The reaction mixture is then allowed to warm to ambient temperature and stirred until all starting material is consumed. If required, further Et₃N (4.64 mL, 33.3 mmol) and cyclopropanecarbonyl chloride (33.3 mmol) is added to ensure complete reaction. Following solvent evaporation in vacuo the resultant residue is treated with 7 N methanolic ammonia solution (50 mL) and stirred at ambient temp, (for 1-16 h) to hydro lyse any bis-acylated product. Product isolation is made by removal of volatiles in vacuo followed by trituration with Et₂0 (50 mL). The solids are collected by filtration, washed with H₂0 (2x50mL), acetone (50 mL) and Et₂0 (50 mL), then dried in vacuo to give the desired compound.

1.1.3. Compound 1

[00209] 4-[4-(4,4,5,5-Tetramethyl-[l ,3,2]dioxaborolan-2-yl)-benzyl] hiomoφholine , l -dioxide (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water (4: 1). K₂CO₃ (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N₂. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS0₄ and evaporated in vacuo.

[00210] The final compound is obtained after purification by flash chromatography.

[00211] Alternatively, after completion of the reaction, a palladium scavenger such as 1 ,2-bis(diphenylphosphino)ethane, is added, the reaction mixture is allowed to cool down and a filtration is performed. The filter cake is reslurried in a suitable solvent (e.g. acetone), the solid is separated by filtration, washed with more acetone, and dried. The resulting solid is resuspended in water, aqueous HC1 is added, and after stirring at room temperature, the resulting solution is filtered on celite (Celpure P300). Aqueous NaOH is then added to the filtrate, and the resulting suspension is stirred at room temperature, the solid is separated by filtration, washed with water and dried by suction. Finally the cake is re-solubilised in a mixture of THF/H₂0, treated with a palladium scavenger (e.g. SMOPEX 234) at 50°C, the suspension is filtered, the organic solvents are removed by evaporation, and the resulting slurry is washed with water and methanol, dried and sieved, to obtain the desired compound as a free base.

1.2. Route 2

1.2.1. Step 1: cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2, 4]triazolo[l, 5- a] pyridin-2-yl] -amide

[00212] 4-(Hydroxymethyl)phenylboronic acid (l . l eq.) is added to a solution of cyclopropanecarboxylic acid (5-bromo-[l ,2,4]triazolo[l ,5-a]pyridin-2-yl)-amide in 1 ,4-dioxane/water

(4:1). K2CO3 (2 eq.) and PdC^dppf (0.03 eq.) are added to the solution. The resulting mixture is then heated in an oil bath at 90°C for 16h under N₂. Water is added and the solution is extracted with ethyl acetate. The organic layers are dried over anhydrous MgS0₄ and evaporated in vacuo. The resulting mixture is used without further purification.

1.2.2. Step 2: Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5- a Jpyridin-2-ylJ -amide

[00213] To a solution of cyclopropanecarboxylic acid [5-(4-hydroxymethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl] -amide (1.0 eq) in chloroform is slowly added phosphorus tribromide (1.0 eq.). The reaction mixture is stirred at room temperature for 20 h, quenched with ice and water (20 mL) and extracted with dichloromethane. The organic layer is dried over anhydrous MgSO i, filtered and concentrated to dryness. The resulting white residue is triturated in dichloromethane/diethyl ether 2:1 to afford the desired product.

1.2.3. Step 3:

[00214] Cyclopropanecarboxylic acid [5-(4-bromomethyl-phenyl)-[l,2,4]triazolo[l,5-a]pyridin-2-yl]-amide (l eq) and DIPEA (2 eq) are dissolved in DCM/MeOH (5: 1 v:v) under N₂ and thiomorpho line 1,1-dioxide (1.1 eq) is added dropwise. The resulting solution is stirred at room temperature for 16h. After this time, the reaction is complete. The solvent is evaporated. The compound is dissolved in DCM, washed with water and dried over anhydrous MgSO i. Organic layers are filtered and evaporated. The final compound is isolated by column chromatography using EtOAc to afford the desired product.

…………………

PATENT

http://www.google.co.in/patents/WO2013189771A1?cl=en

Example 1. Synthesis of the compounds

1.1. Route 1

1.1.1. Synthesis of 5-Bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamine (Intermediate 3)

led to 5 °C was added ethoxycarbonyl isothiocyanate (173.0 mL, 1.467 mol) dropwise over 15 min. The reaction mixture was then allowed to warm to room temp. (20 °C) and stirred for 16 h. Evaporation in vacuo gave a solid which was collected by filtration, thoroughly washed with petrol (3×600 mL) and air-dried to afford (2). The thiourea was used as such in the next step without any purification.

[00157] ^lH (400 MHz, CDC1₃) δ 12.03 (IH, br s, NH), 8.81 (IH, d, J 7.8 Hz, H-3), 8.15 (IH, br s, NH), 7.60 (IH, t, J 8.0 Hz, H-4), 7.32 (IH, dd, J 7.7 and 0.6 Hz, H-5), 4.31 (2H, q, J 7.1 Hz, CH₂), 1.35 (3H, t, J 7.1 Hz, CH₃).

1.1.1.2. 5-Bromo-f 1,2, 4]triazolo[ 1 ,5-a] pyridin-2-ylamine (3)

[00158] To a suspension of hydroxylamine hydrochloride (101.8 g, 1.465 mol) in EtOH/MeOH (1 : 1, 900 mL) was added NN-diisopropylethylamine (145.3 mL, 0.879 mol) and the mixture was stirred at room temp. (20 °C) for 1 h. l-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (89.0 g, 0.293 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber was required to quench H₂S evolved). After 3 h at reflux, the mixture was allowed to cool and filtered to collect the precipitated solid. Further product was collected by evaporation in vacuo of the filtrate, addition of H₂0 (250 mL) and filtration. The combined solids were washed successively with H₂0 (250 mL), EtOH/MeOH (1 : 1, 250 mL) and Et₂0 (250 mL) then dried in vacuo to afford the triazolopyridine derivative (3) as a solid. The compound was used as such in the next step without any purification.

[00159] ^lH (400 MHz, DMSO-i¼) δ 7.43-7.34 (2H, m, 2 x aromatic-H), 7.24 (1H, dd, J 6.8 and 1.8 Hz, aromatic-H), 6.30 (2H, br, NH₂); m/z 213/215 (1 : 1, M+H⁺, 100%).

1.1.2. Synthesis of 4-[ 4-(4, 4, 5, 5-Tetramethyl-f 1, 3,2] ‘ dioxaborolan-2-yl) -benzyl] ‘- thiomor holine- 1, 1 -dioxide (Intermediate 4)

[00160] 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N₂ and thiomorpholine 1,1 -dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO i. Organic layers were filtered and evaporated. The final compound was isolated without further purification.

1.1.3. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- a ridin-2-ylamine (Formula I)

[00161] 4-[4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzyl]-thiomorpholine-l,l-dioxide (l .leq.) was added to a solution of 5-bromo-[l,2,4]triazolo[l,5-a]pyrid in-2-ylamine (4: 1). K₂CO₃ (2 eq.) and PdC^dppf (0.03 eq.) were added to the solution. The resulting mixture was then heated in an oil bath at 90°C for 16h under N₂. Water was added and the solution was extracted with ethyl acetate. The organic layers were dried over anhydrous MgSC>4 and evaporated in vacuo. The final compound was obtained after purification by flash chromatography.

[00162] ^lH (400 MHz, CDC1₃) δ 7.94-7.92 (d, 2H), 7.52-7.48 (m, 3H), 7.37-7.34 (m, 1H), 7.02-7.00 (m, 1H), 6.00 (d, 2H), 3.76 (d, 2H), 3.15-3.13 (m, 4H), 2.93-2.91 (m, 4H).

[00163] m/z 358.2 (M+H⁺, 100%). 1.2. Route 2

1.2.1. Cyclopropanecarboxylic acid {5-[4-(l, l-dioxo-thiomorpholin-4-ylmethyl)-phenylJ- [l,2,4]triazolo[l,5-a]pyridin-2-yl}-amide (Formula II)

[00164] The compound according to Formula II may be synthesized according to the procedure described in WO 2010/149769.

1.2.2. Synthesis of 5-[4-(l, l-Dioxothiomorpholin-4-ylmethyl)-phenyl]-[l,2,4]triazolo[l,5- aJpyridin-2-ylamine (Formula I)

[00165] The compound according to Formula I can also be produced by hydrolysis of the compound accor ing to Formula II:

[00166] Hydrochloric acid 30% aq (12.06 kg; 3.9 rel. volumes) was added to a slurry of the compound according to Formula II (3.45 kg; 1.0 equiv.) in demineralized water (10.0 kg; 3.0 rel. volumes). Subsequently, a line rinse was performed with demineralized water (3.4 kg; 1.0 rel. volumes). The reaction mixture was heated to 80±5°C for 14.5 h. After completion of the reaction (conversion > 99%>), the reaction mixture was cooled to 20±5°C. The reaction mixture was diluted with demineralized water (6.8 kg; 2.0 rel. volumes) and sodium hydroxide 33%> aq (9.52 kg; 3.7 rel volumes) was dosed at such a rate that the temperature of the reactor contents remained below 35°C. An additional amount of sodium hydroxide 33%> aq (2.55 kg; 1.0 rel. volumes) was needed to get the pH > 10. The product was filtered off, washed twice with demineralized water (1.5 rel. volumes) and dried under vacuum for 1 h, thus yielding the crude compound according to Formula I.

[00167] The crude compound according to Formula I (5.70 kg) was re-slurried in demineralized water (23.0 kg; 8.5 rel. volumes). Hydrochloric acid 30%> aq (1.65 kg; 0.7 rel. volumes) and demineralized water (4.3 kg; 1.6 rel. volumes) were added and the reaction mixture was stirred at 20±5°C for 45 min. As the compound according to Formula I was not dissolved completely, the reaction mixture was stirred at 45±5°C for 1 h. The reaction mixture was filtered and the residue was washed with demineralized water (2.0 kg 0.75 rel. volumes). Sodium hydroxide 33%> aq (1.12 kg; 0.6 rel volumes) was added to the filtrate. An additional amount of sodium hydroxide 33%> aq (1.01 kg) was needed to get the pH > 10. The resulting reaction mixture was stirred at 20±5°C for about 3 h. The product was filtered off, washed twice with demineralized water (4.1 kg; 1.5 rel. volumes), and twice with methyl tert-butyl ether (MTBE; 3.0 kg; 1.5 rel. volumes) and dried under vacuum for 15.5 h on the filter. The product was further dried in a vacuum oven at 40±5°C for 202 h, thus affording the desired compound according to Formula I.

1H NMR PREDICT

13C NMR PREDICT

H EXPLODED

1H NMR FROM NET ABMOLE DMSOD6

SPECTRAL PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY

References

Namour, Florence; Diderichsen, Paul Matthias; Cox, Eugène; Vayssière, Béatrice; Van der Aa, Annegret; Tasset, Chantal; Van’t Klooster, Gerben (2015-02-14). “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”. Clin Pharmacokinet. Epub ahead of print.doi:10.1007/s40262-015-0240-z.
Van Rompaey, L; Galien, R; Van der Aar, E; Clement-Lacroix, P; Van der Aar, E; Nelles, L; Smets, B; Lepescheux, L; Cristophe, T; Conrath, K; Vandeghinste, N; Vayssiere, B; De Vos, S; Fletcher, S; Brys, R; Van’t Klooster, G; Feyen, J; Menet, C (2013-10-01). “Preclinical characterization of GLPG0634, a selective inhibitor of JAK1 for the treatment of inflammatory diseases”. J Immunol. 191(7). doi:10.4049/jimmunol.1201348.
http://acrabstracts.org/abstracts/phase-1-and-phase-2-data-confirm-that-glpg0634-a-selective-jak1-inhibitor-has-a-low-potential-for-drug-drug-interactions/
“Galapagos’ GLPG0634 shows excellent efficacy and safety in rheumatoid arthritis Phase II study” (PDF) (Press release). Retrieved 2015-02-26.
“Galapagos reports that the last patient in DARWIN 1 has completed 12 weeks of treatment” (PDF) (Press release). Retrieved 2015-02-26.
“Galapagos completes recruitment for Darwin 1 study with GLPG0634 (filgotinib) in RA”. EuroInvestor. Retrieved 2015-02-26.
NASDAQ OMX Corporate Solutions. “Galapagos completes recruitment for Darwin 2 monotherapy study with GLPG0634 (filgotinib) in RA”. Yahoo Finance. Retrieved 2015-02-26.

US8551980	Nov 17, 2010	Oct 8, 2013	Bayer Intellectual Property Gmbh	Substituted triazolopyridines
US8796457	Jun 25, 2010	Aug 5, 2014	Galapagos Nv	Compound useful for the treatment of degenerative and inflammatory diseases

Filgotinib
Systematic (IUPAC) name

N-[5-[4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide
Clinical data
Routes of administration	Oral
Pharmacokinetic data
Biological half-life	6 hours^[1]
Identifiers
CAS Registry Number	1206161-97-8
ATC code	L01 XE18
IUPHAR/BPS	7913
ChemSpider	28189566
UNII	3XVL385Q0M
ChEMBL	CHEMBL3301607
Chemical data
Formula	C₂₁H₂₃N₅O₃S
Molecular mass	425.50402 g/mol

Patent	Submitted	Granted
Compound useful for the treatment of degenerative and inflammatory diseases [US8088764]	2010-12-30	2012-01-03
NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES [US2011190260]	2011-08-04

/////////Galapagos, GLPG0634, Filgotinib, PHASE 2

SMILES code: O=C(C1CC1)NC2=NN3C(C4=CC=C(CN5CCS(CC5)(=O)=O)C=C4)=CC=CC3=N2

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REFERENCES

Release

Mechanism of action

Clinical trials and approval

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Phase 2 study: Proof of concept (2011)

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DARWIN 2 trial

DARWIN 3 trial

Time line

References

Follow All About Drugs

D10476, MW591.546 , [US2010267783], MF C₂₉H₃₂Cl₂N₂O₅S, S-888711

Preparation of (E) 3-(1-(2,4-Dichlorobenzyl)-6-(trifluoromethyl)-1H-indazol-3-yl)acrylic Acid (R = CF₃) (Gamendazole) (2)