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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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GSK2248761A , IDX899, Fosdevirine


Image result for GSK2248761A , IDX899, FosdevirineChemSpider 2D Image | fosdevirine | C20H17ClN3O3P

GSK2248761A , IDX899, Fosdevirine,

Fosdevirine; IDX899; IDX-899; GSK2248761; cas 1018450-26-4; GSK-2248761, IDX 12899

1018450-26-4 CAS
R FORM ROTATION (-)
Molecular Formula: C20H17ClN3O3P
Molecular Weight: 413.798 g/mol
 Phosphinic acid, P-[2-(aminocarbonyl)-5-chloro-1H-indol-3-yl]-P-[3-[(1E)-2-cyanoethenyl]-5-methylphenyl]-, methyl ester, [P(R)]-
Methyl (R)-(2-carbamoyl-5-chloro-1H-indol-3-yl){3-[(E)-2-cyanovinyl]-5-methylphenyl}phosphinate
Phosphinic acid, P-[2-(aminocarbonyl)-5-chloro-1H-indol-3-yl]-P-[3-[(E)-2-cyanoethenyl]-5-methylphenyl]-, methyl ester, (R)-
5DV
Methyl (R)-(2-carbamoyl-5-chloro-1H-indol-3-yl)[3-(2-cyanoethyl)-5-methylphenyl]phosphinate

[R(P)]-(2-Carbamoyl-5-chloro-1H-indol-3-yl)[3-(2-cyanovinyl)-5-methylphenyl]phosphinic acid methyl ester

Phase II clinical trials for the treatment of HIV infection

Idenix (Originator)

Fosdevirine, also known as GSK2248761 and IDX899, a Highly Potent Anti-HIV Non-nucleoside Reverse Transcriptase Inhibitor having an EC50 of 11 nM against the Y181C/K103N double mutant. GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

IDX-12899 is a non-nucleoside reverse transcriptase inhibitors (NNRTI) originated by Idenix (acquired by Merck & Co.). It had been in phase II clinical trials for the treatment of HIV infection. However, in 2010, the compound was placed on clinical hold by the FDA. In 2009, the compound was licensed by Idenix to GlaxoSmithKline for the treatment of HIV infection on a worldwide basis.

PATENT

WO2008/042240 A2, 2008, Compound III

compound 66a: racemic form

5-chloro-3-[ methyl 3-((Zζ)-2-cyanovinyl)-5-methylphenyl] phosphinoyl-l//-indole-2- carboxamide.

Figure imgf000091_0003

[00258] Compound 66a was synthesized according to method AL. White solid, 1H NMR (CDCl3, 300 MHz) δ 2.40 (s, 3H), 3.88 (d, J= 11.7 Hz, 3H), 5.89 (d, J= 16.5 Hz, IH), 5.97 (brs, IH), 7.33-7.67 (m, 7H), 10.46 (s, IH), 10.89 (brs, IH), 31P NMR (CDCl3, 121.49 MHz) δ 31.54. MS (ES+) m/z = 414 (MH+).

Example 8

Figure imgf000126_0001

Preparation of Compound HI

Figure imgf000127_0001
Figure imgf000127_0002

305

1 (-)cιnchonιdιne, Acetone

2 1N HCI1 EtOAc

Figure imgf000127_0003

Compound 302

[00348] A suitable reactor was charged Compound 301 (10Og, 0.23mol) and tetrahydrofuran (IL). The resulting solution was chilled between -90° to -100°C under nitrogen using a LN2 / IPA slush bath, then was treated with n-butyl lithium (2.5M in Hexanes, 99ml, 0.25mol) added over 10 minutes. To this was added diethyl chlorophosphite (37.1g, 0.24mol) over 10 minutes. HPLC (Method 001, RT = 18.9 min) showed no starting material and ca. 85% product. The reaction was then diluted with ethyl acetate (IL) and was allowed to warm to -4O0C. The mix was then treated with hydrochloric acid (0.5M, 590ml) and was allowed to warm to ambient temperature and stir for 30 minutes. The resulting layers were separated and the aqueous extracted with ethyl acetate (500ml). The organics were combined and washed with brine (500ml) dried over sodium sulfate, filtered and concentrated to an oil. 88% HPLC AUC (Method 20, RT = 5.8 min) 115g, >100% yield due to impurities and solvent. Used as is in the next step. Compound 303

[00349] A suitable reactor was charged with Compound 302 (111 g, estimated 0.18mol), iodocinnamonitrile (47.1g, 0.175mol), triethylamine (29.3ml, 0.21mol) and toluene (800ml). The resulting mix was degassed by sparging with a stream of nitrogen for 10 minutes at ambient temperature, after which time tetrakis(triphenylphosphine) palladium(O) (10. Ig, 0.0088mol) was added. The mix was sparged for an additional 5 minutes, then was heated to 80°C for 2 hours. HPLC (Method 20, RT = 6.5 min) showed a complete reaction. The mix was cooled to ambient and was filtered through celite and washed with ethyl acetate (400ml). The combined organics were washed with brine (2 x 500ml) then dried over sodium sulfate, filtered and concentrated to a volume of 350ml. The concentrate was cooled to O0C and was stirred for 1 hour, during which time the product crystallized. The solids were filtered and washed with hexane:toluene (2:1, 150ml). Dried to leave 95g, 90% yield, HPLC AUC 98% (Method 20). Used as is in the next reaction. [00350] 303: C29H26ClN2O6PS 597.02gmol‘ m/z (ESI+): 597.0 (MH+, 100%), 599.0 (MH+, 35%) 1H NMR δH (400 MHz, CDCl3): 1.38, 1.48 (2 x 3H, 2 x t, COOCH2CH3, POOCH2CH3), 2.41 (3Η, s, Ar-CH3), 4.09-4.16 (2Η, m, POOCH2CH3), 4.52 (2H, q, COOCH2CH3), 5.93 (IH, d, CH=CHCN), 7.33-7.38 (3Η, m, CH=CHCN, 2 x Ar-H), 7.52 (2Η, t, 2 x Ar-H), 7.64 (1Η, t, Ar-H), 7.74, 7.77 (2 x 1Η, 2 x d, 2 x Ar-H), 7.85 (1Η, d, Ar- H), 7.94 (1Η, dd, Ar-H), 8.08 (2Η, d, 2 x Ar-H) 1H NMR δH (400 MHz, d6-DMSO): 1.26, 1.33 (2 x 3H, 2 x t, COOCH2CH3, POOCH2CH3), 2.34 (3Η, s, Ar-CH3), 3.95-4.10 (2Η, m, POOCH2CH3), 4.40 (2H, q, COOCH2CH3), 6.52 (IH, d, CH=CHCN), 7.52 (1Η, dd, Ar-H), 7.60-7.84 (8Η, m, CH=CHCN, 7 x Ar-H), 8.07 (3 x 1Η, m, 3 x Ar-H)

Compound 304

[003511 A suitable reactor was charged with Compound 303 (537g, 0.90mol) and methylene chloride (2.0L). The resulting solution was cooled to O0C, and was treated with bromotrimethylsilane (45Og, 2.9mol) added over 15 minutes. The reaction was then warmed to 400C for 1.5 hours. ΗPLC (Method 20, RT = 4.4 min) indicated a complete reaction. The excess TMSBr was stripped under vacuum (40 – 45°C) and the resulting sticky solid was resuspended in DCM (2.5L) and chilled to 00C. Oxalyl chloride (156ml, 1.8mol) was added over 15 minutes, followed by N,N-dimethylformamide (13.7ml, 0.18mol) both added at O0C. Gas evolution was observed during the DMF addition. After 1 hour, ΗPLC (Method 20, RT = 6.2 min, sample quenched with anhydrous methanol prior to injection) showed a complete reaction. The solvents were stripped again to remove residual oxalyl chloride and the mix resuspended in chilled methanol (3.0L) at 0° – 5°C, and then was allowed to warm to ambient. After two hours, HPLC indicated a complete reaction (HPLC Method 20, RT = 6.2 min). The solution was concentrated to a volume of 1.5L, and the resulting thin slurry was cooled to 0°C, and was diluted with an aqueous solution of sodium bicarbonate (126g, 3L water). After 2 hours at 50C, the product was filtered and washed with cold water / methanol (2:1, 1.5L) then dried to leave 50Og Compound 304. HPLC (Method 20) purity 92% used as is.

Compound 305

[00352] A suitable reactor was charged with Compound 304 (ca. 28Og, 0.48mol) and tetrahydrofuran (2.8L). The resulting solution was then cooled to 5°C and was treated with lithium hydroxide monohydrate (45g, 1.07mol) added in one portion. The reaction was allowed to warm to ambient, during which time the color lightened and a white precipitate formed. After overnight stirring, HPLC indicated an incomplete reaction (Method 20, product RT = 4.3, partially deprotected RT = 5.1, major impurity RT = 3.8). An additional 10% LiOH-H2O was added, but after 10 hours, the partially deprotected intermediate remained at 5%, and the impurity peak at 3.8 minutes had increased to ca. 25%. The reaction was cooled to 50C and was acidified with hydrochloric acid (5N, 280ml) then was diluted with ethyl acetate (2L). The layers were separated and the aqueous extracted with ethyl acetate (500ml). The combined organics were washed with brine (IL) and dried with sodium sulfate, then concentrated to leave a crude oily solid, Compound 305. Ca. 300g, HPLC AUC 57%.

[00353] The crude product was taken up in acetonitrile (1.2L) at 4O0C, and the product triturated w/ water (1.2L). The resulting slurry was cooled to 50C and was allowed to granulate for 30 minutes, after which time the product was filtered and washed with ACN:H2O (1 :1, 100 ml). Ca. 103g, 88% by HPLC. The product was then recrystallized from 360ml ACN at 400C and 360ml water as before. Filtered, washed and dried to leave 75g Compound 305. HPLC AUC 97%. Used as is in the next step.

Compound 306 (chiral resolution)

[00354] A suitable reactor was charged with Compound 305 (28Og, 0.66mol) and acetone (4.2L). The resulting thin slurry was then treated with (-)-cinchonidine (199g, 0.66mol) added in one portion. After one hour, a solution had formed, and after an additional hour, a white solid precipitated, and the mix was left to stir for an additional two hours (four hours total) after which time the solids were filtered, washed with acetone (200ml) and dried to leave 199g Crude Compound 306 cinchonidine salt. HPLC showed an isomer ratio of 96:4.

[00355] The crude salt was then slurried in ethyl acetate (3L) and hydrochloric acid (IN, 3L). The two phase solution was vigorously stirred for 2 hours at ambient temperature. The layers were separated, and the aqueous extracted with ethyl acetate (3L). The organics were combined, dried with sodium sulfate, and concentrated to leave the free base Compound 306, 107g, 95:5 by chiral HPLC.

[00356] The crude Compound 306 was then suspended in acetone (1.07L) and treated with (-)-cinchonidine (76g, 0.26 mol.) After 4 hours total stir time (as above) the solids were filtered, washed with acetone (200ml) and dried to leave 199g of the salt. HPLC 98.6:1.4.

[00357] The salt was broken by dissolving in ethyl acetate (3L) and hydrochloric acid (IN, 3L). The two phase solution was stirred for 2 hours at ambient temperature. The layers were separated, and the aqueous extracted with ethyl acetate (2L). The organics were combined, dried with sodium sulfate, and concentrated to leave the free base Compound 306, 98g, 98.6:1.4 by chiral HPLC. 70% recovery of the desired isomer, 35% yield from the racemic Compound 306. #6: C20H16ClN2O4P 414.78gmol‘ m/z (ESI+): 415.1 (MH+, 100%), 417.0 (MH+, 35%) [α]D 25 : -47.51 (c, 10.66mgml‘ in EtOAc) [Opposite enantiomer [α]D 25 : +47.26 (c, 9.60mgml‘ in EtOAc)] 1H NMR δH (400 MHz, d6-DMSO): 2.33 (3 H, s, Ar-CH3), 3.71 (3H, d, CH3OP), 6.50 (1Η, d, CH=CHCN), 7.36 (1Η, dd, H-6), 7.57 (1Η, d, H-I), 7.66-7.71 (2Η, m, H-4, Ar-Hortho), 7.67 (1Η, d, CH=CHCN), 7.84 (IH, d, Ar-Hortho), 7.98 (1Η, s, Ar-Hpara), 12.97 (1Η, s, N-H), 14.38 (1Η, br-s, COOH) Multiple δc values indicate splitting of carbon signal due to P. 13C NMR δc (100 MHz, d6-DMSO): 20.68 (Ar-CH3), 51.70 (CH3OP), 98.15 (CH=CHCN), 102.33, 103.85, 1 14.98, 120.91 (3 x Q, 118.47 (CN), 125.39 (C), 126.78 (Q, 127.74, 127.86 (C- Hortho), 129.78, 129.88 (Q, 131.25 (Q, 132.06 (Q, 133.44, 133.55 (Q, 133.89, 134.05 (Q, 134.62, 134.75 (Q, 135.47, 135.66 (Q, 138.78, 138.91 (Q, 149.62 (CH=CHCN), 160.40 (C=O) 31P NMR δP (162 MHz, d6-DMSO): 33.50 (IP, s)

Compound HI

[00358] A suitable reactor was charged with Compound 306 (0.63g, O.OOHmol) and 1 ,2-dimethoxyethane (10ml.) The mix was treated with 1,1-carbonyldiimidazole (0.47g, 0.0028mol) added in one portion, and the mix was allowed to stir at ambient temperature until gas evolution ceased (ca. 1.5 hours.) The solution was then cooled to 50C, and was sparged with ammonia gas for 5 minutes. HPLC (Method 20, product RT=5.0 min) showed a complete reaction after one hour at ambient. The reaction was quenched by the addition of 1Og crushed ice, and was concentrated under reduced pressure to remove the DME. The resulting slurry was stirred for one hour at 50C to granulate the product. The solids were filtered and dried to leave pure Compound III ((2-Carbamoyl-5-chloro-4-fluoro-lH-indol-3- yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyl]-(S)-phosphinic acid methyl ester) as a white solid 0.56g, 89% yield. HPLC (Method 20) chemical purity 98.5%. Chiral purity 97%. [00359] A suitable reactor was charged with Compound 306 (1Og, 0.024mol) and 1,2- dimethoxyethane (150ml). The mix was treated with 1,1-carbonyldiimidazole (7.8g, 0.048mol) added in one portion, and the mix was allowed to stir at ambient temperature until gas evolution ceased. The solution was then cooled to 5°C, and was sparged with ammonia gas for 5 minutes. HPLC (Method 20, product RT=5.0 min) showed a complete reaction after one hour. The reaction was quenched by the addition of lOOg crushed ice, and was concentrated under reduced pressure to remove the DME. The resulting oily solid (in water) was diluted with methanol (20ml) and stirred for one hour at 50C to granulate the product. The solids were filtered and dried to leave pure Compound III ((2-Carbamoyl-5- chloro-4-fluoro-lH-indol-3-yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyI]-(S)-phosphinic acid methyl ester). 9.8g, 98% yield. HPLC (Method 20) chemical purity 99.5%. Chiral purity 94.3%.

Compound III: C20Hi7ClN3O3P 413.79gmol‘ m/z (ESI+): 414.1 (MH+, 100%), 416.1 (MH+, 35%)

vmax (KBr disc) (cm“1) 1620.0 (amide I), 1670.6 (amide II), 2218.7 (CN), 3125.5, 3291.9 (N-H)

[α]D 20 : -75.08 (c, 9.04mgmr’ in CHCl3)

m.p.: 144- 1480C transition to opaque semi-solid, 209-2100C melts

Elemental analysis: C20H17ClN3O3P calculated C 58.05%, H 4.14%, N 10.15%, Cl 8.57%, P 7.49%. Found C 58.13%, H 4.08%, N 10.16%, Cl 8.69%, P 7.44% 

1H NMR δH (400 MHz, d6-DMSO): 2.32 (3H, s, Ar-CH3), 3.74 (3Η, d, CH3OP), 6.52 (1Η, d, CH=CHCN), 7.30 (1Η, dd, H-6), 7.53-7.58 (3Η, m, H-4, H-7, H-6′), 7.68 (1Η, d, CH=CHCN), 7.73 (IH, s, H-4′), 7.75 (1Η, d, H-2′), 8.02, 10.15 (2 x 1Η, 2 x s, NH2), 12.80 (1Η, s, N-H) Multiple δc values indicate splitting of carbon signal due to P. 

13C NMR δc(100 MHz, d6-DMSO): 20.77 (Ar-CH3), 51.75, 51.81 (CH3OP), 98.39, 98.91 (C-3), 98.44 (CH=CHCN), 1 15.05 (C-7), 1 18.53 (CN), 119.96 (C-4), 124.73 (C-6), 126.68 (C-5), 127.15, 127.26 (C-2′), 129.25, 129.35 (C-9), 131.37 (C-4′), 132.45, 134.04 (C-I ‘), 132.69, 132.80 (C-6′), 133.92 (C-8), 134.30, 134.44 (C-3′), 139.33, 139.46 (C-5’), 139.96, 140.17 (C-2), 149.55 (CH=CHCN), 160.65 (C=O)

 31P NMR δP (162 MHz, d6-DMSO): 33.72 (IP, s)

PATENT

http://www.google.ch/patents/WO2009120914A1?cl=en&hl=de

Figure imgf000003_0001

(2-carbamoyl-5-chloro-lH-indol-3-yl)-[3-((E)-2-cyano-vinyl)-5-methyl-phenyl]- (7?)-phosphinic acid methyl ester (I):

WO2008042240A2 * 28. Sept. 2007 10. Apr. 2008 Idenix Pharmaceuticals, Inc. Enantiomerically pure phosphoindoles as hiv inhibitors
US20060074054 * 16. Sept. 2005 6. Apr. 2006 Richard Storer Phospho-indoles as HIV inhibitors

Figure 7 provides an infrared spectrum of Form I.

Paper

Development of an Efficient Manufacturing Process to GSK2248761A API

 GlaxoSmithKline, Medicines Research Center, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
 Merck & Co. Inc., 126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00357
Abstract Image

Amidation of indole 2-carboxylate 1 with ammonia gas via the imidazolide 2 gave GSK2248761A API 3, which was in development for the treatment of HIV. Three significant impurities, namely the phosphinic acid 4, the N-acyl urea 8, and the indoloyl carboxamide 6, were formed during the reaction, and the original process was unable to produce API within clinical specification when run at scale. Investigation into the origin, fate, and control of these impurities led to a new process which was able to produce API within clinical specification.

1H NMR (500 MHz, CDCl3) δ ppm 2.37 (s, 3H), 3.86 (d, J = 15.0 Hz, 3H), 5.86 (d, J = 15.0 Hz, 1H), 5.94 (s, 1H), 7.33 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H), 7.34 (d, J = 15.5 Hz, 1H), 7.39 (s, 1H), 7.49 (dd, J = 9.0 Hz, J = 1.5 Hz, 1H) 7.60 (d, J = 13.5 Hz, 1H), 7.64 (d, J = 13.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 10.40 (s, 1H), 10.88 (s, 1H); 
13C NMR (126 MHz, CDCl3) δ 21.3, 52.1, 98.1, 100.5 (d, J = 152.5 Hz), 113.9, 117.6, 120.9, 126.2, 126.5 (d, J = 11.3 Hz) 128.7, 129.9 (d, J = 10.1 Hz), 131.7, 133.0 (d, J = 151.2 Hz), 133.2 (d, J = 8.8 Hz), 133.4 (d, J = 10.1 Hz), 134.1 (d, J= 15.1 Hz), 138.7, 139.9, 149.2 and 161.2;
 31P NMR (202 MHz, CDCl3) δ 31.4.
IR ν (cm–1) 3280, 3065, 1679, 1619, 1402, 1195 and 1010.
HRMS calcd for C20H18ClN3O3P: 414.0769; HRMS found [M + H]+: 414.0760.
PAPER

Development and Scale-Up of a Manufacturing Route for the Non-nucleoside Reverse Transcriptase Inhibitor GSK2248761A (IDX-899): Synthesis of an Advanced Key Chiral Intermediate

 GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
 Merck & Co., Inc.,126 East Lincoln Avenue, Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00356

Abstract

Abstract Image

A new and improved synthetic route to an intermediate in the synthesis of the phosphinate ester GSK2248761A is described. In the key step, we describe the first process-scale example of a palladium-catalyzed phosphorus–carbon coupling to give the entire backbone of GSK2248761A in one telescoped stage in 65% average yield on a 68 kg scale. This unusual chemistry enabled the route to be reduced from six chemistry stages to four and eliminated a number of environmentally unfriendly reagents and solvents.

REFERENCES

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2: Margolis DA, Eron JJ, DeJesus E, White S, Wannamaker P, Stancil B, Johnson M. Unexpected finding of delayed-onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761). Antivir Ther. 2014;19(1):69-78. doi: 10.3851/IMP2689. Epub 2013 Oct 24. PubMed PMID: 24158593.

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6: Piscitelli S, Kim J, Gould E, Lou Y, White S, de Serres M, Johnson M, Zhou XJ, Pietropaolo K, Mayers D. Drug interaction profile for GSK2248761, a next generation non-nucleoside reverse transcriptase inhibitor. Br J Clin Pharmacol. 2012 Aug;74(2):336-45. doi: 10.1111/j.1365-2125.2012.04194.x. PubMed PMID: 22288567; PubMed Central PMCID: PMC3630753.

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8: Klibanov OM, Kaczor RL. IDX-899, an aryl phosphinate-indole non-nucleoside reverse transcriptase inhibitor for the potential treatment of HIV infection. Curr Opin Investig Drugs. 2010 Feb;11(2):237-45. Review. PubMed PMID: 20112173.

9: Zhou XJ, Garner RC, Nicholson S, Kissling CJ, Mayers D. Microdose pharmacokinetics of IDX899 and IDX989, candidate HIV-1 non-nucleoside reverse transcriptase inhibitors, following oral and intravenous administration in healthy male subjects. J Clin Pharmacol. 2009 Dec;49(12):1408-16. doi: 10.1177/0091270009343698. Epub 2009 Sep 23. PubMed PMID: 19776293.

10: Zhou XJ, Pietropaolo K, Damphousse D, Belanger B, Chen J, Sullivan-Bólyai J, Mayers D. Single-dose escalation and multiple-dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects. Antimicrob Agents Chemother. 2009 May;53(5):1739-46. doi: 10.1128/AAC.01479-08. Epub 2009 Feb 17. PubMed PMID: 19223643; PubMed Central PMCID: PMC2681571.

11: Mascolini M, Larder BA, Boucher CA, Richman DD, Mellors JW. Broad advances in understanding HIV resistance to antiretrovirals: report on the XVII International HIV Drug Resistance Workshop. Antivir Ther. 2008;13(8):1097-113. PubMed PMID: 19195337.

12: Dalton P. Two new NNRTIs enter the pipeline. Proj Inf Perspect. 2008 Sep;(46):13. PubMed PMID: 19048672.

13: Sweeney ZK, Klumpp K. Improving non-nucleoside reverse transcriptase inhibitors for first-line treatment of HIV infection: the development pipeline and recent clinical data. Curr Opin Drug Discov Devel. 2008 Jul;11(4):458-70. Review. PubMed PMID: 18600563.

/////////////GSK2248761A , IDX899, Fosdevirine, PHASE 2

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Netarsudil


Netarsudil.png

Netarsudil

Molecular Formula: C28H27N3O3
Molecular Weight: 453.542 g/mol

Netarsudil; UNII-W6I5QDT7QI; W6I5QDT7QI; 1254032-66-0; Netarsudil [USAN]; AR-11324 free base

1422144-42-0 (mesylate)   1254032-66-0 (free base)   1253952-02-1 (HCl)

[4-[(2S)-3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl]phenyl]methyl 2,4-dimethylbenzoate

Image result for NetarsudilImage result for Netarsudil

Netarsudil Mesylate
CAS: 1422144-42-0 (mesylate)
Chemical Formula: C30H35N3O9S2

Molecular Weight: 645.742

1422144-42-0 [RN]
4-[(2S)-3-Amino-1-(6-isoquinolinylamino)-1-oxo-2-propanyl]benzyl 2,4-dimethylbenzoate methanesulfonate (1:2)
Benzoic acid, 2,4-dimethyl-, [4-[(1S)-1-(aminomethyl)-2-(6-isoquinolinylamino)-2-oxoethyl]phenyl]methyl ester, methanesulfonate (1:2)

Netarsudil dimesylate is a light yellow-to-white powder that is freely soluble in water, soluble in methanol, sparingly soluble in dimethyl formamide, and practically insoluble in dichloromethane and heptane.

Netarsudil ophthalmic solution 0.02% is supplied as a sterile, isotonic, buffered aqueous solution of netarsudil dimesylate with a pH of approximately 5 and an osmolality of approximately 295 mOsmol/kg. It is intended for topical application in the eye. Each mL of netarsudil contains 0.2 mg of netarsudil (equivalent to 0.28 mg of netarsudil dimesylate). Benzalkonium chloride, 0.015%, is added as a preservative. The inactive ingredients are: boric acid, mannitol, sodium hydroxide to adjust pH, and water for injection

Netarsudil, also known as AR-11324, is a Rho-associated protein kinase inhibitor. Netarsudil is potential useful for treating glaucoma and/or reducing intraocular pressure. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Netarsudil inhibited kinases ROCK1 and ROCK2 with a Ki of 1 nM each, disrupted actin stress fibers and focal adhesions in TM cells with IC50s of 79 and 16 nM, respectively, and blocked the profibrotic effects of TGF-β2 in HTM cells. Netarsudil produced large reductions in IOP in rabbits and monkeys that were sustained for at least 24 h after once daily dosing, with transient, mild hyperemia observed as the only adverse effect.

Netarsudil (trade name Rhopressa) is a drug for the treatment of glaucoma. In the United States, the Food and Drug Administrationhas approved a 0.02% ophthalmic solution for the lowering of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.[1]

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCK signaling plays an important role in many diseases including diabetes, neurodegenerative diseases such as Parkinson´s disease and amyotrophic lateral sclerosis, pulmonary hypertension and cancer. It has been shown to be involved in causing tissue thickening and stiffening around tumours in a mouse model of skin cancer, principally by increasing the amount of collagen in the tissue around the tumour.

WO 2014144781Image result for Netarsudil

SYNTHESIS

WO2010127329

 

 

CONTINUED………..

PATENT

PATENT

WO 2014144781

CN 107434780

https://www.google.com/patents/CN107434780A?cl=en

Synthesis of Compound 12

Figure CN107434780AD00153

[0091] The 2,4-dimethyl benzoic acid (1.5g, IOmmol) and a catalytic amount of DMF was added to the toluene and cooled to 2-5 ° C, was added dropwise oxalyl chloride (I.64g, 13_〇1 ), warmed to room temperature after dropwise, stirred overnight, during which a solid gradually dissolved to give a clear solution, evaporated to dryness under reduced pressure to give a yellow oil with dichloromethane (IOml) was dissolved in dichloromethane to give the acid chloride ;

[0092] Compound 11 (3.2g, 7.7mmo 1) and triethylamine (2ml) were added 20ml of dichloromethane, nitrogen, the above prepared acid chloride solution in dichloromethane dropwise at 0-5 ° C the increases after mixing, overnight; TLC (dichloromethane: methanol = 20: 1) to monitor the reaction, completion of the reaction, evaporated to dryness under reduced pressure, and then stirred with saturated sodium carbonate solution, filtered, the filter cake was washed with water 3 times, dried to give 3.9g white solid, i.e. compound 12; purity: 991%, optical purity: 100% (CHIRALPAK AS-H, 0.46cm IDX15cm L, Me0H + 0.1DEA) / C02 = 20/80 (V / V, 2.0ml / min), R-type, Rt = 3 · 253min; S type Rt = 4.3min).

Compound 12 (3.9g) in DCM was added, with stirring to obtain clear solution, was then added dropwise I, a solution of hydrogen chloride in dioxane 15ml 4_ (concentration 4mol / L, 4mol HCl gas dissolved in two IL oxygen six ring), and then stirred for 4 hours at room temperature, rotary evaporated under reduced pressure, and filtered to give 3.65g product as a white solid, was obtained HNMR detectable substance is the AR-13324 hydrochloride, which IHNMR spectrum Referring to FIG. 1 , MS, purity, 99.4%, lHNMR (400MHz, DMS0,300) S (Ppm) c3Il .773 (s, 1H), 9.702 (s, lH), 8.740 (d, lH), 8.560 (d, 1H), 8.469 (d, 1H), 8.360 (d, 1H), 8.280 (s, 3H), 8.158 (dd, lH), 7.777 (d, lH), 7.577 (d, 2H), 7.496 (d, 2H), 7.134 (s, lH), 7.111 (d, lH), 5.281 (s, 2H), 4.504 (q, lH), 3.609 (q, lH), 3.139 (q, lH), 2.483 (s, 3H), 2.302 ( s, 3H).

Example 2

[0097] In this embodiment, the same processing steps except that Compound 12, the other the same as in Example 1.

[0098] Compound 12 processing steps are as follows: The compound is dissolved in 12 (3.9g) 40ml of dichloromethane, followed by dropwise addition of methanesulfonic acid (2g, 21.6mmol), stirred at room temperature overnight, rotary evaporated under reduced pressure, IOOml diethyl ether was added thereto, followed by stirring, a large amount of white solid was filtered, dried to give a white solid (4.54 g of), yield 97.8%, purity 98.2%, the resulting substance was detected IHNMR AR-13324 is the mesylate salt.

References

Patent ID

Patent Title

Submitted Date

Granted Date

US9643927 Process for the preparation of kinase inhibitors and intermediates thereof
2015-11-17
2017-05-09
Patent ID

Patent Title

Submitted Date

Granted Date

US2016346269 COMBINATION THERAPY
2016-08-15
US2014275160 COMBINATION THERAPY
2014-03-14
2014-09-18
US2016243105 COMBINATION THERAPY
2016-04-29
2016-08-25
US9415043 COMBINATION THERAPY
2014-03-14
2014-09-18
US2017204065 PROCESS FOR THE PREPARATION OF KINASE INHIBITORS AND INTERMEDIATES THEREOF
2017-03-31
Netarsudil
Netarsudil.svg
Clinical data
Trade names Rhopressa
Synonyms AR-11324
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
UNII
Chemical and physical data
Formula C28H27N3O3
Molar mass 453.54 g·mol−1

REFERENCES

1: Sturdivant JM, Royalty SM, Lin CW, Moore LA, Yingling JD, Laethem CL, Sherman B, Heintzelman GR, Kopczynski CC, deLong MA. Discovery of the ROCK inhibitor netarsudil for the treatment of open-angle glaucoma. Bioorg Med Chem Lett. 2016 May 15;26(10):2475-80. doi: 10.1016/j.bmcl.2016.03.104. Epub 2016 Apr 1. PubMed PMID: 27072905.

2: Ren R, Li G, Le TD, Kopczynski C, Stamer WD, Gong H. Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms. Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6197-6209. doi: 10.1167/iovs.16-20189. PubMed PMID: 27842161; PubMed Central PMCID: PMC5114035.

3: Li G, Mukherjee D, Navarro I, Ashpole NE, Sherwood JM, Chang J, Overby DR, Yuan F, Gonzalez P, Kopczynski CC, Farsiu S, Stamer WD. Visualization of conventional outflow tissue responses to netarsudil in living mouse eyes. Eur J Pharmacol. 2016 Sep 15;787:20-31. doi: 10.1016/j.ejphar.2016.04.002. Epub 2016 Apr 13. PubMed PMID: 27085895; PubMed Central PMCID: PMC5014700.

4: Lin CW, Sherman B, Moore LA, Laethem CL, Lu DW, Pattabiraman PP, Rao PV, deLong MA, Kopczynski CC. Discovery and Preclinical Development of Netarsudil, a Novel Ocular Hypotensive Agent for the Treatment of Glaucoma. J Ocul Pharmacol Ther. 2017 Jun 13. doi: 10.1089/jop.2017.0023. [Epub ahead of print] PubMed PMID: 28609185.

5: Lu LJ, Tsai JC, Liu J. Novel Pharmacologic Candidates for Treatment of Primary Open-Angle Glaucoma. Yale J Biol Med. 2017 Mar 29;90(1):111-118. eCollection 2017 Mar. Review. PubMed PMID: 28356898; PubMed Central PMCID: PMC5369028.

/////////////Netarsudil, fda 2017, Rhopressa, AR-11324, AR 11324 

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FDA approves new treatment for certain digestive tract cancers Lutathera (lutetium Lu 177 dotatate)


Image result for lutetium Lu 177 dotatate

lutetium Lu 177 dotatate

FDA approves new treatment for certain digestive tract cancers

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs. Continue reading.\

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm594043.htm?utm_campaign=01262018_PR_FDA%20approves%20new%20treatment%20for%20digestive%20cancers&utm_medium=email&utm_source=Eloqua

January 26, 2018

Release

The U.S. Food and Drug Administration today approved Lutathera (lutetium Lu 177 dotatate) for the treatment of a type of cancer that affects the pancreas or gastrointestinal tract called gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera is indicated for adult patients with somatostatin receptor-positive GEP-NETs.

“GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment.”

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutathera is a radioactive drug that works by binding to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of Lutathera was supported by two studies. The first was a randomized clinical trial in 229 patients with a certain type of advanced somatostatin receptor-positive GEP-NET. Patients in the trial either received Lutathera in combination with the drug octreotide or octreotide alone. The study measured the length of time the tumors did not grow after treatment (progression-free survival). Progression-free survival was longer for patients taking Lutathera with octreotide compared to patients who received octreotide alone. This means the risk of tumor growth or patient death was lower for patients who received Lutathera with octreotide compared to that of patients who received only octreotide.

The second study was based on data from 1,214 patients with somatostatin receptor-positive tumors, including GEP-NETS, who received Lutathera at a single site in the Netherlands. Complete or partial tumor shrinkage was reported in 16 percent of a subset of 360 patients with GEP-NETs who were evaluated for response by the FDA. Patients initially enrolled in the study received Lutathera as part of an expanded access program. Expanded access is a way for patients with serious or immediately life-threatening diseases or conditions who lack therapeutic alternatives to gain access to investigational drugs for treatment use.

Common side effects of Lutathera include low levels of white blood cells (lymphopenia), high levels of enzymes in certain organs (increased GGT, AST and/or ALT), vomiting, nausea, high levels of blood sugar (hyperglycemia) and low levels of potassium in the blood (hypokalemia).

Serious side effects of Lutathera include low levels of blood cells (myelosuppression), development of certain blood or bone marrow cancers (secondary myelodysplastic syndrome and leukemia), kidney damage (renal toxicity), liver damage (hepatotoxicity), abnormal levels of hormones in the body (neuroendocrine hormonal crises) and infertility. Lutathera can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lutathera are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

Lutathera was granted Priority Review, under which the FDA’s goal is to take action on an application within six months where the agency determines that the drug, if approved, would significantly improve the safety or effectiveness of treating, diagnosing or preventing a serious condition. Lutathera also received Orphan Drugdesignation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Lutathera to Advanced Accelerator Applications.

 

MORE FROM PUBLIC DOMAIN……………..

WATCH THIS SPACE FOR SYNTHESIS COMING

Dotatate lutenium Lu-177.png

Dotatate lutenium Lu-177; 437608-50-9; DTXSID20195927

2-[4-[2-[[(2R)-1-[[(4R,7S,10S,13R,16S,19R)-10-(4-aminobutyl)-4-[[(1S,2R)-1-carboxy-2-hydroxypropyl]carbamoyl]-7-[(1R)-1-hydroxyethyl]-16-[(4-hydroxyphenyl)methyl]-13-(1H-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicos-19-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-2-oxoethyl]-7,10-bis(carboxylatomethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetate;lutetium(3+)

Image result for lutetium Lu 177 dotatate

 

Lutetium-177

Lutetium 1777

Lutetium-177 has been quite a late addition as an isotope of significance to the nuclear medicine yet it is making big strides especially as a therapeutic radiopharmaceutical for neuroendocrine tumours in the form of 177Lu-DOTA-TATE on regular basis as described by Das & Pillai (2013). 

 
Lutetium-177 a lanthanide is an f block element that has a half-life of 6.7 days and decays mainly by beta emission to Hf-177, is accompanied by two gamma ray emissions. These radionuclide properties are very similar to those of I-131 which has long served as a therapeutic radionuclide, it was therefore not surprising that Lu-177 also emerged as a highly valuable radionuclide for similar applications,
 
There are several other upcoming applications especially for bone pain palliatiion. As a result of its convenient production logistics Lu-177 as discussed by Pillai et al (2003) is fast emerging a radionuclide of choice in radionuclide therapy (RNT).
 
Lu-177 can be prepared in a nuclear reactor by one of the two reactions given below :
176Lu(n,gamma)177Lu or
 
176Yb(n,gamma)177Yb –beta–> 177Lu
 
The former reaction has a high thermal neutron capture cross section and is presently the method adopted at our reactors in spite of the  formation of long lived Lu-177m whose yield is very much low and is considered insignificant to cause any great concern.
Lutetium-177 Impact 
Recently there has been a rush of several research reviews and articles where Lu-177 holds the centre stage, for example, Banerjee et al (2015) have reviewed the chemistry and applications of Lu-177; Dash et al (2015) reviewed its production and available options; Knapp & Pillai (2015) highlighted its usefulness in cancer treatment and chronic diseases and Pillai and Knapp (2015) have discussed the evolving role of Lu-177 in nuclear medicine with this ready availability of Lu-177. Peptide receptor radionuclide therapy is one of the upcoming field of investigation where Lu-177 holds much promise among few other radionuclides. Indeed Lutetium-177 has covered a good distance especially for Therapeutic and as a palliative radiopharmaceutical.
 
Chemistry
Das et al (2014) have described the preparation of Lu-177 EDTMP kit.
Parus et al (2015) have discussed chemistry of bifunctional chelating agents for binding Lu-177.
Gupta et al (2014) have compiled methods of labelleing antibdoies with radioiodine and radiometals. 
 
Applications
Limouris (2012) has reviewed applications in neuroendocrine tumors with focus on Liver metastasis. Das and Banerjee (2015) described the potential theranostic applications with Lu-177.
Anderson et al (1960) were among the first to use Lutetium (as chloride and citrate) in a clinical trial which were not so successful and did not encourage much promise. Keeling et al (1988) published their results with in vitro uptake of Lutetium hydroxylapatite particles. Lu-EDTMP as bone palliating agent by Ando et al (1998) soon followed,  However the greatest impact was seen with the advent of a somatostatin analogue Lu-DOTATATE for targetting neuroendocrine tumors reported by Kwekkeboom et al (2001) and reviewed recently by Bodei et al (2013).
PRRNT  – IAEA (2013) has brought out a human health series booklet on the subject with emphasis on neuroendocrine tumors.
177Lu Labelled Peptides in NET Kam et al (2012).
177Lu- DOTATATE – PRRNT – Bakker et al (2006)
177Lu-EDTMP – Bone Pain Palliation –  Bahrami-Samani et al (2012)
177Lu-EDTMP – Pharmacokinetics, dosimetry and Therapeutic efficacy – Chakraborty S et al (2015)
177Lu-Hydroxylapatite – Radiosynovectomy – Kamalleshwaran et al. (2014) Shinto et al. (2015)
117Lu- Radioimmunotherapy – Kameshwaran et al (2015) 
177Lu – Pretargeted Radioimmunotherapy (PRIT) Frost et al (2015).
 
More specific applications and additional information about the highly valuable therapeutic isotope would soon be added.
 
References and Notes
Anderson J, Farmer FT, Haggith JW, Hill M. (1960). The treatment of myelomatosis with Lutetium. Br J Radiol. 33:374-378.
Ando A, Ando L, Tonami N, Kinuya S, Kazuma K, Kataiwa A, Nakagawa M, Fujita N. (1998). 177Lu-EDTMP: a potential therapeutic bone agent. Nucl Med Commun. 19: 587-591.
Bahrami-Samani A, Anvari A, Jalilian AR, Shirvani-Arani S, Yousefnia H, Aghamiri MR, Ghannadi-Maragheh M. (2012). Production, Quality Control and Pharmacokinetic Studies of 177Lu-EDTMP for Human Bone Pain Palliation Therapy Trials. Iran J Pharm Res. 11:137-44.
Bakker WH, Breeman WAP, Kwekkeboom DJ, De Jong LC, Krenning EP. ((2006) Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate. Q J Nucl Med Mol Imaging 50: 265-271.

Banerjee S, Pillai MR, Knapp FF (2015). Lutetium-177 Therapeutic Radiopharmaceuticals: Linking Chemistry, Radiochemistry, and Practical Applications. Chem Rev. 115: 2934-2974.
 
Bodei L, Mueller-Brand J, Baum RP, Pavel ME, Hörsch D, O’Dorisio MS, O’Dorisio TM, Howe JR, Cremonesi M, Kwekkeboom DJ, Zaknun JJ. (2013).The joint IAEA, EANM, and SNMMI practical guidance on peptide receptor radionuclide therapy (PRRNT) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2013 40:800-16.
 
Chakraborty S, Balogh L, Das T, Polyák A, Andócs G, Máthé D, Király R, Thuróczy J, Chaudhari PR, Jánoki GA, Jánoki G, Banerjee S, Pillai MR (2015). Evaluation of 177Lu-EDTMP in dogs with spontaneous tumor involving bone: Pharmacokinetics, dosimetry and therapeutic efficacy. Curr Radiopharm (ahead of Pub)
Das T, Banerjee S. (2015). Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr Radiopharm. (ahead of print).
Das T , Sarma HD, Shinto A, Kamaleshwaran KK, Banerjee S. (2014). Formulation, Preclinical Evaluation, and Preliminary Clinical Investigation of an In-House Freeze-Dried EDTMP Kit Suitable for the Preparation of Lu-177-EDTMP. Cancer Biotherap Radiopharm. 29: (ahead of publication).
Das T, Pillai M.R.A. (2013).Options to meet the future global demand of radionuclides for radionuclide therapy. Nucl Med Biol. 40: 23-32.
 
Dash A, Pillai MR, Knapp FF Jr. (2015). Production of 177Lu for targeted radionuclide therapy : Available options. Nucl Med Mol Imaging. 49: 85-107. 

Frost SH, Frayo SL, Miller BW, Orozco JJ, Booth GC, Hylarides MD, Lin Y, Green DJ, Gopal AK, Pagel JM, Bäck TA, Fisher DR, Press OW. (2015) Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models. PLoS One. 2015 Mar 18;10(3):e0120561.
 
Gupta S, Batra S, Jain M (2014) Antibody labeling with radioiodine and radiometals. Methods Mol Biol. 2014;1141:147-57. 
IAEA (2013). Peptide receptor radionuclide therapy (PRRNT) for neuroendocrine tumors. IAEA Human Health Series No. 20., IAEA, Vienna. 
 
Kam BLR, Teunissen JJM, Krenning EP, de Herder WW, Khan S, van Vliet EI, Kwekkeboom DJ. (2012). Lutetium-labelled peptides for therapy of neuroendocrine tumours.  Eur J Nucl Med Mol Imaging 39 (Suppl 1):S103–S112.
 
Kamaleshwaran KK, Rajamani V, Thirumalaisamy SG, Chakraborty S, Kalarikal R, Mohanan V, Shinto AS.(2014). 

Kameshwaran M, Pandey U, Dhakan C, Pathak K, Gota V, Vimalnath KV, Dash A, Samuel G. (2015) .Synthesis and Preclinical Evaluation of (177)Lu-CHX-A”-DTPA-Rituximab as a Radioimmunotherapeutic Agent for Non-Hodgkin’s Lymphoma. Cancer Biother Radiopharm. 2015 Aug;30(6):240-6

Kwekkeboom DJ, Bakker WH, Kooij PP, Konijnenberg MW, Srinivasan A, Erion JL, Schmidt MA, Bugaj JL, de Jong M, Krenning EP.. (2001). [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients.Eur J Nucl Med.  28: 1319-1325.

Parus JL, Pawlak D, Mikolajczak R, Duatti A. (2015) Chemistry and bifunctional chelating agents for binding 177Lu Curr Radiopharm (Ahead of Pub)
 
Limouris G. (2012) Neuroendocrine tumors: a focus on liver metastatic lesions. Front Oncol. 2:20 (Ahead of Pub) PMC article
Pillai MR, (Russ) Knapp FF. (2015). Evolving Important Role of Lutetium-177 for Therapeutic Nuclear Medicine Curr Radiopharm (ahead of print).
Pillai MR, Chakraborty S, Das T, Venkatesh M, Ramamoorthy N. (2003). Production logistics of 177Lu for radionuclide therapy. Appl Radiat Isot. 59: 109-118.
 
Shinto AS, Kamaleshwaran KK, Vyshakh K, Thirumalaisamy SG, Karthik S, Nagaprabhu VN, Vimalnath KV, Das T, Chakraborty S, Banerjee S. (2015)  Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra‑Articular Administration of 177Lu‑Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience. World J Nucl Med. 14: (ahead of print).
 
Videos
DOTA-TATE
DOTATATE.svg
Names
Other names

DOTA-(Tyr3)-octreotate
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
Properties
C65H90N14O19S2
Molar mass 1,435.63 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

DOTA-TATEDOTATATE or DOTA-octreotate is a substance which, when bound to various radionuclides, has been tested for the treatment and diagnosis of certain types of cancer, mainly neuroendocrine tumours.

Chemistry and mechanism of action

DOTA-TATE is an amide of the acid DOTA (top left in the image), which acts as a chelator for a radionuclide, and (Tyr3)-octreotate, a derivative of octreotide. The latter binds to somatostatin receptors, which are found on the cell surfaces of a number of neuroendocrine tumours, and thus directs the radioactivity into the tumour.

Usage examples

Gallium (68Ga) DOTA-TATE (GaTate[1]) is used for tumour diagnosis in positron emission tomography (PET).[2] DOTA-TATE PET/CT has a much higher sensitivitycompared to In-111 octreotide imaging.[1]

Lutetium (177Lu) DOTA-TATE[3] has been tested for the treatment of tumors such as carcinoid and endocrine pancreatic tumor. It is also known as Lutathera.[4]

Patients are typically treated with an intravenous infusion of 7.5 GBq of lutetium-177 octreotate. After about four to six hours, the exposure rate of the patient has fallen to less than 25 microsieverts per hour at one metre and the patients can be discharged from hospital.

A course of therapy consists of four infusions at three monthly intervals.[5]

Availability

Lu177 octreotate therapy is currently available under research protocols in five different medical centers in North America: Los Angeles (CA), Quebec City, (Qc), Birmingham, AL, Edmonton, (Ab), London, (On) as Houston (Tx) on clinical trial.[6] Medical centers in Europe also offer this treatment. For instance: Cerrahpasa Hospital in TurkeyUppsala Centre of Excellence in Neuroendocrine Tumors in Sweden and Erasmus University in the Netherlands.[7] In Israel, treatment is available at Hadassah Ein Kerem Medical Center. In Australia, treatment is available at St George Hospital and Royal North Shore Hospital, Sydney;[8] the Royal Brisbane and Women’s Hospital in Brisbane [9], the Peter MacCallum Cancer Centre [1] and at the Department of Nuclear Medicine at Fremantle Hospital in Western Australia.[10] In Aarhus universitet hospital in Denmark. In the coming years such therapy will also become commercially available in Latvia, Riga – “Clinic of nuclear medicine”.

See also

  • DOTATOC or edotreotide, a similar compound

References

  1. Jump up to:a b c Hofman, M. S.; Kong, G.; Neels, O. C.; Eu, P.; Hong, E.; Hicks, R. J. (2012). “High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours”. Journal of Medical Imaging and Radiation Oncology56 (1): 40–47. doi:10.1111/j.1754-9485.2011.02327.xPMID 22339744.
  2. Jump up^ Breeman, W. A. P.; De Blois, E.; Sze Chan, H.; Konijnenberg, M.; Kwekkeboom, D. J.; Krenning, E. P. (2011). “68Ga-labeled DOTA-Peptides and 68Ga-labeled Radiopharmaceuticals for Positron Emission Tomography: Current Status of Research, Clinical Applications, and Future Perspectives”. Seminars in Nuclear Medicine41 (4): 314–321. doi:10.1053/j.semnuclmed.2011.02.001PMID 21624565.
  3. Jump up^ Bodei, L.; Cremonesi, M.; Grana, C. M.; Fazio, N.; Iodice, S.; Baio, S. M.; Bartolomei, M.; Lombardo, D.; Ferrari, M. E.; Sansovini, M.; Chinol, M.; Paganelli, G. (2011). “Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study”. European Journal of Nuclear Medicine and Molecular Imaging38(12): 2125–2135. doi:10.1007/s00259-011-1902-1PMID 21892623.
  4. Jump up^ Radiolabeled Peptide Offers PFS Benefit in Midgut NET
  5. Jump up^ Claringbold, P. G.; Brayshaw, P. A.; Price, R. A.; Turner, J. H. (2010). “Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours”. European Journal of Nuclear Medicine and Molecular Imaging38 (2): 302–311. doi:10.1007/s00259-010-1631-xPMID 21052661.
  6. Jump up^ Clinical trial number NCT01237457 for “177Lutetium-DOTA-Octreotate Therapy in Somatostatin Receptor-Expressing Neuroendocrine Neoplasms” at ClinicalTrials.gov
  7. Jump up^ “PRRT Behandelcentrum Rotterdam”PRRT Behandelcentrum RotterdamErasmus Universiteit.
  8. Jump up^ http://www.swslhd.nsw.gov.au/liverpool/pet/PET.html
  9. Jump up^ https://agitg.org.au/control-nets-study-set-to-commence
  10. Jump up^ Turner, J. H. (2012). “Outpatient therapeutic nuclear oncology”. Annals of Nuclear Medicine26 (4): 289–97. doi:10.1007/s12149-011-0566-zPMID 22222779.

//////////////Lutathera, lutetium Lu 177 dotatate, fda 2018, PRIORITY REVIEW, ORPHAN DRUG

CC(C1C(=O)NC(CSSCC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)N1)CCCCN)CC2=CNC3=CC=CC=C32)CC4=CC=C(C=C4)O)NC(=O)C(CC5=CC=CC=C5)NC(=O)CN6CCN(CCN(CCN(CC6)CC(=O)[O-])CC(=O)[O-])CC(=O)[O-])C(=O)NC(C(C)O)C(=O)O)O.[Lu+3]

Delafloxacin


Delafloxacin.svg

ChemSpider 2D Image | Delafloxacin | C18H12ClF3N4O4

Delafloxacin.png

Delafloxacin

  • Molecular FormulaC18H12ClF3N4O4
  • Average mass440.760 Da

Delafloxacin, ABT-492, RX-3341, WQ-3034, A-319492

1-(6-Amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-7-(3-hydroxy-1-azetidinyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid
189279-58-1 [RN]
3-Quinolinecarboxylic acid, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-
T66 BN EVJ DVQ HF JG B- BT6NJ CF EF FZ& I- AT4NTJ CQ [WLN]
1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylic acid
MOA:DNA gyrase enzyme inhibitor; DNA topoisomerase Ⅳ inhibitor
Indication:Community-acquired pneumonia (CAP); Complicated skin and soft tissue infections
Status:FDA 2017
Company:Wakunaga (Originator) , Melinta Therapeutics

Delafloxacin is a Fluoroquinolone Antibacterial. The chemical classification of delafloxacin is Fluoroquinolones.

Image result for delafloxacin

Delafloxacin is a fluoroquinolone antibiotic which has been used in trials studying the treatment and basic science of Gonorrhea, Hepatic Impairment, Bacterial Skin Diseases, Skin Structure Infections, and Community Acquired Pneumonia, among others. It was approved in June 2017 under the trade name Baxdela for use in the treatment of acute bacterial skin and skin structure infections.
Image result for delafloxacin
Delafloxacin meglumine; 352458-37-8; UNII-N7V53U4U4T; Delafloxacin (meglumine); Delafloxacin meglumine [USAN]; N7V53U4U4T, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxoquinoline-3-carboxylic acid;(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol
D-Glucitol, 1-deoxy-1-(methylamino)-, 1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6-fluoro-1,4-dihydro-7-(3-hydroxy-1-azetidinyl)-4-oxo-3-quinolinecarboxylate (1:1)

Delafloxacin (INN) (trade name Baxdela) is a fluoroquinolone antibiotic used to treat acute bacterial skin and skin structure infections.[1] It was developed and marketed by Melinta Therapeutics (formerly Rib-X Pharmaceuticals),[1] which subsequently merged with Cempra.[2]

Image result for delafloxacin

syn

CN 104876911

Medical use

Delafloxacin is used to treat acute bacterial skin and skin structure infections caused by designated susceptible bacteria.[1]

Susceptible bacteria are:[1]

  • Gram-positive organisms: Staphylococcus aureus (including methicillin-resistant [MRSA] and methicillin-susceptible [MSSA] isolates), Staphylococcus haemolyticusStaphylococcus lugdunensisStreptococcus agalactiaeStreptococcus anginosus group, Streptococcus pyogenes, and Enterococcus faecalis
  • Gram-negative organisms: Escherichia coliEnterobacter cloacaeKlebsiella pneumoniae, and Pseudomonas aeruginosa.

It has not been tested in pregnant women.[1]

Adverse effects

Like other drugs in the fluoroquinolone class, delafloxacin contains a black box warning about the risk of tendinitis, tendon rupture, peripheral neuropathy, central nervous system effects, and exacerbation of myasthenia gravis. The label also warns against the risk of hypersensitivity reactions and Clostridium difficile-associated diarrhea.[1]

Adverse effects occurring in more than 2% of clinical trial subjects included nausea, diarrhea, headache, elevated transaminases, and vomiting.[1]

Image result for delafloxacin

Interactions

Like other fluoroquinolones, delafloxacin chelates metals including aluminum, magnesium, sucralfate, iron, zinc, and divalent and trivalent cations like didanosine; using this drugs with antacids, some dietary supplements, or drugs buffered with any of these ions will interfere with available amounds of delafloxacin.[1]

Pharmacology

The half-life varies in around 8 hours at normal doses. Excretion is 65% through urine, mostly in unmetabolized form, and 28% via feces. Clearance is reduced in people with severe kidney disease.[3]

Delafloxacin is more active (lower MIC90) than other quinolones against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). In contrast to most approved fluoroquinolones, which are zwitterionic, delafloxacin has an anionic character, which results in a 10-fold increase in delafloxacin accumulation in both bacteria and cells at acidic pH. This property is believed to confer to delafloxacin an advantage for the eradication of Staphylococcus aureus in acidic environments, including intracellular infections.[3]

Chemistry

The chemical name is 1-Deoxy-1 (methylamino)-D-glucitol, 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl) 4-oxo-1,4-dihydroquinoline-3-carboxylate (salt).[1]

The injectable form of delafloxacin is sold as the meglumine salt of the active ingredient and its United States Adopted Name, delafloxacin meglumine, reflects that; the injection formulation also includes EDTA and sulfobutylether-β-cyclodextrin. The tablet is made of delafloxacin, citric acid anhydrous, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, sodium bicarbonate, and sodium phosphate monobasic monohydrate.[1]

History

Delafloxacin was known as ABT-492, RX-3341, and WQ-3034 while it was under development.[4]

Rib-X Pharmaceuticals acquired delafloxacin from Wakunaga Pharmaceutical in 2006.[5] Rib-X was renamed to Melinta Therapeutics in 2013.[6]

Key clinical trials for delafloxacin have been performed by Melinta regarding indications for skin and skin structure infections as well as complicated bacterial infections and uncomplicated gonorrhea. The trial on gonorrhea was terminated before data was released.[7]

Delafloxacin was approved by the FDA in June 2017, after it was noninferior to vancomycin plus aztreonam in two trials on 1042 patients with acute bacterial skin and skin structure infection.[8] New Drug Applications (NDA) for delafloxacin (Baxdela) 450 mg tablets and 300 mg injections were approved by the FDA in June 2017.[9]

The FDA obligated Melinta to conduct further studies as follows:[9]

  • a 5-year surveillance study to determine if resistance emerges, with the final report due in December 2022
  • a study of the IV form in pregnant rats to determine distribution to the reproductive tract, due June 2018, with further studies required if there is significant distribution.

Melinta merged with Cempra in August, 2017.[2]

Melinta has entered into commercialization and distribution agreements with both Menarini Therapeutics (March 2017) and Eurofarma Laboratórios (January 2015) for international commercialization of delafloxacin. The agreement with Menarini allows them to commercialize and distribute in 68 countries, including Europe, China, and South Korea among others. A similar agreement with Eurofarma allows for commercialization in Brazil.[7]

PATENT

CN103936717A

 de Iaf Ioxacin Preparation

Figure CN103936717BD00132

[0101] was added to the S-neck flask resultant product of Example 11 (3.5 Yap, dirty 〇1 0.76) implemented 01. (35 blood) milky white suspension, was added glacial acetic acid (3. OmL), stirred at room temperature to embrace completely clear solution was added dropwise distilled water 70 fed blood, filter, wash coating, evaporated to dryness to give a pale yellow powder 3. Og, purity 99.8% (HPLC), m / z (MH + M41.03, IH NMR (400MHz, DMSO) S4.20 (m, 2H), 4.45 (m, lH), 4.61 (m, 2H), 5.63 (d, lH), 6.69 (s, 2H), 7.81 (d, lH), 7.95 (dd, lH), 8.69 (d, lH), 14.34 (brs, lH).

PAPER

Org. Process Res. Dev. 200610, 803-807.

Chlorination at the 8-Position of a Functionalized Quinolone and the Synthesis of Quinolone Antibiotic ABT-492

GPRD Process Research and Development, Abbott Laboratories, Bldg. R8/1, 1401 Sheridan Road, North Chicago, Illinois 60064-6285, U.S.A.
Org. Process Res. Dev.200610 (4), pp 803–807
DOI: 10.1021/op0600557
Abstract Image

The total synthesis of quinolone antibiotic ABT-492 has been achieved in 67% yield over nine steps from 2,4,5-trifluorobenzoic acid. The highlights of this synthesis include a novel chemoselective chlorination at the 8-position of a highly elaborated quinolone core. In addition, a Lewis acid promoted cyclization reaction to form the quinolone heterocycle was developed which was incorporated into a one-pot, three-step cyclization/coupling/protection sequence that proceeds in 93% yield.

1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6-fluoro-7-(3-hydroxyazetidin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid (ABT-492), NCS Process: . Mp:  238−241 °C. 1H NMR (CDCl3) δ 14.63 (brs, 1H), 8.70 (d, J = 0.7 Hz, 1H), 7.95 (dd, J = 9.9, 0.7 Hz, 1H), 7.83 (d, J = 13.6 Hz, 1H), 6.75 (s, 2H), 5.75 (d, J = 5.8 Hz, 1H), 4.61 (m, 12H), 4.47 (m, 1H), 4.18 (m, 2H). Anal. Calcd for C18H12ClF3N4O4:  C, 49.05; H, 2.74; N, 12.71. Found:  C, 48.90; H, 2.48; N, 12.62.

PATENT

WO2006015194A2.

EXAMPLE 5
A solution of 2,4,5-trifluorobenzoic acid (139.5Kg) in DMF (8.4Kg) and toluene (613Kg) was treated with thionyl chloride (139.4Kg), stirred at 60°C for 3.5 hours, cooled to 250C, concentrated to 20% of its original volume, treated with toluene (600Kg), distilled and stored at ambient temperature.

EXAMPLE 6
A suspension of potassium ethyl malonate (50.8Kg) and magnesium chloride
(34.5Kg) in toluene (130Kg) below 00C was treated with THF (265L), cooled to 0°C, treated with triethylamine (75Kg), warmed to 5O0C, stirred for 1-5 hours, cooled to 00C, treated with 22% (w/w) of EXAMPLE 5 in toluene (163Kg), warmed to ambient temperature, stirred for 2 hours, added to 2M HCl (407Kg), stirred for 30 minutes, separated from the water layer and washed with water. This procedure was repeated, and the organic layers were combined, concentrated with an ethanol (150L) azeotrope, treated with water (30% by weight of the organic layer), stirred for 3 hours at 00C, and filtered. The andfiltrant was washed with 3:1 ethanol/water and dried under vacuum at 35-45°C to provide 86Kg of product. H NMR (CDCl3) (keto) δ 7.75 (ddd, J=10.8, 10.8, 6.0Hz, IH), 7.02 (ddd, IH), 4.27 (q, J=7.2Hz, 2H), 3.95 (d, 4.2Hz, 2H), 1.35 (t, J=7.3Hz, 3H); (enol) δ 12.72 (s, IH), 7.85 (ddd, J=10.5, 9.6, 6.6Hz, IH), 6.96 (ddd, J=10.5, 10.5, 6.6Hz, IH), 5.84 (s, IH), 4.23 (q, J=7.2Hz, 2H), 1.27 (t, J=7.4Hz, 3H).

EXAMPLE 7A
A solution of EXAMPLE 6 (83.2Kg) in triethyl orthoformate (80.1Kg) at reflux was stirred for 0.5-1 hour, treated with acetic anhydride (103.5Kg), stirred for 12 hours and cooled to ambient temperature to provide a solution that was used immediately.

EXAMPLE 7B
The solution of EXAMPLE 7A was treated with N-methylpyrrolidinone (210Kg), acetonitrile (161Kg) and water (3Kg), added to a suspension of EXAMPLE 4 (57.4Kg) in 1 : 1 N-methylpyrrolidinone (210Kg) and acetonitrile (161Kg), stirred for 2 hours, added to water (662Kg) and filtered. The fϊltrant was washed with (2:1) acetonitrile/water and water and dried under vacuum at 600C to provide 119.5Kg of product. Mp 157-16O0C; 1H NMR (CDCl3, 300 MHz) (E) δ 1.15 (t, 3H), 4.16 (q, 2H), 4.64 (br s, 2H), 6.90 (m, IH), 7.22 (t, IH), 7.32 (m, IH), 9.03 (d, IH), 12.44 (bd, IH); (Z) δ 1.03 (t, 3H), 4.11 (q, 2H), 4.60 (br s, 2H), 6.90 (m, IH), 7.20 (t, IH), 7.48 (m, IH), 8.90 (d, IH), 11.17 (bd, IH).

EXAMPLE 8A
A mixture of EXAMPLE 7 (115Kg) and lithium chloride (24.3Kg) in
N-methylpyrrolidinone (769Kg) below 350C was treated with DBU (946.1Kg) and stirred for 2 hours to provide a solution of EXAMPLE 8 A that was used immediately.

EXAMPLE 8B
The solution of EXAMPLE 8A below 4O0C was treated with EXAMPLE 2 (33.9Kg) and DBU (109Kg) and stirred for 2-5 hours to provide a solution of EXAMPLE 8B that was used immediately.

EXAMPLE 8C
The solution of EXAMPLE 8B was treated with isobutyric anhydride (99.7Kg), stirred at 350C for 1-2 hours, cooled to 20-300C, treated with ethyl acetate (104Kg) and 10% aqueous citric acid (570Kg) and filtered. The filtrant was washed with water and dried under vacuum at 500C to provide 136Kg of product. 1H NMR (DMSO-d6, 400 MHz) δ 8.49 (s, IH), 8.00 (dd, J=9.0, 9.3 Hz, IH), 7.75 (d, J=12.8 Hz, IH), 6.79 (br s, 2H), 5.95 (dd, J=I.5, 7.6 Hz, IH), 5.21 (m, IH), 4.36 (t, J=7.4 Hz, 2H), 4.02 (q, J=7.0 Hz, 2H), 3.95 (dd, J=3.7, 9.2 Hz, 2H), 2.58 (hept, J=7.0 Hz, IH), 1.26 (t, J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 6H).

EXAMPLE 10
A solution of N-chlorosuccinimide (25.3Kg) in methyl acetate (419Kg) at 170C was treated with sulfuric acid (560 g), transferred to a slurry of EXAMPLE 8 (92.7Kg) in ethyl acetate (244Kg) at 17°C while maintaining the reaction temperature at 17°C,
quenched/washed with 1.5% aqueous sodium bicarbonate (370Kg), washed with
10% aqueous sodium sulfite (200Kg) and concentrated. The concentrate was dissolved in isopropanol, treated with 4% (w/w) aqueous potassium hydroxide (750Kg), stirred at 5O0C until hydrolysis was complete, passed through a polishing filter, treated with 12% aqueous acetic acid (410Kg) and filtered. The filtrant was washed with water and dried at 5O0C to provide 73Kg of product. 1H NMR (CDCl3) δ 14.63 (brs, IH), 8.70 (d, J=0.7Hz, IH), 7.95 (dd, J=9.9, 0.7Hz, IH), 7.83 (d, J=13.6Hz, IH), 6.75 (s, 2H), 5.75 (d, J=5.8Hz, IH), 4.61 (m, 12H), 4.47 (m, IH), 4.18 (m, 2H).

PATENT

https://www.google.com/patents/CN104876911A?cl=en

Image result for delafloxacin

 Currently, 德拉沙 star for the synthesis mainly in the following two ways:

[0004] 1, Chinese patent CN1201459A _2,4,5_ trifluorobenzoyl from 3-chloro-ethyl ester synthesis De Lasha star. Used in this reaction is N, N- dimethylformamide high temperature and potassium carbonate cyclization, prone to impurities, after cyclization is hydrolyzed required, increase the reaction step, a low yield. Reaction scheme is as follows:

[0005]

Figure CN104876911AD00031

[0006] 2, published in the Journal of Organic Chemistry (Org Process Res & Dev2006,4, 751) provides a new synthesis method 德拉沙 star from 2,4,5_ trifluoroacetic acid as the starting material, synthetic Germany Lassa star. This reaction because of the need in eight selective chlorination, so 7-hydroxy need protection, reaction step increase. And when eight were chlorinated 7 substituent easily broken, harsh reaction conditions, the reaction yield is low, is not suitable for mass production. Reaction scheme is as follows:

[0007]

Figure CN104876911AD00041

Example: 8_-Chloro-6-fluoro-1- (6-amino-3,5-difluoro-2-yl) -7- (3-hydroxy-1-azetidinyl) – 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (Dela Sha star) Synthesis of

[0025] 3-chloro-2,4,5-trifluoro-benzoyl acetate (78,0.025111〇1) in 501,111 flask, triethylorthoformate (5. 9g, 0. 04mol) and vinegar anhydride, heated at reflux for 3h ~ 5h, evaporated under reduced pressure excess triethyl orthoformate and acetic anhydride, was added N- methylpyrrolidone was diluted, and then 2,6-diamino-3,5-difluoro-pyridine was suspended ( 3. 8g, 0. 026mol) and N- methylpyrrolidone were suspended, was added dropwise to the above solution, after completion of the reaction was added anhydrous lithium chloride (2. 6g) and DBU (4.6g, 0.03mol) (1 1,8-diazabicyclo [5.4.0] undec-ene _7_) was heated with stirring, HPLC monitored the reaction was complete. Then 3-hydroxy-azetidine hydrochloride (3. 52g) was added to the above solution was added dropwise DBU, the reaction was continued to completion. In the aqueous solution of isopropanol and potassium hydroxide, heating the hydrolysis, the hydrolysis is completed after adjusting PH = 3 solid precipitated. Filtering, washing, to give a yellow solid (7. 82g), yield 71%.

[0026] MP: 238-241 ° C

[0027] Tuen bandit 1 (square)?! (: 13) 14.32 0 ^ 8,1 1), 8.51 ((1, J = 0.7Hz, lH), 7.96 (dd, J = 9 · 9,0 · 7Ηζ , 1H), 7 · 64 (d, J = 13. 6Hz, 1H), 6 · 92 (s, 2H), 5 · 86 (d, J = 5. 8Hz, 1H), 4 · 89 (m, 12H ), 4 · 32 (m, 1H), 4 · 18 (m, 2H).

References

  1. Jump up to:a b c d e f g h i j “Delafloxacin tablets US label” (PDF). FDA. June 2017. Retrieved July 9,2017.  This article incorporates text from this source, which is in the public domain. For label updates, see FDA index page for NDA 208610 for tablets, and see FDA index page for NDA 208611 for injectable form.
  2. Jump up to:a b “Cempra Press Releases”.
  3. Jump up to:a b Candel, FJ; Peñuelas, M (2017). “Delafloxacin: design, development and potential place in therapy”Drug design, development and therapy11: 881–891. doi:10.2147/DDDT.S106071PMC 5367733Freely accessiblePMID 28356714.
  4. Jump up^ “Delafloxacin”. AdisInsight. Retrieved 10 July 2017.
  5. Jump up^ Cartwright, Heather (12 July 2011). “Rib-X Pharmaceuticals Signs Global Antibiotic Research Collaboration with Sanofi”PharmaDeals Review (7). doi:10.3833/pdr.v2011i7.1494. Archived from the original on 25 April 2012.
  6. Jump up^ Stearns, John (August 1, 2016). “Melinta Therapeutics takes aim at deadly drug-resistant bacteria”Hartford Business Journal.
  7. Jump up to:a b Markham, Anthony (July 2017). “Delafloxacin: First Global Approval” Check |url=value (help)Drugs77: 1481–1486 – via Springer.
  8. Jump up^ Osborne, Randy (20 June 2017). “Melinta’s I.V., oral delafloxacin wins FDA nod in skin infections”BioWorld.
  9. Jump up to:a b “NDA Approval Letter: NDA 208610 and NDA 208611” (PDF). FDA. June 19, 2017.
  10. Cited Patent Filing date Publication date Applicant Title
    CN1201459A * Sep 20, 1996 Dec 9, 1998 涌永制药株式会社 Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising same as active ingredient
    JP2005097116A * Title not available
    WO2006015194A2 * Jul 29, 2005 Feb 9, 2006 Abbott Laboratories Preparation of pyridonecarboxylic acid antibacterials
  11. FDA Orange Book Patents

    FDA Orange Book Patents: 1 of 8 (FDA Orange Book Patent ID)
    Patent 8871938
    Expiration Sep 23, 2029
    Applicant MELINTA
    Drug Application N208610 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)
    FDA Orange Book Patents: 2 of 8 (FDA Orange Book Patent ID)
    Patent 9539250
    Expiration Oct 7, 2025
    Applicant MELINTA
    Drug Application N208611 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)
    FDA Orange Book Patents: 3 of 8 (FDA Orange Book Patent ID)
    Patent 7728143
    Expiration Nov 20, 2027
    Applicant MELINTA
    Drug Application N208611 (Prescription Drug: BAXDELA. Ingredients: DELAFLOXACIN MEGLUMINE)

    View All 8 FDA Orange Book Patents

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Submitted Date

Granted Date

EP0911327 NOVEL PYRIDONECARBOXYLIC ACID DERIVATIVES OR THEIR SALTS AND ANTIBACTERIAL AGENT COMPRISING THE SAME AS THE ACTIVE INGREDIENT
1999-04-28
2001-12-05
US2012065186 ANTIMICROBIAL COMPOSITIONS
2011-05-11
2012-03-15
US2012156259 Biodegradable Polyethylene Glycol Based Water-Insoluble Hydrogels
2010-07-30
2012-06-21
US2007249577 Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
2007-10-25
US2007238719 Method for reducing the risk of or preventing infection due to surgical or invasive medical procedures
2007-10-11
Patent ID

Patent Title

Submitted Date

Granted Date

US6156903 Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
2000-12-05
US6133284 Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
2000-10-17
EP0992501 Pyridonecarboxylic acid derivatives as antibacterial agents
2000-04-12
2002-08-28
US5998436 Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
1999-12-07
EP0952151 Intermediates for use in preparing novel pyridonecarboxylic acid derivatives or their salts
1999-10-27
2003-05-28
Patent ID

Patent Title

Submitted Date

Granted Date

US8535655 BIODEGRADABLE POLYMER – BIOACTIVE MOIETY CONJUGATES
2011-10-06
US2012202756 USE OF PRODRUGS TO AVOID GI MEDIATED ADVERSE EVENTS
2011-10-05
2012-08-09
US8563598 BETA-LACTONES AS ANTIBACTERIAL AGENTS
2011-08-11
US2010040548 HIGH PENETRATION PRODRUG COMPOSITIONS OF ANTIMICROBIALS AND ANTIMICROBIAL-RELATED COMPOUNDS
2010-02-18
US6586420 Quinolinecarboxylic acid derivative or its salt
2003-07-01
Patent ID

Patent Title

Submitted Date

Granted Date

US9439888 Tetrazolones as a carboxylic acid bioisosteres
2016-01-25
2016-09-13
US8809286 CONJUGATED ANTIMICROBIAL AGENTS
2012-01-26
US2012157371 HIGH PENETRATION PRODRUG COMPOSITIONS OF ANTIMICROBIALS AND ANTIMICROBIAL-RELATED COMPOUNDS
2011-12-12
2012-06-21
US8962786 CHAIN EXTENDERS
2011-11-24
US9409896 Sustained release pharmaceutical compositions comprising an antibacterial agent
2011-11-01
2016-08-09
Patent ID

Patent Title

Submitted Date

Granted Date

US8252813 Salt and crystalline forms thereof of a drug
2010-02-05
2012-08-28
US9539250 Salt and Crystalline Forms Thereof of a Drug
2015-02-03
2015-07-16
US8273892 Salt and crystalline forms thereof of a drug
2010-04-20
2012-09-25
US8895033 SUSTAINED RELEASE FORMULATIONS USING NON-AQUEOUS CARRIERS
2011-09-01
US9701647 Tetrazolones as a carboxylic acid bioisosteres
2016-08-10
2017-07-11
Patent ID

Patent Title

Submitted Date

Granted Date

US8871938 Process for making quinolone compounds
2013-07-09
2014-10-28
US8497378 Process for making quinolone compounds
2009-09-23
2013-07-30
US7728143 Salt and crystalline forms thereof of a drug
2005-10-07
2010-06-01
US8969569 Salt and crystalline forms thereof of a drug
2014-02-07
2015-03-03
US8648093 Salt and crystalline forms thereof of a drug
2012-08-27
2014-02-11
Delafloxacin
Delafloxacin.svg
Clinical data
Trade names Baxdela
Synonyms ABT-492; RX-3341; WQ-3034
Routes of
administration
Oralintravenous injection
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C18H12ClF3N4O4
Molar mass 440.76 g/mol
3D model (JSmol)

/////////////Delafloxacin, ABT-492, RX-3341, WQ-3034, FDA 2017, A-319492

C1C(CN1C2=C(C=C3C(=C2Cl)N(C=C(C3=O)C(=O)O)C4=NC(=C(C=C4F)F)N)F)O

Naldemedine, ナルデメジントシル酸塩


str1

Naldemedine.svg

ChemSpider 2D Image | Naldemedine | C32H34N4O6

NALDEMEDINE.png

Naldemedine

  • Molecular FormulaC32H34N4O6
  • Average mass570.636 Da
CAS 916072-89-4 [RN]
CAS Number

FDA APPROVED 2017

Morphinan-7-carboxamide, 17-(cyclopropylmethyl)-6,7-didehydro-4,5-epoxy-3,6,14-trihydroxy-N-[1-methyl-1-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-, (5α)-
(5α)-17-(Cyclopropylmethyl)-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-propanyl]-6,7-didehydro-4,5-epoxymorphinan-7-carboxamide
(4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,7,9-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]-1,2,4,5,7a,13-hexahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-6-carboxamide
S-297,995
S-297995
UNII:03KSI6WLXH
Naldemedine is an opioid receptor antagonist [FDA Label]. It is a modified form of [DB00704] to which a side chain has been added to increase molecular weight and polar surface area resulting in restricted transport across the blood brain barrier. Naldemedine was approved in 2017 in both the US and Japan for the treatment of Opioid-induced Constipation.
Naldemedine, also known as S 297995, is a peripherally-selective μ-opioid receptor antagonist under development by Shionogi for the treatment of opioid-induced adverse effects including constipation, nausea, and vomiting. Clinical studies have thus far found it to possess statistically significant effectiveness for these indications and to be generally well-tolerated with predominantly mild to moderate gastrointestinal side effects. No effects indicative of central opioid withdrawal or impact on the analgesic or mydriatic effects of co-administered opioids have been observed.
Image result for naldemedine

Naldemedine (INNUSANS-297,995Symproic) is a peripherallyselective μ-opioid receptor antagonist developed by Shionogi which is approved for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.[1] Clinical studies have thus far found it to possess statistically significant effectiveness for these indications and to be generally well-tolerated with predominantly mild to moderate gastrointestinal side effects.[2][3] No effects indicative of central opioid withdrawal or impact on the analgesic or mydriatic effects of co-administered opioids have been observed.[2]

Image result for naldemedineImage result for naldemedine

Image result for naldemedine

ナルデメジントシル酸塩

Commercialization

Naldemedine is manufactured by Shionogi Inc., a U.S. based subsidiary of Shionogi & Co., Ltd. Shionogi & Co., Ltd. (SGIOF) is a Japanese pharmaceutical company founded in 1878 based in Osaka, Japan. Shionogi Inc. is fully funded by its parent company, Shionogi & Co., Ltd. The parent company specializes in pharmaceuticals, diagnostic reagents and medical devices in Japan and internationally. Naldemedine is their only gastroenterology product in the United States.

In the US market, Shionogi Inc. has partnered with Purdue Pharma in a joint venture for US commercialization of Symproic.[4] Purdue Pharma LP is a privately held pharmaceutical company based in the United States that specializes in chronic pain disorders.[5]

Purdue Pharma appealed to remove the Class II scheduling of Symproic as accordant to the Controlled Substances Act. The appeal was posted to the Federal Register on July 12, 2017.[6] The Drug Enforcement Administration officially removed the Class II scheduling in September 2017.[7]

SYN

US 8084460

WO 2012063933

Manufacturer Finances

Since 2015, Shionogi & Co., Ltd. has produced increasing net income. At the end of fiscal year 2016, Shionogi & Co., Ltd. had a net income of $66,687,000. At the end of fiscal year 2017, they increased their net income to $83,879,000.[8] How much of this is attributed to sales of Symproic is unknown. Shionogi & Co., Ltd. ends their fiscal year on March 31 of each year. Considering the drug was only FDA approved on March 23 of 2017, the true valuation of the drug is yet to be seen. Purdue Pharma has begun advertising for the medication to be available by October 2017.[9]

Intellectual Property

There are currently three patents issued for naldemedine tosylate by the United States Patent and Trademark Office. All patents are owned by Shionogi Inc. and will expire from 2026-2031.[10] Naldemedine tosylate has 46 other patents in 18 different countries.[11]

Preclinical Trials

12 Phase I clinical trials were reported for the use of naldemedine in healthy volunteers.[12] In a single ascending dose study, subjects received one dose of naldemedine (0.1–100 mg) or one dose of a placebo. In a multiple ascending dose study, subjects received once daily naldemedine (3–30 mg) or placebo for 10 days. Maximum plasma concentrations were reached within 0.5-0.75 hours. There were no reported major safety concerns, even at doses 150-500 times the available dose of 0.2 mg. In both studies, gastrointestinal events occurred more frequently with naldemedine, but researchers concluded these to be treatment related.[13]

Clinical Trials

The approval of naldemedine came from the results of the COMPOSE program, a phase three clinical studies program conducted in adults 18–80 years of age with chronic non-cancer pain opioid induced constipation. COMPOSE-I and COMPOSE-II were 12-week double blind randomized controlled trials comparing the use of naldemedine to placebo in the patient population. COMPOSE-I began in August 2013 until January 2015 in 68 outpatient clinic in seven countries. COMPOSE-II began in November 2013 until June 2015 taking place in 69 outpatient clinics in six countries. In both trials, patients were randomly assigned to receive either naldemedine 0.2 mg or placebo once daily for 12 weeks. A responder had at least three spontaneous bowel movements per week with an increase of one spontaneous bowel movement for nine of the 12 weeks, including three of the final four weeks of the study. In COMPOSE-I and COMPOSE-II, the proportion of responders were significantly higher in the naldemedine group than the placebo group. Adverse events were similar in both trials, however, patients in the naldemedine group had slightly higher rates of adverse events.[14]

COMPOSE-III was a 52 week clinical trial examining the long term safety with naldemedine in patients with non cancer chronic pain. Results from this trial showed statistical significance for increased weekly bowel movements and no opioid withdrawal symptoms. The study also concluded adverse effects were more similar between two groups.[12]

All trials were conducted following Good Clinical Practice guidelines.[12]

Patent ID

Patent Title

Submitted Date

Granted Date

US9108975 CRYSTAL OF 6, 7-UNSATURATED-7-CARBAMOYL MORPHINAN DERIVATIVE AND METHOD FOR PRODUCING THE SAME
2011-11-11
2013-09-05
US9315512 Crystal of 6, 7-unsaturated-7-carbamoyl morphinan derivative and method for producing the same
2015-08-04
2016-04-19
US8536192 6, 7-unsaturated-7-carbamoyl substituted morphinan derivative
2011-11-30
2013-09-17
US8084460 6, 7-unsaturated-7-carbamoyl substituted morphinan derivative
2009-08-13
2011-12-27
US2015216804 PREPARATION CONTAINING 6, 7-UNSATURATED-7-CARBAMOYL MORPHINAN DERIVATIVES
2013-05-13
2015-08-06

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3 (FDA Orange Book Patent ID)
Patent 9108975
Expiration Nov 11, 2031
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)
FDA Orange Book Patents: 2 of 3 (FDA Orange Book Patent ID)
Patent RE46375
Expiration Oct 5, 2026
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)
FDA Orange Book Patents: 3 of 3 (FDA Orange Book Patent ID)
Patent RE46365
Expiration Jan 11, 2028
Applicant SHIONOGI INC
Drug Application N208854 (Prescription Drug: SYMPROIC. Ingredients: NALDEMEDINE TOSYLATE)

References

  1. Jump up^ “FDA Approves Symproic (naldemedine) for the Treatment of Opioid-Induced Constipation – Chemdiv”Chemdiv. 2017-03-27. Retrieved 2017-04-05.
  2. Jump up to:a b De Sarro, Giovambattista; Kelly S. Sprawls; Egilius L.H. Spierings; Dustin Tran (2012-03-07). “Drugs in Development for Opioid-Induced Constipation” (PDF). In Catto-Smith G., Anthony. Constipation – Causes, Diagnosis and Treatment. p. 7. doi:10.5772/30377ISBN 978-953-51-0237-3. Retrieved 12 May 2012.
  3. Jump up^ Shionogi (2009-03-27). “Research and Development at Shionogi (as of March 2009)”(PDF). Retrieved 2012-05-12.
  4. Jump up^ “SHIONOGI AND PURDUE PHARMA ESTABLISH ALLIANCE FOR JOINT U.S. COMMERCIALIZATION OF NALDEMEDINE”Purdue Pharma. Purdue Pharma. Retrieved 31 October 2017.
  5. Jump up^ “FDA Approves Symproic® (naldemedine) Once-Daily Tablets C-II for the Treatment of Opioid-Induced Constipation in Adults with Chronic Non-Cancer Pain”Purdue Pharma. Purdue Pharma. Retrieved 31 October 2017.
  6. Jump up^ “Schedules of controlled substances: removal of naldemedine from control” (PDF). Federal Register. Federal Register. Retrieved 1 November 2017.
  7. Jump up^ “Symproic Now Available for Opioid-Induced Constipation”MPR. 2017-10-12. Retrieved 2017-11-08.
  8. Jump up^ “Shionogi & Co., Ltd”Yahoo Finance. Yahoo Finance. Retrieved 31 October 2017.
  9. Jump up^ “Opioid Induced Constipation”Opioid Induced Constipation. Purdue Pharma. Retrieved 31 October 2017.
  10. Jump up^ “Generic Symproic Availability”Drugs.com. Drugs.com. Retrieved 31 October 2017.
  11. Jump up^ “Naldemedine tosylate – generic drug details”Drug Patent Watch. Drug Patent Watch. Retrieved 31 October 2017.
  12. Jump up to:a b c “Center for Drug Evaluaiton and Research Medication Review” (PDF). FDA. FDA. Retrieved 31 October 2017.
  13. Jump up^ Fukumura, K; Yokota, T; Baba, Y; Arjona Ferreira, JC (27 September 2017). “Phase 1, Randomized, Double-Blind, Placebo-Controlled Studies on the Safety, Tolerability, and Pharmacokinetics of Naldemedine in Healthy Volunteers”. Clinical pharmacology in drug developmentdoi:10.1002/cpdd.387PMID 28960888.
  14. Jump up^ Hale, M; Wild, J; Reddy, J; Yamada, T; Arjona Ferreira, JC (August 2017). “Naldemedine versus placebo for opioid-induced constipation (COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials”. The Lancet. Gastroenterology & Hepatology2 (8): 555–564. doi:10.1016/S2468-1253(17)30105-XPMID 28576452.
Naldemedine
Naldemedine.svg
Clinical data
Routes of
administration
Oral
ATC code
  • None
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
Formula C32H34N4O6
Molar mass 570.63556 g/mol
3D model (JSmol)

//////////S-297995, Naldemedine, FDA 2017, ナルデメジントシル酸塩 ,  Symproic

CC(C)(C1=NC(=NO1)C2=CC=CC=C2)NC(=O)C3=C(C4C56CCN(C(C5(C3)O)CC7=C6C(=C(C=C7)O)O4)CC8CC8)O

AK-2-202


Med. Chem. Commun., 2018, Advance Article
DOI: 10.1039/C7MD00656J, Research Article
Angela F. Ku, Gregory D. Cuny
Potent beta-1 and beta-2 adrenergic receptor antagonism via a conformationally restricted aporphine scaffold with defined stereochemistry has been developed.

Discovery of 7-hydroxyaporphines as conformationally restricted ligands for beta-1 and beta-2 adrenergic receptors

 Author affiliations

Abstract

A series of (−)-nornuciferidine derivatives was synthesized and the non-natural enantiomer of the aporphine alkaloid was discovered to be a potent β1– and β2-adrenergic receptor ligand that antagonized isoproterenol and procaterol induced cyclic AMP increases from adenylyl cyclase, respectively. Progressive deconstruction of the tetracyclic scaffold to less complex cyclic and acyclic analogues revealed that the conformationally restricted (6a-R,7-R)-7-hydroxyaporphine 2 (AK-2-202) was necessary for efficient receptor binding and antagonism.

STR1STR2STR3

(6aR,7R)-1,2-Dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinolin-7-ol (2) To a solution of S2 (10 mg, 0.031 mmol) in THF (2 mL) was added 2 N NaOH(aq) (1 mL), and the mixture was stirred at 70 oC for 2 days. After being quenched with H2O (10 mL), the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (CH3OH/CH2Cl2, 5:95 to 10:90) to afford 2 (7.6 mg, 82%) as a pale yellow solid; mp 89−91 oC; [] 24 D +78 (c 0.58, CHCl3); 1H NMR (CDCl3, 500 MHz) 8.37−8.35 (1 H, m), 7.73−7.72 (1 H, m), 7.38−7.33 (2 H, m), 6.65 (1 H, s), 4.55 (1 H, d, J = 11.5 Hz), 3.88 (3 H, s), 3.67 (1 H, d, J = 11.5 Hz), 3.64 (3 H, s), 3.40−3.37 (1 H, m), 3.10−3.03 (1 H, m), 2.98 (1 H, td, J = 11.5, 3.5 Hz), 2.73 (1 H, d, J = 16.0 Hz); 13C NMR (CDCl3, 125 MHz) 152.5, 145.1, 139.0, 130.2, 129.4, 128.1, 127.8, 127.4, 125.9, 124.3, 123.1, 111.8, 72.0, 60.3, 59.0, 55.9, 42.0, 28.9; HRMS (ESI/Q-TOF) m/z [M + H]+ calculated for C18H20NO3 298.1438; found 298.1440

http://pubs.rsc.org/en/Content/ArticleLanding/2018/MD/C7MD00656J?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FMD+%28RSC+-+Med.+Chem.+Commun.+latest+articles%29#!divAbstract

SIMILAR IN LIT

  • (-)-Nornuciferidine
  •  112494-69-6
    Molecular Weight297.35, C18 H19 N O3
    4H-​Dibenzo[de,​g]​quinolin-​7-​ol, 5,​6,​6a,​7-​tetrahydro-​1,​2-​dimethoxy-​, (6aS-​cis)​-
    S S ISOMER
    STR1
    http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.5b00007/suppl_file/ol5b00007_si_001.pdf

    Synthetic Studies of 7-Oxygenated Aporphine Alkaloids: Preparation of (−)-Oliveroline, (−)-Nornuciferidine, and Derivatives

    Department of Chemistry and Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Science and Research Building 2, Rm 549A, Houston, Texas 77204, United States
    Org. Lett.201517 (5), pp 1134–1137
    DOI: 10.1021/acs.orglett.5b00007

    Abstract

    Abstract Image

    7-Oxygenated aporphines 16 possessing anti-configurations have previously been reported. In order to explore their bioactivities, a synthesis was established by utilizing a diastereoselective reductive acid-mediated cyclization followed by palladium-catalyzed ortho-arylations. Moderate XPhos precatalyst loading (10 mol %) and short reaction times (30 min) were sufficient to mediate the arylations. Alkaloids 15 were successfully prepared, while (−)-artabonatine A was revised to syn-isomer 30. Consequently, (−)-artabonatine E likely also has a syn-configuration (31).

///////////AK-2-202, 

LASMIDITAN


Lasmiditan skeletal.svg

LASMIDITAN, COL-144 , LY-573144

613677-28-4 HYDROCHLORIDE
439239-90-4 (free base)

2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide

2,4,6-trifluoro-N-{6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2-yl}benzamide

CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

UNII:760I9WM792

Lasmiditan succinate; UNII-W64YBJ346B; Lasmiditan succinate [USAN]; W64YBJ346B; 439239-92-6; Lasmiditan succinate (USAN)

Lasmiditan succinate.png

Molecular Formula: C42H42F6N6O8
Molecular Weight: 872.822 g/mol

Lasmiditan (COL-144) is an investigational drug for the treatment of acute migraine. It is being developed by Eli Lilly and is in phase III clinical trials. It is a first-in-class “neurally acting anti-migraine agent” ditan.

WO-2018010345,  from Solipharma and the inventor on this API. Eli Lilly , following its acquisition of CoLucid Pharmaceuticals , is developing lasmiditan, a 5-HT 1f agonist, for treating acute migraine.

WATCH THIS SPACE, SYNTHESIS COMING………..

noname01

 

SYN 2

noname01

Mechanism of action

Lasmiditan is a serotonin receptor agonist that, like the unsuccessful LY-334,370, selectively binds to the 5-HT1F receptor subtype. A number of triptans have been shown to act on this subtype as well, but only after their affinity for 5-HT1B and 5-HT1D has been made responsible for their anti-migraine activity. The lack of affinity for these receptors might result in fewer side effects related to vasoconstriction compared to triptans in susceptible patients, such as those with ischemic heart diseaseRaynaud’s phenomenon or after a myocardial infarction,[1] although a 1998 review has found such side-effects to rarely occur in patients taking triptans.[2][3]

Discovery and development

Lasmiditan was discovered by Eli Lilly and Company and was out-licensed to CoLucid Pharmaceuticals in 2006, until CoLucid was bought by Eli Lilly in 2017 to reacquire the drug.[4] The drug is protected by patents until 2031.[5]

Phase II clinical trials for dose finding purposes were completed in 2007 for an intravenous form[6] and in early 2010 for an oral form.[7]Two separate Phase III clinical trials for the oral version are currently ongoing under special protocol agreements with the US Food and Drug Administration (FDA). Eli Lilly has stated that they intend to submit a new drug application to the FDA in early 2018.[5]

As of 2017, three phase III clinical trials have been completed or are in progress. The SPARTAN trial compares placebo with 50, 100, and 200 mg of lasmiditan.[8] SAMURAI compared placebo with 100 and 200 mg doses of lasmidatin. In 2016, CoLucid announced that the trial had met its primary and secondary endpoints of patients being pain-free two hours after dosing.[5] GLADIATOR is an open-labelstudy comparing 100 and 200 mg doses of lasmidatin in patients that received the drug as part of a prior trial.[9] In August 2017 topline results from the SPARTAN trial showed that the drug induced met its primary and secondary endpoints in the trial. The primary result showed a statistically significant improvement in pain relief relative to placebo 2 hours after the first dose. The secondary result showed a statistically significantly greater percentage of patients were free of their most bothersome symptom (MBS) compared with placebo at two hours following the first dose. [10]

Novel crystalline forms of a 5-HT1F receptor agonist, particularly lasmiditan – designated as Forms 1-3 and A-D – processes for their preparation and compositions comprising them are claimed. Also claim is their use for treating anxiety, fatigue, depression, premenstrual syndrome, trauma syndrome, memory loss, dementia (including Alzheimer’s), autism, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, epilepsy, anorexia nervosa, alcoholism, tobacco abuse, mutism and trichotillomania.

Biological Activity

Lasmiditan (also known as COL-144 and LY573144) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist.

In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370.

In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis).

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Image result for LASMIDITAN

Image result for LASMIDITAN

PATENT

WO 03084949

https://www.google.co.in/patents/WO2003084949A1?cl=en

8. 2,4,6-Trifluoro-N-[6-(l -methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000035_0001

Combine 2-amino-6-(l-methylpiperidin-4-ylcarbonyl)pyridine (0.20 g, 0.92 mmol), 2,4,6-Trifluorobenzoyl chloride (0.357 g, 1.84 mmol), and 1 ,4-Dioxane (10 mL), and stir while heating at reflux. After 3 hr., cool the reaction mixture to ambient temperature and concentrate. Load the concentrated mixture onto an SCX column (lOg), wash with methanol, and elute with 2M ammonia in methanol. Concentrate the eluent to obtain the free base of the title compound as an oil (0.365 g (>100%)). Dissolve the oil in methanol (5 mL) and treat with ammonium chloride (0.05 g, 0.92 mmol). Concentrate the mixture and dry under vacuum to obtain the title compound. HRMS Obs. m/z 378.1435, Calc. m/z 378.1429; m.p. 255°C (dec).

Examples

21. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide

Figure imgf000049_0001

Add triethylamine (10.67 mL, 76.70 mmol, 2.4 eq) to a solution of 2-amino-(6-(l- methylpiperidin-4-ylcarbonyl)-pyridine (7g, 31.96 mmol, 1 eq) in anhydrous THF (100 mL) under a nitrogen atmosphere. Add 2,4,6-triflubenzoylchloride (7.46g, 5 mL, 38.35 mmol, 1.20 eq) dropwise at room temperature. After 2 hrs., add additional 2,4,6- triflubenzoylchloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) to the reaction mixture and agitate the mixture for an additional 3 hrs. Quench the reaction with distilled water (10 mL) and 30%o NaOH (15 mL). Stir the resulting biphasic system for 1 hour and then separate the phases. Extract the organic fraction by adding H2O (75 mL) and acetic acid (12 mL), followed by cyclohexane (70 mL). Wash the organic fraction with H2O (50 mL) containing acetic acid (1 mL). Combine all the aqueous fractions and washes and neutralize the mixture with 30% NaOH (15 mL). Extract with methyl-tert- butyl ether (MTBE) (3×50 mL). Combine the organic fractions and dry with MgSO4, filter, concentrate under reduce pressure, and vacuum dry at room temperature, to obtain the title compound as a light-brown solid (11.031 g, 91 % yield).

Mass spectrum, (Electrospray) m/z = 378 (M+l); Η NMR (250 MHz, Chloroform-D) ppm 1.54 (m, 2 H) 2.02 (m, 2 H) 2.13 (t, J=l 1.48 Hz, 2 H) 2.29 (s, 3 H) 2.80 (m, J=l 1.96 Hz, 1 H) 3.56 (m, 1 H) 4.26 (d, J=7.87 Hz, 1 H) 6.17 (d, J=8.50 Hz, 1 H) 6.75 (m, 2 H) 7.45 (t, J=7.87 Hz, 1 H) 7.53 (m, 1 H) 7.95 (s, 1 H); 13C-NMR: (62.90 MHz, Chloroform-D) ppm 202.78; 162.6 (dm C-F-couplings); 162.0 (m C-F-couplings); 160.1 (m C-F-couplings); 158.1 ; 150.0; 139.7; 1 19.3; 1 17.9; 1 10.2 (m C-F-couplings); 100.9 (m C-F-couplings); 55.2; 46.5; 41.9; 28.1

22. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide mono-hydrochloride salt

Figure imgf000049_0002

Dissolve 2,4,6-trifluoro-N-[6-(l-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]- benzamide – free base (5g, 23.26mmol) in isopropanol (50 mL) at room temperature and add a solution of 3.3 M diethylether/HCl (8 mL). Heat the reaction mixture under reflux for 30 minutes. Cool the reaction mixture to room temperature and agitate for 2 hrs. Filter the resulting white precipitate and rinse with isopropanol (5 mL). Dry the residual solid under reduce pressure at 40°C overnight to obtain the title compound (5.12 g, 93% yield). M.p. 223-224°C (sublimation); Η NMR (400 MHz, d6-DMSO) d ppm 1.94 (m, 2 H) 2.14 (m, J=11.15 Hz, 2 H) 2.74 (s, 3 H) 2.99 (m, J=9.19 Hz, 2 H) 3.49 (m, J=1 1.15 Hz, 2 H) 3.77 (m, 1 H) 7.41 (t, J=8.71 Hz, 2 H) 7.78 (d, J=7.43 Hz, 1 H) 8.10 (t, J=7.92 Hz, 1 H) 8.37 (d, J=6.85 Hz, 1 H) 10.50 (s, 1 H) 1 1.51 (s, 1 H); 13C-NMR: (100.61 MHz, Chloroform-D) ppm 200.7; 130.6-158.0 (m, C-F-couplings); 150.4; 150.1; 140.2; 118.5; 1 18.2; 11 1.9; 101.3 (t, C-F couplings); 52.8; 42.6; 25.2

23. 2,4,6-Trifluoro-N-[6-(l-methyl-piperidine-4-carbonyl)-pyridin-2-yl]- benzamide hemi-succinate salt

Figure imgf000050_0001

Add succinic acid (0.25g, 2.148 mmol, 0.5eq) to a solution of 2,4,6-trifluoro-N-[6-

(l-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide – free base (1.62g, 4.297 mmol, leq) in acetone (16.2 mL), at room temperature. Warm the solution under reflux for 30 minutes. Cool the solution to room temperature and filter off the resulting white precipitate. Rinse the precipitate with acetone (0.2 mL) and dry under vacuum at 50°C for 16 hours to provide the title compound (1.5g, 80% yield). M.p. 198.5°C; mass spectrum (Electrospray) m/z = 495.45

The following examples are prepared by combinatorial chemistry techniques as follows:

Examples 24-54

Figure imgf000050_0002

Combine R-acid (300 μL of 0.5M solution in dimethylformamide (DMF)), HATU (57 mg, 0.15 mmol), collidine (19 μL, 0.15 mmol), 2-amino-(6-(l-methylpiperidin-4- ylcarbonyl)-pyridine and DMF (1.5 mL), and agitate for 48 hr. Dilute the reaction mixture with 10% acetic acid in methanol (0.5 L). Load the resulting reaction mixture onto a 2 g SCX column. Wash the column thoroughly with methanol and then elute with 1 M ammonia in methanol. Concentrate the eluent and further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 24-54.

Examples 55-58

Figure imgf000051_0001

Heat R-acid chloride (300 μL of 0.5M solution in pyridine) to 55°C, add 2-amino- (6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine), and continue heating the reaction mixture for 24 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high- throughput mass guided chromatography. This procedure is repeated in parallel for examples 55-58.

Examples 59-71

Figure imgf000051_0002

Heat 2-amino-(6-(l-methylpiperidin-4-ylcarbonyl)-pyridine (200 μL of 0.5M solution in pyridine) to 55°C then add R-acid chloride (0.10 mmol), heat for 2 hr. Concentrate the reaction mixture and then dilute with 10% Acetic acid in methanol (0.5 mL) and methanol (0.5 mL). Load the resulting reaction mixture directly onto a 2 g SCX column. Thoroughly wash the column with methanol and then elute the column with 1 M ammonia in methanol. Concentrate the eluent and then further purify the product by high-throughput mass guided chromatography. This procedure is repeated in parallel for examples 59-71.

PATENT

WO 2018010345

Lasmiditan, also known as COL-144, LY573144, is a 5-HT 1F receptor agonist. Can be used to inhibit neuronal protein extravasation, to treat or prevent migraine in patients with diseases or conditions associated with other 5-HT 1F receptor dysfunction. The chemical name is 2,4,6-trifluoro-N- [6 – [(1 -methylpiperidin-4-yl) carbonyl] -pyridin- 2-yl] -benzamide, which has the chemical structure shown below I) shows:
Lasmiditan is a new and selective 5-HT 1F receptor agonist. It acts against migraine and other 5-HT 1F receptor related diseases by enhancing 5-HT 1F receptor activation while avoiding vasoconstrictive activity and inhibiting neuronal protein extravasation such as Migraine (including migraine, migraine headache, neurovascular headache), general pain, trigeminal neuralgia, anxiety, panic disorder, depression, post traumatic syndrome, dementia and the like.
Patent document CN100352817C reports on Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride and the synthetic preparation thereof, and discloses the mass spectra of Lasmiditan, Lasmiditan hemisuccinate and Lasmiditan hydrochloride, 1 H-NMR, 13 C -NMR detection data and the melting points of Lasmiditan hemisuccinate and Lasmiditan hydrochloride. The inventor of the present invention has found that Lasmiditan, which is obtained according to the preparation method of Example 17 and Example 21 in CN100352817C, is a light brown oily amorphous substance, which has the defects of instability, moisture absorption and poor morphology.
Example 8 of patent document CN100352817C reports the preparation of Lasmiditan hydrochloride, which mentions Lasmiditan free base as an oily substance. The Lasmiditan hydrochloride obtained according to the preparation method of Example 8 in CN100352817 is a white amorphous substance which also has the disadvantages of unstable crystalline form, high hygroscopicity and poor topography.
The synthesis of Lasmiditan hemisuccinate intermediate, including Lasmiditan and Lasmiditan hydrochloride, is reported in Example 2 of U.S. Patent No. 8,697,876 B2. The inventor’s study found that Lasmiditan prepared according to US8697876B2 is also a pale brown oily amorphous substance and Lasmiditan hydrochloride is also a white amorphous substance.
In view of the deficiencies in the prior art, there is still a need in the art for the development of crystalline polymorphic Lasmiditan solid forms with more improved properties to meet the rigorous requirements of pharmaceutical formulations for physico-chemical properties such as morphology, stability and the like of active materials.
Preparation 1 Preparation of Lasmiditan (Prior Art)
Lasmiditan was prepared as described in Example 21 of CN100352817C by the following procedure: Triethylamine (10.67 mL, 76.70 mmol, 2.4 equiv) was added to a solution of 2-amino- (6- (1-methylpiperidine -4-yl) -carbonyl) -pyridine (7 g, 31.96 mmol, 1 eq) in dry THF (100 mL). 2,4,6-Trifluorobenzoyl chloride (7.46 g, 5 mL, 38.35 mmol, 1.20 equiv.) Was added dropwise at room temperature. After 2 hours, an additional 2,4,6-trifluorobenzoyl chloride (0.75 mL, 0.15 eq) and triethylamine (1.32 mL, 0.3 eq) were added to the reaction mixture and the mixture was stirred for a further 3 h. The reaction was quenched with distilled water (10 mL) and 30% NaOH (15 mL). The resulting two-phase system was stirred for 1 hour, then the two phases were separated. By addition of H 2 to extract the organic portion O (75mL) and acetic acid (12mL), followed by addition of cyclohexane (70mL). The organic portion was washed with water (50 mL) containing acetic acid (1 mL). All aqueous phases were combined, washed and neutralized with 30% NaOH (15 mL). Extract with methyl tert-butyl ether (MTBE) (3 x 50 mL). The organic phases were combined, dried MgS04 . 4 dried, filtered, and concentrated under reduced pressure and dried in vacuo at room temperature to give the title compound as a pale brown solid (11.031g, 91% yield).
The 1 H-NMR (CDCl 3 ) data of the product are as follows:
1 H NMR (400 MHz, CHLOROFORM-D) ppm 1.54 (m, 2H) 2.02 (m, 2H) 2.13 (t, J = 18.37 Hz, 2H) 2.29 (s, 3.56 (d, J = 12.59 Hz, 1H) 6.17 (d, J = 13.6 Hz, 1H) 6.75 (m, 2H) 7.45 (t, J = 12.59 Hz, 1H) 7.53 (m, 1H ) 7.95 (s, 1H).
The isothermal adsorption curve shown in Figure 5, in the 0% to 80% relative humidity range of 9.5% weight change.
The above characterization results show that Lasmiditan obtained by the preparation method of Example 21 according to CN100352817C is amorphous.
Preparation 2 Preparation of Lasmiditan hydrochloride (Prior Art)
The Lasmiditan hydrochloride was prepared as described in Example 8 of CN100352817C by the following procedure: A mixture of 2-amino-6- (1-methylpiperidin-4-yloxy) pyridine Trifluorobenzoyl chloride (3.57 g, 18.4 mmol) and 1,4-dioxane (100 mL) were combined and heated to reflux with heating. After 3 hours, cool the reaction mixture to room temperature, reduce pressure and concentrate. The concentrated mixture was loaded onto a SCX column (10 g), washed with methanol and eluted with 2M ammonia in methanol. The eluate was concentrated to give the title compound as an oily free base (3.65 g (> 100%)). The oil was dissolved in methanol (50 mL) and treated with ammonium chloride (0.5 g, 9.2 mmol). The mixture was concentrated and dried in vacuo to give a white amorphous.
IC characterization showed that Lasmiditan hydrochloride salt formed by Lasmiditan and hydrochloric acid in a molar ratio of 1: 1.
The XRPD pattern shown in Figure 19, no diffraction peaks, no amorphous.
The PLM pattern is shown in Figure 20 as an irregular, unpolarized solid.
The isotherm adsorption curve is shown in FIG. 21, with a weight change of 8.1% in a relative humidity range of 0% to 80%.
The above characterization results show that: Lasmiditan hydrochloride obtained by the preparation method of Example 8 with reference to CN100352817C is amorphous.
Example 1
Take 500mg of Lasmiditan of Preparation 1, add 1mL methanol solution containing 5% water to clarify, evaporate the crystals at room temperature and evaporate dry after 1 day to obtain 487mg Lasmiditan Form 1 in 95% yield.

References

  1.  “Molecule of the Month July 2010: Lasmiditan hydrochloride”Prous Science. Retrieved 2011-08-03.
  2.  Dahlöf, CG; Mathew, N (1998). “Cardiovascular safety of 5HT1B/1D agonists–is there a cause for concern?”. Cephalalgia : an international journal of headache18 (8): 539–45. doi:10.1046/j.1468-2982.1998.1808539.xPMID 9827245.
  3.  Mutschler, Ernst; Geisslinger, Gerd; Kroemer, Heyo K.; Schäfer-Korting, Monika (2001). Arzneimittelwirkungen (in German) (8th ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. p. 265. ISBN 978-3-8047-1763-3OCLC 47700647.
  4.  http://www.fiercebiotech.com/biotech/lilly-buys-migraine-biotech-colucid-for-960m-and-drug-it-out-licensed
  5.  http://adisinsight.springer.com/drugs/800028519
  6.  Clinical trial number NCT00384774 for “A Placebo-Controlled Adaptive Treatment Assignment Study of Intravenous COL-144 in the Acute Treatment of Migraine” at ClinicalTrials.gov
  7.  Clinical trial number NCT00883051 for “Dose-ranging Study of Oral COL-144 in Acute Migraine Treatment” at ClinicalTrials.gov
  8. Clinical trial number NCT02605174 for “Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute Treatment of Migraine (SPARTAN)” at ClinicalTrials.gov
  9.  Clinical trial number NCT02565186 for “An Open-label, Long-term, Safety Study of Lasmiditan for the Acute Treatment of Migraine (GLADIATOR)” at ClinicalTrials.gov
  10.  https://investor.lilly.com/releasedetail.cfm?ReleaseID=1036101
Lasmiditan
Lasmiditan skeletal.svg
Clinical data
Routes of
administration
By mouthintravenous
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C19H18F3N3O2
Molar mass 377.36 g/mol
3D model (JSmol)

/////////////LASMIDITAN, phase III, LILY, COL-144 , LY-573144, CoLucid Pharmaceuticals, PHASE 3, MIGRAINE

CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.CN1CCC(CC1)C(=O)C2=NC(=CC=C2)NC(=O)C3=C(C=C(C=C3F)F)F.C(CC(=O)O)C(=O)O

NASTORAZEPIDE


imgNastorazepide.png

Nastorazepide (Z-360)
CAS: 209219-38-5
Chemical Formula: C29H36N4O5
Molecular Weight: 520.61994

UNII-R22TMY97SG; 209219-38-5;

Phase II, treatment of pancreatic cancer.

(R)-3-(3-(5-cyclohexyl-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)ureido)benzoic acid

Image result

Nastorazepide, also known as Z-360, is a selective, orally available, 1,5-benzodiazepine-derivative gastrin/cholecystokinin 2 (CCK-2) receptor antagonist with potential antineoplastic activity. Z-360 binds to the gastrin/CCK-2 receptor, thereby preventing receptor activation by gastrin, a peptide hormone frequently associated with the proliferation of gastrointestinal and pancreatic tumor cells.

In January 2018, Zeria is developing nastorazepide calcium (phase II clinical trial), a CCK2 receptor antagonist, for the treatment of pancreatic cancer.

Zeria is developing nastorazepide calcium (Z-360), an oral CCK2 receptor (gastrin receptor) antagonist, for the potential treatment of pancreatic cancer. In September 2005, a phase Ib/IIa trial began in the UK for pancreatic cancer ,  in February 2008, the trial was completed ; in June 2008, data were presented . In March 2010, the drug was listed as being in phase II preparation in Europe ; in August 2011, this was still the case . In April 2014, a phase II trial began in patients with metastatic pancreatic adenocarcinoma in Japan, Korea and Taiwan. In November 2015, the drug was listed as being in phase II development

343326-69-2

Nastorazepide (calcium salt)

CAS No. : 343326-69-2

M.Wt:540.62Formula:C29H36N4O5Ca0.5

Cholecystokinin (CK) is a digestive hormone produced and released in the duodenum, jejunal membrane and is known to have actions such as secretion of secretion, constriction of the gallbladder, stimulation of insulin secretion and the like. C CK is also known to exist in high concentrations in the cerebral cortex, hypothalamus and hippocampus, and it is also known that it has actions such as suppression of food intake, memory enhancement, anxiety action and the like. On the other hand, gastrin is a gastrointestinal hormone produced and released in G cells distributed in the pyloric region of the stomach, and it is known that it has gastric acid secretion action, contraction action of the gastric pyloric part and gallbladder, and the like. These C CK and gastrin have the same 5 amino acids at the C-terminus, and all express the action through the receptor. C CK receptors are classified into peripheral type C CK – A distributed in the ile, gall bladder and intestinal tract and central type C CK – B distributed in the brain. The gastrin receptor and the CKK – B receptor show similar properties in receptor binding experiments and sometimes called C CK 1 B / gastrin receptor due to high homology. These receptors, such as gastrin or a CCK-B receptor antagonist compound, are useful in the treatment of gastric ulcers, duodenal ulcers, gastritis, reflux esophagitis, splenitis, Zollinger-EUison syndrome, cavitary G cell hyperplasia, basal hyperplasia, Choleditis, gallstone stroke, gastrointestinal motility disorder, sensitive bowel syndrome, certain tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson’s disease, late onset dyskinesia, It is expected to be useful for treatment and prevention of La Tourette’s syndrome, addiction due to drug ingestion, and withdrawal symptoms. It is also expected that the induction of analgesia or the enhancement of induction of analgesia by opioid drugs is expected (Journal of Pharmacology, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18, 919-931 (1993), American Journal of Physiology, Vol.

As a gastrin receptor antagonist already, prolumide is known as a therapeutic agent for gastric ulcer and gastritis. However, proglumide has considerably low affinity for gastrin or CKK-B receptor and its therapeutic effect is weak. In addition, L – 3 6 4, 7 1 8 (Dibazepide, Japanese Unexamined Patent Publication No. 616366), L -3 6 5, 2 6 0 (Japanese Patent Laid-Open No. 6 3- 9), and the like, have been reported to exhibit either CKK-A receptor antagonism or CKK-B receptor antagonism. Furthermore, it is disclosed that a compound having a strong C 4 C – – B receptor antagonistic effect suppresses gastric acid secretion by pentagastrin stimulation (International Patent Publication WO 94/438, International Patent Publication WO 95/18110) , It is not always satisfactory and clinically applicable gastrin or CKK-B receptor antagonist has not yet been provided.

Compounds capable of strongly binding to gastrin or cholecystokinin receptors are expected for the prevention and treatment of diseases involving their respective receptors in the digestive tract and the central nervous system.

PRODUCT PATENT WO1998025911

Inventors Katsuo ShinozakiTomoyuki YonetaMasakazu MurataNaoyoshi MiuraKiyoto MaedaLess «
Applicant Zeria Pharmaceutical Co., Ltd.

SYNTHESIS WO 2017030859

PATENT

WO 9825911

https://www.google.co.in/patents/WO1998025911A1?cl=und

PATENT

WO2017175854

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017175854&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Compound A ((R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 1,3,4,5-tetrahydro- 2H- 1,5-benzodiazepine -3-yl) ureido] benzoate) has the following structural formula and can be produced by the method described in Patent Document 1.
[Chemical formula 1]
Example 1
Compound A 20.0 g of amorphous substance was suspended in 253 mL of methanol. After dissolving by heating, it was cooled and the precipitated crystals were collected by filtration and washed with methanol. The obtained wet crystals were dried under reduced pressure.
1 H-NMR (DMSO-d 6 ) δ: 1.18 (18H, s), 1.10-2.03 (20H, m), 3.17 (12H, d), 3.19-3.29 (4H, m), 3.37-3.44 (2H, (2H, m), 7.07-7.12 (2H, m), 4.07-4.16 (4H, br)
IR (KBr) cm -1 : 2935 (2H, m), 7.15 (2H, t), 7.22-7.29 (4H, m), 7.50-7.56 (4H, m), 7.88 , 2361, 1648, 1553, 1497, 1388, 1219, 776
 The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG. 2. From NMR, IR and FIG. 2, the obtained crystals were Compound AI type crystals.
Example 5
Compound A 50.0 g of amorphous material was suspended in 380 mL of isopropanol (IPA). After dissolving by heating, it was cooled and precipitated. Precipitated crystals were collected by filtration and washed with IPA to obtain wet crystals. This was dried under reduced pressure. The powder X-ray diffraction spectrum of the obtained crystal is shown in FIG.
1 H-NMR (DMSO-d 6 ) [delta]: 1.04 (24H, d), 1.18 (18H, s), 1.10-2.03 (20H, m), 3.16-3.28 (4H, m), 3.37-3.45 (2H, (2H, m), 7.07-7.12 (2H, m), 3.72-3.83 (4H, m), 4.33-4.43 (8H, m), 5.13 (2H, d), 6.71
IR (KBr) cm -1 : 2933 (2H, m), 7.15 (2H, t), 7.21-7.30 (4H, m), 7.48-7.54 (4H, m), 7.84 , 2361, 1653, 1553, 1498, 1394, 1219, 769
 From NMR, IR and FIG. 4, the obtained crystals were Compound AIII type crystals.

PATENT

WO-2018008569

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018008569&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Process for producing a calcium salt of a 1,5-benzodiazepine compound – nastorazepide calcium – a cholecystokinin CCK2 receptor antagonist. Useful for the treatment of gastritis, reflux esophagitis, Zollinger-Ellison syndrome.

Example 1
(1) (R) – (-) – 2-Oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (compound 2)), 139.3 g of 1-chloropinacolone and 8.3 g of tetrabutylammonium bromide in 1432 ml of toluene was added dropwise 461 g of 30% sodium hydroxide aqueous solution at 10 ° C. or lower. After stirring for 1 hour, the aqueous layer was removed. To the toluene layer, 620 ml of water was added and the liquid was separated, and the toluene layer was used for the next step.
(2) 628.9 g of hydrochloric acid was added dropwise to the toluene layer obtained in the previous step at 30 ° C. or lower. After stirring for 30 minutes, liquid separation was carried out, and the aqueous layer was separated. It was neutralized with 908.5 g of 30% sodium hydroxide aqueous solution and extracted with 1432 ml of toluene. The toluene layer was separated with 620 g of a 20% sodium chloride aqueous solution, and toluene was distilled off under reduced pressure. (R) – (-) – 1 -tert-butylcarbonylmethyl-2-oxo-3-amino-5- cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (Compound (6) ) Was obtained.
(3) The (R) – (-) – 1-tert-butylcarbonylmethyl-2-oxo-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1 , 5-benzodiazepine (Compound (6)), 221.8 g of 3-phenyloxycarbonylaminobenzoic acid, 174.5 g of triethylamine and 77.7 g of water were added and the mixture was stirred at 45 to 50 ° C. for 2 hours. To the reaction solution were added 1375 ml of ethanol and 930 ml of water, and 62.9 g of hydrochloric acid was added dropwise at 30 ° C. or lower. The precipitated crystals were centrifuged.
The obtained crystals were heated to dissolve in 4714 ml of ethanol at 60 ° C., and 2790 ml of water was added dropwise to precipitate crystals. The precipitated crystals were separated by centrifugation and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl- 5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoic acid (Compound (5)) 0.5 ethanolate monohydrate 430.2 g.
(4) (R) – (-) – 3- [3- (1-tert-Butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H- 1,5-benzodiazepine -3-yl) ureido] benzoic acid (Compound (5)) 0.5 Ethanol solvate monohydrate 430.3 g was suspended in 1645 ml of isopropyl alcohol (IPA), sodium hydroxide 31.6 g / A solution of 934 ml of water was added dropwise to dissolve (a).
112.7 g of calcium chloride dihydrate was dissolved in 3012 ml of water. Here, the solution of (a) was added dropwise at 10 ° C. or lower. After dropping, the temperature was raised to 50 ° C., after stirring for 2 hours, it was cooled to 10 ° C. or lower. The precipitated powder was centrifuged and washed with a mixed solution of IPA 658 ml / water 2065 ml, followed by 4303 ml of water and dried under reduced pressure to give (R) – (-) – 3- [3- (1-tert- Oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl) ureido] benzoate (compound (1)). The powder X-ray diffraction spectrum was measured (as 7% water content), and the obtained compound (1) was amorphous.
Example 2 In
step (4) of Example 1, investigation was carried out by changing the amount of the solvent and sodium hydroxide.
First, when the IPA / water ratio is 1 / 2.5 to 1/10, preferably 1 / 2.75 to 1/8, more preferably 1 / 2.75 to 1/5, the compound (1 ) Amorphous can be stably obtained.
Next, when the amount of sodium hydroxide is 1.0 to 1.10 mol with respect to the compound (1) and the amount of calcium chloride is 0.5 to 1.5 mol with respect to the compound (1), the amount of the compound 1) can be obtained in high yield.
Further, it was found that impurities are not produced when the reaction temperature of the compound (1) and sodium hydroxide in the step (4) is 20 ° C. or less, more preferably 10 ° C. or less, further preferably 0 to 10 ° C.
Patent ID

Patent Title

Submitted Date

Granted Date

US2008161293 Antitumor Agent
2008-07-03
Patent ID

Patent Title

Submitted Date

Granted Date

US2015038495 THERAPEUTIC AGENT FOR PAIN
2014-09-24
2015-02-05
US2011059956 THERAPEUTIC AGENT FOR PAIN
2011-03-10
US2017151256 ANTITUMOR AGENT
2017-02-10
US2010143366 ANTITUMOR AGENT
2010-06-10
US2010086553 ANTITUMOR AGENT
2010-04-08
Patent ID

Patent Title

Submitted Date

Granted Date

US6747022 Calcium salts of 1, 5-benzodiazepine derivatives, process for producing the salts and drugs containing the same
2003-05-22
2004-06-08
US6239131 1, 5 Benzodiazepine derivatives
2001-05-29
EP0945445 1, 5-BENZODIAZEPINE DERIVATIVES 1, 5-BENZODIAZEPINE DERIVATIVES
1999-09-29
2005-12-28
US2015050212 CHOLECYSTOKININ B RECEPTOR TARGETING FOR IMAGING AND THERAPY
2013-02-22
2015-02-19
US2012010401 METHOD FOR MANUFACTURING 1, 5-BENZODIAZEPINE DERIVATIVE
2012-01-12

1: Kato H, Seto K, Kobayashi N, Yoshinaga K, Meyer T, Takei M. CCK-2/gastrin receptor signaling pathway is significant for gemcitabine-induced gene expression of VEGF in pancreatic carcinoma cells. Life Sci. 2011 Oct 24;89(17-18):603-8. doi: 10.1016/j.lfs.2011.07.019. Epub 2011 Aug 3. PubMed PMID: 21839751.

////////////NASTORAZEPIDE, phase II, treatment of pancreatic cancer,

O=C(O)C1=CC=CC(NC(N[C@@H]2CN(C3CCCCC3)C4=CC=CC=C4N(CC(C(C)(C)C)=O)C2=O)=O)=C1

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids


Green Chem., 2018, 20,108-112
DOI: 10.1039/C7GC02913F, Communication
Open Access Open Access
Creative Commons Licence  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
Manuel Kockinger, Tanja Ciaglia, Michael Bersier, Paul Hanselmann, Bernhard Gutmann, C. Oliver Kappe
Difluoromethylated esters, malonates and amino acids (including the drug eflornithine) are obtained by a gas-liquid continuous flow protocol employing the abundant waste product fluoroform as an atom-efficient reagent.

Utilization of fluoroform for difluoromethylation in continuous flow: a concise synthesis of α-difluoromethyl-amino acids

Author affiliations

Abstract

Fluoroform (CHF3) can be considered as an ideal reagent for difluoromethylation reactions. However, due to the low reactivity of fluoroform, only very few applications have been reported so far. Herein we report a continuous flow difluoromethylation protocol on sp3 carbons employing fluoroform as a reagent. The protocol is applicable for the direct Cα-difluoromethylation of protected α-amino acids, and enables a highly atom efficient synthesis of the active pharmaceutical ingredient eflornithine.

Methyl 3,3-(difluoro)-2,2-diphenylpropanoate (2a) The product mixtures were collected and the solvent removed in vacuo. The products were isolated by thin layer chromatography (dichloromethane/hexane = 3/2 (v/v)). Yield: 173 mg (0.62 mmol, 62%); 93% by 19F NMR ;light yellow viscous liquid. 1 H NMR (300 MHz, D2O): δ = 7.45 – 7.19 (m, 10H), 6.90 (t, 2 JHF = 55.0 Hz, 1H), 3.79 (s, 3H). 13C NMR (75 MHz, D2O): δ = 171.1, 136.3, 129.8, 128.3, 128.2, 115.6 (t, 1 JCF = 246.2 Hz), 64.7, 53.1.19F NMR (282 MHz, D2O):δ = -123.0 (d, 2 JHF = 55.0 Hz).

STR1 STR2 STR3

Conclusions

A gas–liquid continuous flow difluoromethylation protocol employing fluoroform as a reagent was reported. Fluoroform, a by-product of Teflon manufacture with little current synthetic value, is the most attractive reagent for difluoromethylation reactions. The continuous flow process allows this reaction to be performed within reaction times of 20 min with 2 equiv. of base and 3 equiv. of fluoroform. Importantly, the protocol allows the direct Cα-difluoromethylation of protected α-amino acids. These compounds are highly selective and potent inhibitors of pyridoxal phosphate-dependent decarboxylases. The starting materials are conveniently derived from the commercially available α-amino acid methyl esters, and the final products are obtained in excellent purities and yields after simple hydrolysis and precipitation. The developed process appears to be especially appealing for industrial applications, where atom economy, sustainability, reagent cost and reagent availability are important factors.

//////////

OLINCIGUAT


img2D chemical structure of 1628732-62-6

OLINCIGUAT

cas 1628732-62-6
Chemical Formula: C21H16F5N7O3
UNII-PD5F4ZXD21
Molecular Weight: 509.4

Olinciguat is a guanylate cyclase activator drug candidate.

(2R)-3,3,3-trifluoro-2-{[(5-fluoro-2-{1-[(2-fluorophenyl)methyl]- 5-(1,2-oxazol-3-yl)-1H-pyrazol- 3-yl}pyrimidin-4-yl)amino]methyl}-2-hydroxypropanamide

  • Originator Ironwood Pharmaceuticals
  • Class Antifibrotics; Cardiovascular therapies
  • Mechanism of Action Soluble guanylyl cyclase agonists
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • Phase II Gastrointestinal disorders; Sickle cell anaemia
  • Phase I Cardiovascular disorders; Fibrosis

Most Recent Events

  • 03 Jan 2018 Pharmacodynamics data from a preclinical trial in Cardiovascular disorders presented at the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH-2017)
  • 21 Dec 2017 Phase-II clinical trials in Sickle cell anaemia in USA (PO)
  • 09 Dec 2017 Adverse events, pharmacokinetic and pharmacodynamics data from a phase Ib trial in healthy volunteers presented at the 59th Annual Meeting and Exposition of the American Society of Hematology

IW-1701

Currently in Phase II Clinical Development

Area of focus:

Achalasia and Sickle Cell Disease
Dysregulation of the nitric oxide-soluble guanylate cyclase-cyclical guanosine monophosphate (NO-sGC-cGMP) signaling pathway is believed to be linked to multiple vascular and fibrotic diseases, such as achalasia and sickle cell disease.

Our candidate:

IW-1701 is an investigational soluble guanylate cyclase (sGC) stimulator from Ironwood’s diverse library of sGC stimulators, which are being investigated for their potential effects on vascular and fibrotic diseases. The compound has been shown in nonclinical studies to modulate the NO-sGC-cGMP signaling pathway and is currently being evaluated in a Phase II study in achalasia. IW-1701 is wholly-owned by Ironwood Pharmaceuticals.

sGC is the primary receptor for NO in vivo. sGC can be activated via both NO-dependent and NO-independent mechanisms. In response to this activation, sGC converts Guanosine-5′-triphosphate (GTP) into the secondary messenger cGMP. The increased level of cGMP, in turn, modulates the activity of downstream effectors including protein kinases, phosphodiesterases (PDEs) and ion channels.

In the body, NO is synthesized from arginine and oxygen by various nitric oxide synthase (NOS) enzymes and by sequential reduction of inorganic nitrate. Three distinct isoforms of NOS have been identified: inducible NOS (iNOS or NOS II) found in activated macrophage cells; constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmission and long term potentiation; and constitutive endothelial NOS (eNOS or NOS III) which regulates smooth muscle relaxation and blood pressure. Experimental and clinical evidence indicates that reduced concentrations orbioavailability of NO and/or diminished responsiveness to endogenously produced NO contributes to the development of disease.

NO-independent, heme -dependent sGC stimulators, have shown several important differentiating characteristics, when compared to sGC activators, including crucial dependency on the presence of the reduced prosthetic heme moiety for their activity, strong synergistic enzyme activation when combined with NO and stimulation of the synthesis of cGMP by direct stimulation of sGC, independent of NO. The benzylindazole compound YC-1 was the first sGC stimulator to be identified. Additional sGC stimulators with improved potency and specificity for sGC have since been developed.

Compounds that stimulate sGC in an NO-independent manner offer considerable advantages over other current alternative therapies that target the aberrant NO pathway. There is a need to develop novel, well-characterized stimulators of sGC. Compound I is an sGC stimulator that has demonstrated efficacy for the treatment of a number of NO related disorders in preclinical models. Compound I was previously described in WO2014144100, Example 1, as a light orange solid. Compound I may be present in various crystalline forms and may also form several pharmaceutically acceptable salts.

Compounds which enhance eNOS transcription: for example those described in WO

02/064146, WO 02/064545, WO 02/064546 and WO 02/064565, and corresponding patent documents such as US2003/0008915, US2003/0022935, US2003/0022939 and US2003/0055093. Other eNOS transcriptional enhancers including those described in US20050101599 (e.g. 2,2-difluorobenzo[l,3]dioxol-5-carboxylic acid indan-2-ylamide, and 4-fluoro-N-(indan-2-yl)-benzamide), and Sanofi-Aventis compounds AVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al., Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1 : abstract number P 1487);

NO independent heme-independent sGC activators, including, but not limited to: -2667 (see patent publication DE19943635)

HMR-1766 (ataciguat sodi

S 3448 (2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomoφholine-4-sulfonyl)-phenyl)-benzamide (see patent publi

HMR-1069 (Sanofi-Aventis).

(7) Heme-dependent sGC stimulators including, but not limited to:

YC-1 (see patent publications EP667345 and DE19744026)

Riociguat (BAY 63-2521, Adempas, commercial product, described in DE19834044)

Neliciguat (BAY 60-4552, described in WO 2003095451)

Vericiguat (BAY 1021189, clinical backup to Riociguat),

BAY 41-2272 (described in DE19834047 and DE19942809)

BAY 41-8543 (described in DE I 9834044)

Etriciguat (described in WO 2003086407)

CFM-1571 (see patent publicatio

A-344905, its acrylamide analo analogue A-778935.

A-344905;

Compounds disclosed in one of publications: US20090209556, US8455638, US20110118282 (WO2009032249), US20100292192, US20110201621, US7947664, US8053455 (WO2009094242), US20100216764, US8507512, (WO2010099054) US20110218202 (WO2010065275),

US20130012511 (WO2011119518), US20130072492 (WO2011149921), US20130210798

(WO2012058132) and other compounds disclosed in Tetrahedron Letters (2003), 44(48): 8661-8663.

Pictorial synthesis

FROM PATENTS

CONSTRUCT YOUR OWN

SIDE CHAIN SHOWN ABOVE

                     FINAL STEP SHOWN ABOVE  OLINCIGUAT

PATENT

WO2014144100, Example 1

Inventors Takashi NakaiJoel MooreNicholas Robert PerlRajesh R. IyengarAra MermerianG-Yoon Jamie ImThomas Wai-Ho LeeColleen HudsonGlen Robert RENNIEJames JiaPaul Allen RENHOWETimothy Claude BardenXiang Y YuJames Edward SHEPPECKKarthik IyerJoon JungLess «
Applicant Takashi NakaiJoel MooreNicholas Robert PerlIyengar Rajesh RAra MermerianG-Yoon Jamie ImThomas Wai-Ho LeeColleen HudsonRennie Glen RobertJames JiaRenhowe Paul AllenTimothy Claude BardenXiang Y YuSheppeck James EdwardKarthik IyerJoon JungLess «

PATENT

WO 2016044447

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016044447

Inventors Timothy Claude BardenJames Edward SHEPPECKGlen Robert RENNIEPaul Allan RenhoweNicholas PerlTakashi NakaiAra MermerianThomas Wai-Ho LeeJoon JungJames JiaKarthik IyerRajesh R. IyengarG-Yoon Jamie Im
Applicant Ironwood Pharmaceuticals, Inc.

Compound 195

lntermediate-36 Compound 195

[00463] lntermediate-36 (35 mg, 0.09 mmol),

(R)-2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (60 mg, 0.35 mmol) and

N-ethyl-N-isopropylpropan-2-amine (0.10 mL, 0.56 mmol) were mixed in dimethylsulfoxide (1.5 mL) and heated at 95°C for 8 hr. The solution was cooled to room temperature, diluted with water (2 mL) and the pH taken to 2-3 with 1 N (aq) HC1. The solution was mixed with ethyl acetate (50 mL) and the organic phase was washed with water (2 x 5 mL), brine, then dried over Na2S04, filtered and concentrated by rotary evaporation. The residue was subjected to preparative reverse phase HPLC

. . . t . + + . using a giauiciu ui water acetonitri e . tni uoroacetic aci as e uant to give me iouu i s a wnite solid (11 mg, 23% yield). ¾-NMR (400 MHz, CD3OD) δ 8.83 (br s, 1H), 8.27 (br s, 1H), 7.49 (br s,

1H), 6.9-7.0 (m, 2H), 6.5-6.6 (m, 2H), 5.86 (s, 2H), 4.35 (d, 1H), 4.16 (d, 1H) ppm. Note: exchangable protons all appeared under the residual HOD peak at 4.91 ppm.

PATENT

WO-2018009609

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018009609&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Novel crystalline solid forms of olinciguat (presumed to be IW-1701), an SGC stimulator and their salts, such as hydrochloride acid (designated as Forms A, B, D, E, F, H and G), processes for their preparation and compositions comprising them are claimed. Also claimed are processes for preparing the crystalline forms. Further claimed are their use for treating cancer, sickle cell disease, osteoporosis, dyspepsia, Duchenne muscular dystrophy, amyotrophic lateral sclerosis and spinal muscle atrophy

In one aspect, the invention relates to crystalline solid forms of Compound I, depicted below:

Compound I

[0009] For purposes of this disclosure, “Compound I,” unless otherwise specifically indicated, refers to the free base or to the hydrochloric acid salt of the structure denoted above. Compound I, as its crystalline free base, is highly polymorphic and known to have seven crystalline forms (Forms A, B, D, E, F, G and H) as well as multiple solvates. Compound I was previously described in

WO2014144100, Example 1, as a light orange solid.

[0010] In one embodiment, the crystalline solid forms of Compound I here disclosed are polymorphs of the free base. In another embodiment, a crystalline solid form of Compound I is the hydrochloric acid salt. In one embodiment, the polymorphs of Compound I are crystalline free base forms. In another embodiment, they are solvates.

[001 1] In another aspect, also provided herein are methods for the preparation of the above described crystalline free forms and salts of Compound I.

[0012J In another aspect, the invention relates to pharmaceutical compositions comprising one or more of the polymorphs of Compound I herein disclosed, or the hydrochloric acid salt of Compound I, and at least one pharmaceutically acceptable excipient or carrier. In another embodiment, the invention relates to pharmaceutical dosage forms comprising said pharmaceutical compositions.

[0013] In another embodiment, the invention relates to a method of treating a disease, health condition or disorder in a subject in need thereof, comprising administering, alone or in combination therapy, a therapeutically effective amount of a polymorph of Compound I herein disclosed, or a mixture of polymorphs thereof, or its hydrochloric acid salt , to the subject; wherein the disease or disorder is one that may benefit from sGC stimulation or from an increase in the concentration of NO and/or cGMP.

EXAMPLES

Example 1: Preparation of crude Compound I

i): Coupling of Compound (1′) and 7V,0-Dimethylhydroxylamine to provide N-methoxy-N-methylisoxazole-3-carboxamide (2′)

[00238] Isooxazole-3-carboxylic acid ((l’)> 241.6 g, 2137 mmoles, 1.0 equiv.), toluene (1450 mL) and DMF (7.8 g, 107 mmoles, 0.05 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The resulting slurry was heated to 45-50 °C. Oxalyl chloride (325 g, 2559 mmoles, 1.2 equiv.) was then charged via an addition funnel over the course of 2 h while maintaining the reaction temperature between 45 to 50 °C and a vigorous gas evolution was observed. A brown mixture was obtained after addition. The brown mixture was heated to 87 to 92 °C over 1 h and stirred at 87 to 92 °C for 1 h. The reaction was completed as shown by HPLC. During heating, the brown mixture turned into a dark solution. The reaction was monitored by quenching a portion of the reaction mixture into piperidine and monitoring the piperidine amide by HPLC. The dark mixture was cooled to 20-25 °C and then filtered through a sintered glass funnel to remove any insolubles. The dark filtrate was concentrated under reduced pressure to a volume of 400 mL dark oil.

[00239] Potassium carbonate (413 g, 2988 mmoles, 1.4 equiv.) and water (1000 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction solution was cooled to -10 to -5 °C. N,0-dimethylhydroxyamine hydrochloride (229 g, 2348 mmoles, 1.1 equiv.) was charged to a suitable reaction vessel and dissolved in water (1000 mL). The N,0-dimethylhydroxyamine solution and dichloromethane (2500 mL) were then charged to the potassium carbonate solution.

[00240] The above dark oil (400 mL) was then charged slowly via an addition funnel while maintaining the reaction temperature -10 to 0 °C. The addition was slightly exothermic and a brown mixture was obtained after addition. The mixture was stirred at 0 to 5 °C over 20 min. and then warmed to 20 to 25 °C. The bottom organic layer was collected and the top aq. layer was extracted with dichloromethane (400 mL). The combined organic layers were washed with 15% sodium chloride solution (1200 mL). The organic layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure to give intermediate (2′) as a dark oil (261.9 g, 97 wt%, 76% yield, 3 wt% toluene by Ή-ΝΜΡν, 0.04 wt % water content by KF). Ή-ΝΜΡν (500 MHz, CDC13) δ ppm 8.48 (s, 1 H); 6.71(s, 1 H); 3.78 (s, 3 H); 3.38 (s, 3 H).

ii): alkylation of Compound (2′) and ethyl propiolate to provide (E)-ethyl 4-(isoxazol-3-yl)-2-(methox methyl)amino)-4-oxobut-2-enoate (3′)

(2′) (3′)

[00241] Intermediate (2′) (72.2 g, 96 wt%, 444 mmoles, 1.0 equiv.), ethyl propiolate (65.7 g, 670 mmoles, 1.5 equiv.) and anhydrous THF (650 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to -65 to -55 °C. Sodium bis(trimethylsilyl)amide in THF (1 M, 650 mL, 650 mmoles, 1.46 equiv.) was then charged slowly via an addition funnel while maintaining the reaction temperature -65 to -55 °C. The mixture was stirred below -55 °C over 10 min. after addition was complete. Then 1 N HC1 (650 mL, 650 mmoles, 1.46 equiv.) was charged to quench the reaction while maintaining the reaction temperature below -20 °C followed immediately with the addition of ethyl acetate (1500 mL) and water (650 mL). The top ethyl acetate layer was collected and the bottom aqueous layer was extracted with ethyl acetate (800 mL). The combined organic layers were washed with 10% citric acid (1000 mL) and saturated sodium chloride solution (650 mL). The organic layer was concentrated under reduced pressure to give a dark oil.

[00242] The dark oil was dissolved in a solution of dichloromethane/ethyl acetate/heptane

(150mL/100mL/100mL). The solution was loaded on a silica pad (410 g) and the silica pad was eluted with ethyl acetate/heptane (1/1 v/v). The filtrate (~ 3000 mL) was collected and then concentrated under reduced pressure to a volume of 150 mL to give a slurry upon standing. Heptane (200 mL) was then added to the slurry and the slurry was concentrated under reduced pressure to a volume of 150 mL. The resulting slurry was filtered, and the filter cake was washed with heptane (150 mL). The filter cake was then air dried overnight to furnish intermediate (3′) as a brown solid (63.4 g, 56% yield, >99% pure by HPLC). i-NMR (500 MHz, CDC13) δ ppm 8.42 (d, J=1.53 Hz, 1 H); 6.76 (d, J=1.53 Hz, 1 H); 6.18 (s, 1 H); 4.47 (q, J=7.07 Hz, 2H); 3.75 (s, 3 H); 3.21 (s, 3 H); 1.41 (t, J=7.17 Hz, 3 H). iii): cyclization of Compound 3′ and 2-fluorobenzylhydrazine to provide ethyl l-(2-fluorobenz l)-5-(isoxazol-3-yl)-lH-pyrazole-3-carboxylate (4′)

[00243] Intermediate (3′) (72.9 g, 287 mmoles, 1.0 equiv.) and absolute ethanol (730 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 0 to 5 °C. 2-Fluorobenzylhydrazine (48.2 g, 344 mmoles, 1.2 equiv.) was then charged to the mixture. The mixture was stirred at 0 to 10 °C over 1 h and then warmed to 20 to 25 °C and stirred at 20 to 25 °C over 16 h. The reaction was completed by HPLC. Concentrated HCl (33.9 g, 37 wt%, 344 mmoles, 1.2 equiv.) was charged to the reaction mixture over 1 min and the batch temperature exothermed from 20 °C to 38 °C. A slurry was obtained. The mixture was cooled to 0 to 10 °C over 1 h and stirred at 0-10 °C for 1 h. The resulting slurry was filtered, and the filter cake was washed with ethanol (200 mL). The filter cake was dried under vacuum at 30 to 40 °C over 16 h to furnish intermediate (4′) as an off-white solid (81.3 g, 90% yield, >99% pure by HPLC). ¾-NMR (500 MHz, CDC13) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 7.15 – 7.26 (m, 2 H); 6.94 – 7.08 (m, 2H); 6.77 – 6.87 (m, 1 H); 6.55 (d, J=1.68 Hz, 1 H); 5.95 (s, 2 H); 4.43 (q, J=7.02 Hz, 2 H); 1.41 (t, J=7.17 Hz, 3 H).

iv): amination of Compound (4′) to provide l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazole-3-carboximidamide hydrochloride (5’B)

[00244] Anhydrous ammonium chloride (267 g, 4991 mmoles, 5.0 equiv.) and toluene (5400 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Trimethylaluminum in toluene (2 M, 2400 mL, 4800 mmoles, 4.8 equiv.) was charged

slowly via an addition funnel while maintaining the reaction temperature at 20 to 40 °C (Note:

Methane gas evolution was observed during addition). Then the mixture was heated to 75 to 80 °C over 30 min. and a clear white solution was obtained. Intermediate (4′) (315 g, 999 mmoles, 1.0 equiv.) was charged to reaction mixture in four equal portions over 1 h at 75 to 90 °C. The reaction was stirred at 80 to 90 °C over 30 min. and then heated to 100 to 110 °C and stirred at 100 to 110 °C over 3 h. The reaction was completed by HPLC. The reaction mixture was cooled to 10 to 20 °C and methanol (461 g, 14.4 moles, 14.4 equiv.) was charged slowly via an addition funnel while

maintaining the reaction temperature 10-40 °C. Note the quenching was very exothermic and a lot gas evolution was observed. A thick slurry was obtained. A 3N HQ (6400 mL, 3 N, 19.2 moles, 19.2 equiv.) was then charged slowly via an addition funnel while maintaining the reaction temperature at 20 to 45 °C. The mixture was heated to 80 to 85 °C and stirred at 80 to 85 °C over 10 min. to obtain a clear biphasic mixture. The mixture was cooled to 0 to 5 °C over 3 h and stirred at 0 to 5 °C over 1 h. The resulting slurry was filtered, and the filter cake was washed with water (3000 mL). The filter cake was dried under vacuum at 40 to 50 °C over 24 h to furnish intermediate (5’B) as an off-white solid (292 g, 91% yield, >99% pure by HPLC). ¾-ΝΜΡν (500 MHz, DMSO- 6) δ ppm 9.52 (s, 2 H); 9.33 (s, 2 H); 9.18 (d, J=1.53 Hz, 1 H); 7.88 (s, 1 H); 7.29 – 7.38 (m, 1 H); 7.19 – 7.25 (m, 1 H); 7.10 – 7.16 (m, 1 H); 7.03 (d, J=1.53 Hz, 1 H); 6.92 – 6.98 (m, 1 H); 5.91 (s, 2 H). M.P. 180-185 °C.

v): cyclization of Compound (5’B) and diethyl fluoromalonate to provide 5-fluoro-2-(l-(2-fluorobenz l)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidine-4,6-diol (6′)

(5’B) (6·)

[00245] Intermediate (5’B) (224.6 g, 698 mmoles, 1.0 equiv.), methanol (2250 mL) and diethyl fluoromalonate (187 g, 1050 mmoles, 1.5 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Then sodium methoxide in methanol solution (567 g, 30 wt %, 3149 mmoles, 4.5 equiv.) was charged via an addition funnel while maintaining the reaction temperature 20 to 35 °C. The mixture was stirred at 20 to 35 °C over 30 min. and a light suspension was obtained. The reaction was completed by HPLC. A solution of 1.5 N HQ (2300 mL, 3450 mmoles, 4.9 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature 20 to 30 °C. A white suspension was obtained. The pH of the reaction mixture was to be ~1 by pH paper. The slurry was stirred at 20 to 30 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of methanol and water (500 mL/500 mL), and then with water (1000 mL). The filter cake was dried under vacuum at 50 to 60 °C over 16 h to furnish intermediate (6′) as an off-white solid (264 g, 97% yield, >99% pure by HPLC). ¾-NMR (500 MHz,

DMSO- s) δ ppm 12.82 (br. s., 1 H); 12.31 (br. s., 1 H); 9.14 (d, J=1.53 Hz, 1 H); 7.55 (s, 1 H); 7.31 -7.37 (m, 1 H); 7.18 – 7.25 (m, 1 H); 7.10 – 7.15 (m, 2 H); 6.97 – 7.02 (t, J=7.55 Hz, 1 H); 5.88 (s, 2 H).

vi): chlorination of Compound (6′) to provide 3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-l-(2-fluorobenz l)-lH-pyrazol-5-yl)isoxazole (7′)

(6«) (7«)

[00246] Intermediate (6′) (264 g, 71 1 mmoles, 1.0 equiv.), acetonitrile (4000 mL) and N,N-dimethylaniline (138 g, 1 137 mmoles, 1.6 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70-80 °C. Then phosphorous oxychloride (655 g, 4270 mmoles, 6.0 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature 70 to 80 °C. The mixture was stirred at 75 to 80 °C over 22 h and a brown solution was obtained. The reaction was completed by HPLC. Then the mixture was cooled to between 0 and 5 °C and cotton like solids precipitated out at 25 °C. Water (3000 mL) was charged slowly via an addition funnel while maintaining the reaction temperature at 0 to 10 °C. The slurry was stirred at 0 to 10 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of acetonitrile and water (500 mL/500 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (7′) as an off-white solid (283 g, 98% yield, >99% pure by HPLC). ‘H-NMR (500 MHz, CDC13) δ ppm 8.48 (d, J=1.68 Hz, 1 H); 7.44 (s, 1 H); 7.19 – 7.25 (m, 1 H); 6.96 – 7.08 (m, 2 H); 6.81 – 6.88 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

vii): substitution of Compound (7′) with meth oxide to provide 3-(3-(4-chloro-5-fluoro-6-m

(7′) (8′)

[00247] Methanol (3400 mL) and sodium methoxide in methanol (154 mL, 5.4 M, 832 mmoles,

1.2 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 23 to 27 °C. Intermediate (7′) (283 g, 693 mmoles, 1.0 equiv.) was charged to the mixture in small portions (5-10 g each portion) over 40 min while maintaining the reaction temperature 23 to 27 °C. The slurry was stirred at 23 to 27 °C over 30 min. The reaction was completed by HPLC. The resulting slurry was filtered, and the filter cake was washed with methanol (850 mL) and then water (850 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (8′) as an off-white solid (277 g, 99% yield, 97% pure by HPLC). i-NMR (500 MHz, CDCl3) 5 ppm 8.47 (d, J=1.83 Hz, 1 H); 7.38 (s, 1 H); 7.18 – 7.25 (m, 1 H); 7.01 – 7.08 (m, 1 H); 6.94 – 7.00 (m, 1 H); 6.81 – 6.88 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 6.00 (s, 2 H); 4.21 (s, 3 H).

viii): hydrogenation of Compound (8′) to provide 3-(3-(5-fluoro-4-methoxypyrimidin-2-yl)-l-(2-fluorobenz l)-lH-pyrazol-5-yl)isoxazole (9′)

[00248] Intermediate (8′) (226 g, 560 mmoles, 1.0 equiv.), palladium (10% on activated carbon, nominally 50% water wet, 22.6 g, 0.01 moles, 0.018 equiv), tetrahydrofuran (3400 mL) and triethylamine (91 g, 897 mmoles, 1.6 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Nitrogen was bubbled into the reaction mixture via teflon tubing over 10 min. at 20 to 30 °C. Then the mixture was heated to 40 to 50 °C and hydrogen gas was bubbled into the reaction mixture via teflon tubing over 6 h while maintaining the reaction temperature 40 to 50 °C. The reaction was completed by HPLC. Nitrogen was then bubbled into the reaction mixture via teflon tubing over 10 min. at 40 to 50 °C The reaction mixture was hot filtered through Hypo Supercel™ and the filter cake was washed with tetrahydrofuran (2000 mL). The filtrate was concentrated under reduced pressure to a volume of -1300 mL to give a slurry. Tetrahydrofuran was then solvent exchanged to methanol under reduced pressure via continuously feeding methanol (3000 mL). The final volume after solvent exchange was 1300 mL. The resulting slurry was filtered, and the filter cake was washed with methanol (500 mL). The filter cake was dried under vacuum at 20 to 25 °C over 16 h to furnish intermediate (9′) as a white solid (192 g, 93% yield, 98% pure by HPLC). ¾-NMR (500 MHz, CDC13) δ ppm 8.47 (d, J=1.68 Hz, 1 H); 8.41 (d, J=2.59 Hz, 1 H); 7.36 (s, 1 H); 7.17 – 7.24 (m, 1 H); 6.95 – 7.07 (m, 2 H); 6.83 – 6.90 (m, 1 H); 6.60 (d, J=1.68 Hz, 1 H); 5.99 (s, 2 H); 4.19 (s, 3 H).

ix: demethylation of Compound (9′) to provide 5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidin-4-ol (10′)

[00249] Intermediate (9′) (230 g, 623 mmoles, 1.0 equiv.), Me OH (3450 mL) and cone. HC1

(307 g, 37 wt%, 3117 mmoles, 5.0 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was heated to 60 to 65 °C and a solution was obtained. The mixture was then stirred at 60 to 65 °C over 17 h and a slurry was obtained. The reaction was completed by HPLC. The slurry was cooled to 20 to 25 °C over 2 h and stirred at 20 to 25 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with methanol (1000 mL). The filter cake was dried under vacuum at 35 to 45 °C over 16 h to furnish intermediate (10′) as a white solid (214 g, 97% yield, >99% pure by HPLC). ¾-NMR (500 MHz, DMSO-t/6) δ ppm 12.90 – 13.61 (br. s., 1 H); 9.11 (d, J=1.68 Hz, 1 H); 8.16 (s, 1 H); 7.64 (s, 1 H); 7.29 – 7.42 (m, 1 H); 7.17 – 7.28 (m, 2 H); 7.08 – 7.15 (m, 1 H); 6.97 (s, 1 H); 5.91 (s, 3 H).

x): chlorination of Compound (10′) to provide 3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-l-(2-fluorobenzyl)-lH-pyrazol-5-yi)isoxazole (Formula IV)


Formula IV

[00250] Intermediate (10′) (214 g, 602 mmoles, 1.0 equiv.), acetonitrile (3000 mL) and NN-dimethylaniline (109 g, 899 mmoles, 1.5 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The slurry mixture was heated to 70 to 80 °C. Then phosphorous oxychloride (276 g, 1802 mmoles, 3.0 equiv.) was charged via an addition funnel over 30 min. while maintaining the reaction temperature 70-80 °C. The mixture was stirred at 75 to 80 °C over 2 h and a green solution was obtained. The reaction was completed by HPLC. Then the mixture was cooled to 0 to 5 °C. Water (1500 mL) was charged slowly via an addition funnel while maintaining the reaction temperature at 0 to 10 °C. The slurry was stirred at 0 to 10 °C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of

acetonitrile and water (500 mL/500 mL) and water (500 mL). The filter cake was dried under vacuum at 30 to 40 °C over 16 h to furnish intermediate of Formula IV as an off-white to pink solid (214 g, 95% yield, >99% pure by HPLC). 1H NMR (500 MHz, CDC13) 5 ppm 8.65 (s, 1 H); 8.48 (d, J=1.68 Hz, 1 H); 7.44 (s, 1 H); 7.21 – 7.25 (m, 1 H); 6.97 – 7.06 (m, 2 H); 6.83 – 6.87 (m, 1 H); 6.61 (d, J=1.68 Hz, 1 H); 6.03 (s, 2 H).

a): Cyanation of intermediate (15) to provide 2-(bromomethyl)-3,3,3-trifluoro-2-((trimethylsilyl)oxy)propanenitrile (16)

(15) (16)

[00251 ] Trimethylsilanecarbonitrile ( 153 g, 1.54 moles, 0.97 equiv) and triethylamine (4.44 mL,

3.22 g, 0.032 mole, 0.02 equiv) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The mixture was cooled to 5 °C. 3-Bromo-l, l, l-trifluoropropan-2-one ((15), 304 g, 1.59 moles, 1.0 equiv) was charged via an addition funnel over 35 min, while maintaining the reaction temperature between 10 to 20 °C. The mixture was stirred at 20 to 30 °C over 3 h after the addition to furnish intermediate (16) as a dense oil which was used directly in the next step. 1H-NMR (500 MHz, CDC13) δ ppm 3.68 (d, J=1 1.14 Hz, 1 H); 3.57 (d, J=11.14 Hz, 1 H), 0.34 – 0.37 (m, 9 H).

b): Conversion of nitrile Compound (16) to amide to provide 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (17)

2

(16) (17)

[00252] Concentrated sulfuric acid (339 mL, 6.37 moles, 4.0 equiv) was stirred in a suitable reaction vessel equipped with a mechanical stirrer, digital thermometer and an addition funnel. The sulfuric acid was heated to 45 °C. The above intermediate (16) was added via an addition funnel over 50 min, while keeping the temperature below 75 °C. The reaction mixture was stirred at 75 °C for 2 h and then allowed to cool to room temperature. ¾-NMR indicated reaction complete. The reaction mixture was cooled to -15 °C and diluted with ethyl acetate (1824 mL) via an addition funnel over 45 min (very exothermic), while keeping the temperature between -15 to 5 °C. Water ( 1520 mL) was added slowly via an addition funnel for 1 h 20 min. (very exothermic) between -10 to 0 °C. The layers were separated and the organic layer was washed with 15% aqueous sodium chloride solution ( 1520

mL), 25% aqueous sodium carbonate solution (911 mL) followed by 15% aqueous sodium chloride solution (911 mL). The organic layer was filtered and concentrated under reduced pressure to get 348 g of intermediate (17) as light yellow oil. This oil was dissolved in methanol (1200 mL) and concentrated to furnish 380 g of intermediate (17). (296 g adjusted weight, 79% yield). i-NMR (500 MHz, CDC13) 5 6.61 – 6.94 (m, 1 H); 5.92 – 6.26 (m, 1 H); 3.93 – 4.00 (m, 1 H); 3.68 (d, J=l 1.14 Hz, 1 H).

c): N-Alkylation of compound (17) to provide of 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (14)

(17) (14)

[00253] A 7 N solution of ammonia in methanol (600 mL, 4.28 moles, 10 equiv) was charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The solution was cooled to 0 to 5 °C. Then the intermediate (17) (102 g, 0.432 moles, 1 equiv) was added via an addition funnel over 30 min at 0 to 5 °C. The reaction mixture was warmed to 20 to 25 °C over 1 h and held for 72 h. The reaction was completed by HPLC. The reaction mixture was cooled to 0 to 5 °C and sodium methoxide (78 mL, 5.4 M, 0.421 moles, 0.97 equiv) was added over 2 min. The reaction mixture was then concentrated under reduced pressure to a volume of 300 mL. 2 L of ethyl acetate was added and concentration was continued under reduced pressure to a volume to 700 mL to get a slurry. 700 mL of ethyl acetate was added to the slurry to make the final volume to 1400 mL. 102 mL of water was added and stirred for 2 min to get a biphasic solution. The layers were separated. The ethyl acetate layer was concentrated under reduced pressure to a volume of 600 mL. Then the ethyl acetate layer was heated to > 60 °C and heptane (600 mL) was added slowly between 55 to 60 °C. The mixture was cooled to 15 to 20 °C to give a slurry. The slurry was stirred at 15 to 20 °C for 2 h and filtered. The solids were dried under vacuum at 25 °C for 16 h to furnish amine (14) as white solid (48 g, 64% yield). ‘H-NMR (500 MHz, MeOH-d4) δ ppm 2.94 (d, J= 13.73 Hz, 1H); 3.24 (d, J= 13.58 Hz, 1H).

d): chiral resolution of amine (14) as the 1:1 salt of (R)-2,2-dimethyl-5- (trifluoromethyl)oxazolidine-5-carboxamide (R)-2-hydroxysuccinate (18A) and (D)-malic acid.

(14) (ISA)

[00254] Amine (14) (105 g, 0.608 moles, 1.0 equiv.), (D)-Malic acid (82 g, 0.608 moles, 1.0 equiv.) and acetone (1571 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was stirred at 20 to 25 °C for 16 h. The resulting slurry was filtered, and the wet cake was washed with acetone (300 mL). The wet cake was charged back to the reaction vessel, and acetone (625 mL) was charged. The slurry was heated to 53 °C and held for 6 h. The slurry was cooled to 20 to 25 °C and held at this temperature for 16 h. The slurry was filtered, and the wet cake was washed with acetone (200 mL). The wet cake was dried under vacuum at 40 °C for 4 h to furnish 82.4 g of the 1 : 1 salt of (18A) and (D)-malic acid as a white solid (82.4 g, 39% yield, 97% ee). i-NMR (500 MHz, D20) δ ppm 4.33 (br, s, 1H); 3.61 (br, d, J= 13.58 Hz, 1H); 3.40 – 3.47 (m, 1H); 2.76 (br, d, J= 15.87 Hz, 1H); 2.53 – 2.63 (m, 1H); 2.16 (br, s, 4H).

e): Coupling of the 1:1 (D)-malic acid salt of intermediate (18A) and Formula IV to provide (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2-hydroxypropanamide (Compound I)

Formula IV Compound I

[00255] The 1: 1 salt of intermediate (18A) and (D)-malic acid (74.1 g, 0.214 moles, 2.5 equiv) and water (44.8 mL) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. The reaction mixture was heated to 70 °C and stirred for 20 min. Acetone generated during the reaction was removed by blowing with nitrogen. The reaction mixture was cooled to 30 to 40 °C and Formula IV (32 g, 0.086 moles, 1.0 equiv), DMSO (448 mL) and Hunig’s base (44.7 mL, 0.257 moles, 3.0 equiv) were charged. The reaction mixture was heated to 90 °C and stirred at 90 °C over 17 h. The reaction was complete by HPLC. Then the mixture was cooled to 60 °C. Another portion of Hunig’s base (104 mL, 0.599 moles, 7.0 equiv) was charged followed by water (224 mL) at 55 to 62 °C. The reaction mixture was stirred for 15 min at 55 to 60 °C to form the seed bed. Water (320 mL) was added via addition funnel at 55 to 62 °C over the course of 30 min, and the resultant slurry was stirred for 1 h at 55 to 60 °C. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of methanol and water (320 mL/320 mL) followed by water (640 mL). The filter cake was then dried under vacuum at 40 °C over 16 h to furnish Compound I as an off-white solid (40 g, 92% yield, 99% pure by HPLC, 98% ee). ¾-NMR (500 MHz, DMSO-t/6) δ ppm 9.10 (s, 1 H); 8.33 (d, J=2.90 Hz, 1 H); 7.93 (s, br, 1 H); 7.90 (s, 1 H); 7.78 (s, br, 1 H); 7.69 (s, br, 1 H); 7.52 (s, 1 H); 7.33 (q, J=7.02 Hz, 1 H); 7.17 – 7.25 (m, 1 H); 7.17 – 7.25

(m, 1 H); 7.10 (t, J=7.48 Hz, l H); 6.98 (t, J=7.55 Hz, 1 H); 5.90 (s, 2 H); 3.92-4.05 (m, 2 H).

////////////OLINCIGUAT, IW-1701, phase 2, ironwood

NC(=O)[C@](O)(CNc1nc(ncc1F)c2cc(c3ccon3)n(Cc4ccccc4F)n2)C(F)(F)F

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