PF-06648671, PF 06648671,  PF-6648671

Phase I Alzheimer’s disease

Originator Pfizer

• 01 Nov 2016 Pfizer completes a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02883114)
• 01 Oct 2016 Pfizer completes a phase I trial in Healthy volunteers in Belgium (NCT02440100)
• 01 Sep 2016 Pfizer initiates a phase I pharmacokinetics trial in Healthy volunteers in USA (PO) (NCT02883114)

SYNTHESIS 

FIRST KEY INTERMEDIATE

CONTD………….

SECOND KEY INTERMEDIATE

contd……………..

Dementia results from a wide variety of distinctive pathological processes. The most common pathological processes causing dementia are Alzheimer’s disease (AD), cerebral amyloid angiopathy (CM) and prion-mediated diseases (see, e.g., Haan et al., Clin. Neurol. Neurosurg. 1990, 92(4):305-310; Glenner et al., J. Neurol. Sci. 1989, 94:1 -28). AD affects nearly half of all people past the age of 85, the most rapidly growing portion of the United States population. As such, the number of AD patients in the United States is expected to increase from about 4 million to about 14 million by 2050.

The present invention relates to a group of γ-secretase modulators, useful for the treatment of neurodegenerative and/or neurological disorders such as Alzheimer’s disease and Down’s Syndrome, (see Ann. Rep. Med. Chem. 2007, Olsen et al., 42: 27-47).

PATENT

WO 2014045156

Preparations

Preparation P1 : 5-(4-Methyl-1 H-imidazol-1 -yl)-6-oxo-1 ,6-dihvdropyridine-2-carboxylic

Step 1 . Synthesis of methyl 6-methoxy-5-(4-methyl-1 /-/-imidazol-1 -yl)pyridine-2- carboxylate (C2).

To a solution of the known 6-bromo-2-methoxy-3-(4-methyl-1 /-/-imidazol-1 – yl)pyridine (C1 , T. Kimura et al., U.S. Pat. Appl. Publ. 2009, US 20090062529 A1 ) (44.2 g, 165 mmol) in methanol (165 ml_) was added triethylamine (46 ml_, 330 mmol) and [1 ,1 ‘-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), dichloromethane complex (6.7 g, 8.2 mmol). The mixture was degassed several times with nitrogen. The reaction was heated to 70 °C under CO atmosphere (3 bar) in a Parr apparatus. After 30 minutes, the pressure dropped to 0.5 bar; additional CO was added until the pressure stayed constant for a period of 30 minutes. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The Celite pad was washed twice with methanol and the combined filtrates were concentrated under reduced pressure. The residue (88 g) was dissolved in ethyl acetate (1 L) and water (700 mL); the organic layer was washed with water (200 mL), and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to provide the title compound. Yield: 42.6 g, quantitative.

Step 2. Synthesis of 5-(4-methyl-1 H-imidazol-1 -yl)-6-oxo-1 ,6-dihydropyridine-2- carboxylic acid, hydrobromide salt (P1 ).

A solution of C2 (3.82 g, 15.9 mmol) in acetic acid (30 mL) and aqueous hydrobromic acid (48%, 30 mL) was heated at reflux for 4 hours. The reaction was allowed to cool to room temperature, and then chilled in an ice bath; the resulting precipitate was collected via filtration and washed with ice water (30 mL).

Recrystallization from ethanol (20 mL) provided the title compound as a light yellow solid. Yield: 3.79 g, 12.6 mmol, 79%. LCMS m/z 220.1 (M+1 ). ¹H N MR (400 MHz, DMSO-c/₆) δ 12.6 (v br s, 1 H), 9.58-9.60 (m, 1 H), 8.07 (d, J=7.6 Hz, 1 H), 7.88-7.91 (m, 1 H), 7.09 (d, J=7.4 Hz, 1 H), 2.34 (br s, 3H). Preparation P2: 5-(4-Methyl-1 H-imidazol-1 -yl)-6-oxo-1 ,6-dihvdropyridine-2-carboxylic acid, hydrochloride salt (P2)

A mixture of C2 (12.8 g, 51 .8 mmol) and 37% hydrochloric acid (25 mL) was heated at reflux for 18 hours. After the reaction mixture had cooled to room

temperature, the solid was collected via filtration; it was stirred with 1 ,4-dioxane (2 x 20 mL) and filtered again, to afford the product as a yellow solid. Yield: 13 g, 51 mmol, 98%. ¹H NMR (400 MHz, CD₃OD) δ 9.52 (br s, 1 H), 8.07 (d, J=7.5 Hz, 1 H), 7.78 (br s, 1 H), 7.21 (d, J=7.5 Hz, 1 H), 2.44 (s, 3H). Preparation P3: 7-(4-Methyl-1 H-imidazol-1 -yl)-3,4-dihvdropyridor2,1 -ciri ,41oxazine-1 ,6- dione (P3)

Compound P2 (65 g, 250 mmol), 1 ,2-dibromoethane (52.5 g, 280 mmol) and cesium carbonate (124 g, 381 mmol) were combined in A/,/V-dimethylformamide (850 mL) and heated at 90 °C for 6 hours. The reaction mixture was then cooled and filtered through Celite. After concentration of the filtrate in vacuo, the residue was dissolved in dichloromethane (500 mL), washed with saturated aqueous sodium chloride solution (100 mL), washed with water (50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was washed with acetonitrile to provide the product. Yield: 46.5 g, 190 mmol, 76%. ¹H NMR (400 MHz, CDCI₃) δ 8.33 (d, J=1 .4 Hz, 1 H), 7.43 (AB quartet, J_AB=7.7 Hz, Δν_ΑΒ=33.4 Hz, 2H), 7.15-7.17 (m, 1 H), 4.66-4.70 (m, 2H), 4.38-4.42 (m, 2H), 2.30 (d, J=0.8 Hz, 3H).

//////////PF-06648671, PF 06648671,  PF-6648671, PHASE 1

FC(F)(F)c5cc(Cl)c(F)cc5[C@H]1CCC[C@H](O1)[C@H](C)N4CCN3C(=CC=C(n2cc(C)nc2)C3=O)C4=O

First speaker of the PM session is Martin Pettersson from @pfizer talking about a gamma secretase modulator for Alzheimer’s #ACSSanFran

AZD 9567

CAS 1893415-00-3

1893415-64-9  as MONOHYDRATE

2,2-Difluoro-N-[(1R,2S)-3-methyl-1-[[1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-indazol-5-yl]oxy]-1-phenylbutan-2-yl]propanamide

Propanamide, N-[(1S)-1-[(R)-[[1-(1,6-dihydro-1-methyl-6-oxo-3-pyridinyl)-1H-indazol-5-yl]oxy]phenylmethyl]-2-methylpropyl]-2,2-difluoro-

2,2-difluoro-N-[(1R,2S)-3-methyl-1-[1-(1-methyl-6-oxopyridin-3-yl)indazol-5-yl]oxy-1-phenylbutan-2-yl]propanamide

2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide

MF C27 H28 F2 N4 O3, MF 494.533

AstraZeneca INNOVATOR

AZD-9567, a glucocorticoid receptor modulator, is in early clinical development at AstraZeneca in healthy male volunteers.

Phase I Rheumatoid arthritis

• Originator AstraZeneca
• Class Antirheumatics
• Mechanism of Action Glucocorticoid receptor modulators
• • 01 Sep 2016 AstraZeneca completes a phase I trial (In volunteers) in Germany (NCT02512575)
  • 24 May 2016 Phase-I clinical trials in Rheumatoid arthritis (In volunteers) in United Kingdom (PO) (NCT02760316)
  • 24 May 2016 AstraZeneca initiates a phase I trial in Rheumatoid arthritis (In volunteers) in Germany (PO) (NCT02760316)
   

Macclesfield AstraZeneca site in Cheshire

Glucocorticoids (GCs) have been used for decades to treat acute and chronic inflammatory and immune conditions, including rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (“COPD”), osteoarthritis, rheumatic fever, allergic rhinitis, systemic lupus erythematosus, Crohn’s disease, inflammatory bowel disease, and ulcerative colitis. Examples of GCs include dexamethasone, prednisone, and

prednisolone. Unfortunately, GCs are often associated with severe and sometimes irreversible side effects, such as osteoporosis, hyperglycemia, effects on glucose metabolism (diabetes mellitus). skin thinning, hypertension, glaucoma, muscle atrophy. Cushing’s syndrome, fluid homeostasis, and psychosis (depression ). These side effects can particularly limit the use of GCs in a chronic setting. Thus, a need continues to exist for alternative therapies that possess the beneficial effects of GCs, but with a reduced likel ihood of side effects.

GCs form a complex with the GC receptor ( GR ) to regulate gene transcription. The GC-GR complex translocates to the cell nucleus, and then binds to GC response elements (GREs) in the promoter regions of various genes. The resulting GC-GR- GRE complex, in turn, activates or inhibits transcription of proximally located genes. The GC-GR complex also (or alternatively) may negatively regulate gene transcription by a process that does not involve DNA binding. In this process, termed transrepression, the GC-GR complex enters the nucleus and directly interacts (via protein-protein interaction) with other transcription factors, repressing their ability to induce gene transcription and thus protein expression.

Some of the side effects of GCs are believed to be the result of cross-reactivity with other steroid receptors (e.g., progesterone, androgen, mineralocorticoid, and estrogen receptors), which have somewhat homologous ligand binding domains; and/or the inability to selectively modulate gene expression and downstream signaling. Consequently, it is believed that an efficacious selective GR modulator (SGRM), which binds to GR with greater affinity relative to other steroid hormone receptors, would provide an alternative therapy to address the unmet need for a therapy that possesses the beneficial, effects of GCs, while, at the same time, having fewer side effects.

A range of compounds have been reported to have SGRM activity. See, e.g., WO2007/0467747, WO2007/114763, WO2008/006627, WO2008/055709, WO2008/055710, WO2008/052808, WO2008/063116, WO2008/076048,

WO2008/079073, WO2008/098798, WO2009/065503, WO2009/142569,

WO2009/142571, WO2010/009814, WO2013/001294, and EP2072509. Still, there continues to be a need for new SGRMs that exhibit, for example, an improved potency, efficacy, effectiveness in steroid-insensitive patients, selectivity, solubility allowing for oral administration, pharmacokinetic profile allowing for a desirable dosing regimen, stability on the shelf {e.g., hydro lytic, thermal, chemical, or photochemical stability), crystallinity, tolerability for a range of patients, side effect profile and/or safety profile.

PATENT

WO 2016046260

Scheme 1 below illustrates a general protocol for making compounds described in this specification, using either an Ullman route or an aziridine route.

Scheme 1

In Scheme 1, Ar is

[182] The amino alcohol reagent used in Scheme 1 may be made using the below Scheme 2.

Scheme 2

The Grignard reagent (ArMgBr) used in Scheme 2 can be obtained commercially, or, if not, can generally be prepared from the corresponding aryl bromide and Mg and/or iPrMgCl using published methods.

[183] The iodo and hydroxy pyridone indazole reagents used in Scheme 1 may be made using the below Scheme 3A or 3B, respectively.

Scheme 3A

[184] Scheme 4 below provides an alternative protocol for making compounds described in this specification.

Scheme 4

Example 1. Preparation of 2,2-difluoro- V-[(lR,2S)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[199] Step A. Preparation of 5-[5-[(te^butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one.

Into a 2 L 4-necked, round-bottom flask, purged and maintained with an inert atmosphere of N₂, was placed a solution of 5-[(tert-butyldimethylsilyl)oxy]-lH-indazole (805 g, 3.2 mol) in toluene (8 L), 5 -iodo-1 -methyl- 1 ,2-dihydropyridin-2-one (800 g, 3.4 mol) and

K3PO4 (1.2 kg, 5.8 mol). Cyclohexane-l,2-diamine (63 g, 0.5 mol) was added followed by the addition of Cul (1.3 g, 6.8 mmol) in several batches. The resulting solution was stirred overnight at 102°C. The resulting mixture was concentrated under vacuum to yield 3.0 kg of the title compound as a crude black solid. LC/MS: m/z 356 [M+H]⁺.

[200] Step B. Preparation of 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one.

Into a 2 L 4-necked, round-bottom flask was placed 5-[5-[(fert-butyldimethylsilyl)oxy]-lH-indazol-l-yl]-l-methyl-l,2-dihydropyridin-2-one (3.0 kg, crude) and a solution of HCl (2 L, 24 mol, 36%) in water (2 L) and MeOH (5 L). The resulting solution was stirred for 1 hr at 40°C and then evaporated to dryness. The resulting solid was washed with water (4 x 5 L) and ethyl acetate (2 x 0.5 L) to afford 480 g (61%, two steps) of the title product as a brown solid. LC/MS: m/z 242 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d6): δ 3.52 (3H, s),6.61 (lH,m),7.06 (2H,m),7.54 (lH,m), 7.77 (lH,m), 8.19 (2H, m) 9.35 (lH,s).

[201] Ste C. Preparation of tert-butyl((lR,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate.

(S)-tert-butyl 3 -methyl- l-oxo-l-phenylbutan-2-ylcarbamate (1.0 kg, 3.5 mol) was dissolved in toluene (4 L). Afterward, 2-propanol (2 L) was added, followed by triisopropoxyaluminum (0.145 L, 0.73 mol). The reaction mixture was heated at 54-58°C for 1 hr under reduced pressure (300-350 mbar) to start azeothropic distillation. After the collection of 0.75 L condensate, 2-propanol (2 L) was added, and the reaction mixture was stirred overnight at reduced pressure to afford 4 L condensate in total. Toluene (3 L) was added at 20°C, followed by 2M HC1 (2 L) over 15 min to keep the temperature below 28°C. The layers were separated (pH of aqueous phase 0-1) and the organic layer was washed successively with water (3 L), 4% NaHCCte (2 L) and water (250 mL). The volume of the organic layer was reduced from 6 L at 50°C and 70 mbar to 2.5 L. The resulting mixture was heated to 50°C and heptane (6.5 L) was added at 47-53°C to maintain the material in solution. The temperature of the mixture was slowly decreased to 20°C, seeded with the crystals of the title compound at 37°C (seed crystals were prepared in an earlier batch made by the same method and then evaporating the reaction mixture to dryness, slurring the residue in heptane, and isolating the crystals by filtration), and allowed to stand overnight. The product was filtered off, washed with heptane (2 x 1 L) and dried under vacuum to afford 806 g (81%) of the title compound as a white solid. ¹HNMR (500 MHz, DMSO-d6): δ 0.81 (dd, 6H), 1.16 (s, 8H), 2.19 (m, 1H), 3.51 (m, 1H), 4.32 (d, 1H), 5.26 (s, 1H), 6.30 (d, 1H), 7.13 – 7.2 (m, 1H), 7.24 (t, 2H), 7.3 – 7.36 (m, 3H).

[202] Step D. Preparation of (lR,2S)-2-amino-3-methyl-l-phenylbutan-l-ol hydrochloride salt.

To a solution of HC1 in propan-2-ol (5-6 N, 3.1 L, 16 mol) at 20°C was added tert-butyl((li?,25)-l-hydroxy-3-methyl-l-phenylbutan-2-yl)carbamate (605 g, 2.2 mol) in portions over 70 min followed by the addition of MTBE (2 L) over 30 min. The reaction mixture was cooled to 5°C and stirred for 18 hr. The product was isolated by filtration and dried to afford 286 g of the title compound as an HC1 salt (61% yield). The mother liquor was concentrated to 300 mL. MTBE (300 mL) was then added, and the resulting precipitation was isolated by filtration to afford additional 84 g of the title compound as a HC1 salt (18% yield). Total 370 g (79%). ¹HNMR (400 MHz, DMSO-d6): δ 0.91 (dd, 6H), 1.61 – 1.81 (m, 1H), 3.11 (s, 1H), 4.99 (s, 1H), 6.08 (d, 1H), 7.30 (t, 1H), 7.40 (dt, 4H), 7.97 (s, 2H).

[203] Step E. Preparation of (2S,35)-2-isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine.

(li?,25)-2-Amino-3-methyl-l-phenylbutan-l-ol hydrochloride (430 g, 2.0 mol) was mixed with DCM (5 L) at 20°C. 4-Nitrobenzenesulfonyl chloride (460 g, 2.0 mol) was then added over 5 min. Afterward, the mixture was cooled to -27°C. Triethylamine (1.0 kg, 10 mol) was slowly added while maintaining the temperature at -18°C. The reaction mixture was cooled to -30°C, and methanesulfonyl chloride (460 g, 4.0 mol) was added slowly while maintaining the temperature at -25 °C. The reaction mixture was then stirred at 0°C for 16 hr before adding triethylamine (40 mL, 0.3 mol; 20 mL ,0.14 mol and 10 mL, 0.074 mol) w at 0°C in portions over 4 hr. Water (5 L) was subsequently added at 20°C, and the resulting layers were separated. The organic layer was washed with water (5 L) and the volume reduced to 1 L under vacuum. MTBE (1.5 L) was added, and the mixture was stirred on a rotavap at 20°C over night and filtered to afford 500 g (70%) of the title product as a solid. ¹HNMR (400 MHz, CDCls): δ 1.12 (d, 3H), 1.25 (d, 3H), 2.23 (ddt, 1H), 2.89 (dd, 1H), 3.84 (d, 1H), 7.08 – 7.2 (m, 1H), 7.22 – 7.35 (m, 4H), 8.01 – 8.13 (m, 2H), 8.22 – 8.35 (m, 2H)

[204] Step F. Preparation of V-((lR,2S)-3-methyl-l-(l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide.

[205] (25′,35)-2-Isopropyl-l-(4-nitrophenylsulfonyl)-3-phenylaziridine (490 g, 1.3 mol) was mixed with 5-(5-hydroxy-lH-indazol-l-yl)-l-methylpyridin-2(lH)-one (360 g, 1.4 mol) in acetonitrile (5 L) at 20°C. Cesium carbonate (850 g, 2.6 mol) was added in portions over 5 min. The reaction mixture was then stirred at 50°C overnight. Water (5 L) was added at 20°C, and the resulting mixture was extracted with 2-methyltetrahydrofuran (5L and 2.5 L). The combined organic layer was washed successively with 0.5 M HC1 (5 L), water (3 x 5L) and brine (5L). The remaining organic layer was concentrated to a thick oil, and then MTBE (2 L) was added. The resulting precipitate was filtered to afford 780 g (purity 71% w/w) of the crude title product as a yellow solid, which was used in the next step without further purification. ¹HNMR (400 MHz, DMSO-d6): δ 0.93 (dd, 6H), 2.01 -2.19 (m, 1H), 3.50 (s, 3H), 3.74 (s, 1H), 5.00 (d, 1H), 6.54 (d, 1H), 6.78 (d, 1H), 6.95 -7.15 (m, 4H), 7.23 (d, 2H), 7.49 (d, 1H), 7.69 (dd, 1H), 7.74 (d, 2H), 8.00 (s, 1H), 8.08 (d, 2H), 8.13 (d, 2H).

[206] Step G. Preparation of 2,2-difluoro- V-[(lR,25)-3-methyl-l-{[l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)-lH-indazol-5-yl]oxy}-l-phenylbutan-2-yl]propanamide.

[207] N-((lR,2S)-3-Methyl- 1 -(1 -(1 -methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)- \H-indazol-5-yloxy)-l-phenylbutan-2-yl)-4-nitrobenzenesulfonamide (780 g, 71%w/w) was mixed with DMF (4 L). DBU (860 g, 5.6 mol) was then added at 20°C over 10 min. 2-Mercaptoacetic acid (170 g, 1.9 mol) was added slowly over 30 min, keeping the temperature at 20°C. After 1 hr, ethyl 2,2-difluoropropanoate (635 g, 4.60 mol) was added over 10 min at 20°C. The reaction mixture was stirred for 18 hr. Subsequently, additional ethyl 2,2-difluoropropanoate (254 g, 1.8 mol) was added, and the reaction mixture was stirred for an additional 4 hr at 20°C. Water (5 L) was then slowly added over 40 min, maintaining the temperature at 20°C. The water layer was extracted with isopropyl acetate (4 L and 2 x 2 L). The combined organic layer was washed with 0.5M HC1 (4 L) and brine (2 L). The organic layer was then combined with the organic layer from a parallel reaction starting from 96 g of N-((li?,25)-3-methyl-l-((l-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)- lH-indazol-5-yl)oxy)- 1 -phenylbutan-2-yl)-4-nitrobenzenesulfonamide, and concentrated to approximate 1.5 L. The resulting brown solution was filtered. The filter was washed twice with isopropyl acetate (2 x 0.5 L). The filtrate was evaporated until a solid formed. The solid was then co evaporated with 99.5% ethanol (1 L), affording 493 g (77%, two steps) of an amorphous solid.

[208] The solid (464 g, 0.94 mol) was dissolved in ethanol/water 2: 1 (3.7 L) at 50°C. The reaction mixture was then seeded with crystals () of the title compound (0.5 g) at 47°C, and a slight opaque mixture was formed. The mixture was held at that temperature for 1 hr. Afterward, the temperature was decreased to 20°C over 7 hr, and kept at 20°C for 40 hr. The solid was filtrated off, washed with cold (5°C) ethanol/water 1 :2 (0.8 L), and dried in vacuum at 37°C overnight to afford 356 g (0.70 mol, 74%, 99.9 % ee) of the title compound as a monohydrate. LC/MS: m/z 495 [M+H]⁺. ‘HNMR (600 MHz, DMSO-d6) δ 0.91 (dd, 6H), 1.38 (t, 3H), 2.42 (m, 1H), 3.50 (s, 3H), 4.21 (m, 1H), 5.29 (d, 1H), 6.53 (d, 1H), 7.09 (d, 1H), 7.13 (dd, 1H), 7.22 (t, 1H), 7.29 (t, 2H), 7.47 (d, 2H), 7.56 (d, 1H), 7.70 (dd, 1H), 8.13 (d, 1H), 8.16 (d, 1H), 8.27 (d, 1H).

[209] The seed crystals may be prepared from amorphous compound prepared according to Example 2 using 2,2-difluoropropanoic acid, followed by purification on HPLC. The compound (401 mg) was weighed into a glass vial. Ethanol (0.4 mL) was added, and the vial was shaken and heated to 40°C to afford a clear, slightly yellow solution. Ethanol/Water (0.4 mL, 50/50% vol/vol) was added. Crystallization started to

occur within 5 min, and, after 10 min, a white thick suspension formed. The crystals were collected by filtration

/////////////AZD 9567, AstraZeneca, lucocorticoid receptor modulator, Rheumatoid arthritis, phase 1, Lena Elisabeth RIPA, Karolina Lawitz, Matti Juhani Lepistö, Martin Hemmerling, Karl Edman, Antonio Llinas

3rd speaker this afternoon in 1st time disclosures is Lena Ripa of @AstraZeneca on a glucocorticoid receptor modulator #ACSSanFran

CC(F)(F)C(=O)N[C@@H](C(C)C)[C@H](Oc1cc2cnn(c2cc1)C=3C=CC(=O)N(C)C=3)c4ccccc4

GSK 3008348

(3S)-3-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl]-4-{(3S)-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]-1-pyrrolidinyl}butanoic acid

cas 1629249-33-7

1-Pyrrolidinebutanoic acid, β-[3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl]-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]-, (βS,3R)-

(S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid

• (βS,3R)-β-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl]-3-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]-1-pyrrolidinebutanoic acid

• Molecular Formula C₂₉H₃₇N₅O₂
• Average mass 487.636 Da

• Originator GlaxoSmithKline

• Mechanism of Action Integrin alphaV antagonists
• Phase I Idiopathic pulmonary fibrosis
• 06 Mar 2017 GlaxoSmithKline plans a phase I trial for Idiopathic pulmonary fibrosis (NCT03069989)
• 01 Jun 2016 GlaxoSmithKline completes a first-in-human phase I trial for Idiopathic pulmonary fibrosis in United Kingdom (Inhalation) (NCT02612051)
• 01 Dec 2015 Phase-I clinical trials in Idiopathic pulmonary fibrosis in United Kingdom (Inhalation) (NCT02612051)

Inventors Niall Andrew ANDERSON, Brendan John FALLON, John Martin Pritchard

Applicant Glaxosmithkline Intellectual Property Development Limited

Niall Anderson

GSK-3008348, an integrin alpha(v)beta6 antagonist, is being developed at GlaxoSmithKline in early clinical studies for the treatment of idiopathic pulmonary fibrosis (IPF).

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a progressive decline in lung function, due to excessive deposition of extracellular matrix (collagen) within the pulmonary interstitium. It affects approximately 500,000 people in the USA and Europe and is poorly treated. IPF inexorably leads to respiratory failure due to obliteration of functional alveolar units. Patients’ mean life-expectancy is less than 3 years following diagnosis.

IPF therefore represents a major unmet medical need for which novel therapeutic approaches are urgently required.1 Pirfenidone (EsbrietTM from Roche), a non-selective kinase inhibitor, is approved for mild and moderate IPF patients in Japan, Europe, Canada and China and for all IPF patients in USA . Furthermore, nintedanib (OfevTM formerly BIBF-1120 from Boehringer-Ingelheim), a multiple tyrosine-kinase inhibitor targeting vascular endothelial factor receptor, fibroblast growth factor and platelet derived growth factor receptor is approved for all patients with IPF in USA and Europe.  Both compounds are administered orally twice or three times per day at high total doses (pirfenidone at 2.4 g/day and nintedanib at 300 mg/day).

Patient compliance is limited by tolerability due to gastro-intenstinal and phototoxicity issues, which require dose titration. (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride  is a first in class compound (descovered by GlaxoSmithKline) undergoing currently Phase I clinical trials for the treatment of IPF.  It is a non-peptidic αvβ6 integrin inhibitor and in cell adhesion assays has high affinity for the human receptor with a pIC50 of 8.4, and lower affinity for other integrins, such as αvβ3 6.0, αvβ5 5.9 and αvβ8 7.7. Inhibition of integrin αvβ6 is thought to prevent pulmonary fibrosis without exacerbating inflammation.

Integrin superfamily proteins are heterodimeric cell surface receptors, composed of an alpha and beta subunit. 18 alpha and 8 beta subunits have been reported, which have been demonstrated to form 24 distinct alpha/beta heterodimers. Each chain comprises a large extracellular domain (>640 amino acids for the beta subunit, >940 amino acids for the alpha subunit), with a transmembrane spanning region of around 20 amino acids per chain, and generally a short cytoplasmic tail of 30-50 amino acids per chain. Different integrins have been shown to participate in a plethora of cellular biologies, including cell adhesion to the extracellular matrix, cell-cell interactions, and effects on cell migration, proliferation, differentiation and survival (Barczyk et al, Cell and Tissue Research, 2010, 339, 269).

Integrin receptors interact with binding proteins via short protein-protein binding interfaces with ligands and the integrin family can be grouped into sub-families that share similar binding recognition motifs in such ligands. A major subfamily is the RGD-integrins, which recognise ligands that contain an RGD (Arginine-glycine-aspartic acid) motif within their protein sequence. There are 8 integrins in this sub-family, namely α_νβι, α_νβ₃, _νβ_{5ι ν}β_6ι α_νβδ, αι¾β₃, α₅βι, α₈βι, where nomenclature demonstrates that α_νβι, α_νβ₃, _νβ_{5ι ν}β_6ι & α_νβδ share a common V subunit with a divergent β subunit, and α_νβι, α₅βι & α₈βι share a common β_!subunit with a divergent a subunit. The βι subunit has been shown to pair with 11 different a subunits, of which only the 3 listed above commonly recognise the RGD peptide motif. (Humphries et al, Journal of Cell Science, 2006, 119, 3901).

Within the 8 RGD-binding integrins are different binding affinities and specificities for different RGD-containing ligands. Ligands include proteins such as fibronectin, vitronectin, osteopontin, and the latency associated peptides (LAPs) of Transforming growth factor βι and β3 (ΤΰΡβι and ΤΰΡβ₃). The binding to the LAPs of ΤΰΡβι and ΤΰΡβ₃ has been shown in several systems to enable activation of the ΤΰΡβι and ΤΰΡβ₃ biological activities, and subsequent ΤΰΡβ- driven biologies (Worthington et al, Trends in Biochemical Sciences, 2011, 36, 47). The specific binding of RGD integrins to such ligands depends on a number of factors, depending on the cell phenotype. The diversity of such ligands, coupled with expression patterns of RGD-binding integrins, generates multiple opportunities for disease intervention. Such diseases include fibrotic diseases (Margadant et al, EMBO reports, 2010, 11, 97), inflammatory disorders, cancer (Desgrosellier et al, Nature Reviews Cancer, 2010, 10, 9), restenosis, and other diseases with an angiogenic component (Weis et al, Cold Spring. Harb. Perspect Med.2011, 1, a006478).

A significant number of a_v integrin antagonists (Goodman et al, Trends in Pharmacological Sciences, 2012, 33, 405) have been disclosed in the literature including antagonist antibodies, small peptides and compounds. For antibodies these include the pan-a_v antagonist Intetumumab, the selective α_νβ3 antagonist Etaracizumab, and the selective a ₆ antagonist STX-100. Cilengitide is a cyclic peptide antagonist that inhibits both α_νβ3 and α_νβ₅, and SB-267268 is an example of a compound (Wilkinson-Berka et al, Invest. Ophthalmol. Vis. Sci, 2006, 47, 1600), which inhibits both α_νβ3 and α_νβ₅. Invention of compounds to act as antagonists of differing combinations of a_v integrins enables novel agents to be generated and tailored for specific disease indications.

Pulmonary fibrosis represents the end stage of several interstitial lung diseases, including the idiopathic interstitial pneumonias, and is characterised by the excessive deposition of extracellular matrix within the pulmonary interstitium. Among the idiopathic interstitial pneumonias, idiopathic pulmonary fibrosis (IPF) represents the commonest and most fatal condition with a median survival of 3 to 5 years following diagnosis. Fibrosis in IPF is generally progressive, refractory to current pharmacological intervention and inexorably leads to respiratory failure due to obliteration of functional alveolar units. IPF affects approximately 500,000 people in the USA and Europe. This condition therefore represents a major unmet medical need for which novel therapeutic approaches are urgently required (Datta A et al, Novel therapeutic approaches for pulmonary fibrosis, British Journal of ^‘Pharmacology’2011163: 141-172).

There are strong in vitro, experimental animal and IPF patient immunohistochemistry data to support a key role for the epithelial-restricted integrin, α _6ι in the activation of TGF-βΙ. Expression of this integrin is low in normal epithelial tissues and is significantly up-regulated in injured and inflamed epithelia including the activated epithelium in IPF. Targeting this integrin therefore reduces the theoretical possibility of interfering with wider TGF-β homeostatic roles. Partial inhibition of the a ₆ integrin by antibody blockade has been shown to prevent pulmonary fibrosis without exacerbating inflammation (Horan GS etal Partial inhibition of integrin a ₆ prevents pulmonary fibrosis without exacerbating inflammation. Am J Respir Crit Care Med2008177: 56-65)

The α_νβ3 integrin is expressed on a number of cell types including vascular endothelium where it has been characterised as a regulator of barrier resistance. Data in animal models of acute lung injury and sepsis have demonstrated a significant role for this integrin in vascular leak since knockout mice show markedly enhanced vessel leak leading to pulmonary oedema or death. Furthermore antibodies capable of inhibiting α_νβ3 function caused dramatic increases in monolayer permeability in human pulmonary artery and umbilical vein endothelial cells in response to multiple growth factors. These data suggest a protective role for α_νβ3 in the maintenance of vascular endothelial integrity following vessel stimulation and that inhibition of this function could drive pathogenic responses in a chronic disease setting (Su et al Absence of integrin α_νβ3 enhances vascular leak in mice by inhibiting endothelial cortical actin formation Am J Respir Crit Care Med 2012 185: 58-66). Thus, selectivity for cl over α ₃ may provide a safety advantage.

It is an object of the invention to provide α_νβ₆ antagonists.

PATENT

WO 2014154725

Scheme 1

Reagents and conditions: (a) iodine, imidazole, triphenylphosphine, DCM, 0°C; (b) 2- methyl-[l,8]-naphthyridine, LiN(TMS)₂, THF, 0°C; (c) 4M HQ in dioxane.

Scheme 2

Reagents and conditions: (a) isobutylene, cone. H₂S0₄, diethyl ether, 24 h; (b) potassium acetate, acetonitrile, 60 °C, 4 h.

Scheme 3. Reagents and Conditions: (a) LiAIH₄, THF; (b) H₂, 5% Rh/C, EtOH

Intermediate 42

iate 39

Scheme 6. Reagents and Conditions: (a) EDC, HOBT, NMM, DCM; (b) H₂, 5% Rh/C, EtOH; (c) TFA, DCM; (d) BH₃.THF; (e) UAIH4, THF, 60°C

Example 1: 3-f3-f3,5-Dimethyl-l pyrazol-l-vnphenvn-4-ff/?)-3-f2-f5,6,7,8- tetrahvdro-l,8-naphthyridin- -vnethvnpyrrolidin-l-vnbutanoic acid

A solution of te/f-butyl 3-(3-(3,5-dimethyl-l pyrazol-l-yl)phenyl)-4-((>?)-3-(2-(5,6,7,8- tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l-yl)butanoate (Intermediate 14) (100 mg, 0.184 mmol) in 2-methylTHF (0.5 mL) was treated with cone. HCI (12M, 0.077 mL, 0.92 mmol) and stirred at 40 °C for 2 h. The solvent was evaporated in vacuo and the residual oil was dissolved in ethanol (2 mL) and applied to a SCX-2 ion-exchange cartridge (5 g), eluting with ethanol (2 CV) and then 2M ammonia in MeOH (2 CV). The ammoniacal fractions were combined and evaporated in vacuo to give the title compound (79 mg, 88%) as an off-white solid: LCMS (System A) RT= 0.86 min, 100%, ES+ve /77/Z488 (M+H)⁺; H NMR δ (CDCI₃; 600 MHz): 7.42 – 7.37 (m, 1H), 7.31 (d, 7=1.5 Hz, 1H), 7.29 (d, 7=0.9 Hz, 1H), 7.23 (d, 7=7.7 Hz, 1H), 7.21 (d, 7=7.3 Hz, 1H), 6.31 (d, 7=7.3 Hz, 1H), 5.99 (s, 1H), 3.55 (br. s., 1H), 3.60 – 3.52 (m, 1H), 3.45 (t, 7=5.4 Hz, 2H), 3.27 (t, 7=10.6 Hz, 1H), 3.09 (br. S.,1H), 2.93 – 2.86 (m, 1H), 2.82 (d, 7=10.1 Hz, 1H), 2.86 – 2.75 (m, 2H), 2.72 (t, 7=6.2 Hz, 1H), 2.74 – 2.67 (m, 2H), 2.75 (d, 7=9.0 Hz, 1H), 2.61 – 2.50 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.33 – 2.26 (m, 1H), 2.24 – 2.11 (m, 1H), 1.94 – 1.86 (m, 2H), 1.94 – 1.84 (m, 1H), 1.78 – 1.66 (m, 1H), 1.65 – 1.51 (m, 1H).

Example 1 was identified by a method described hereinafter as (^-S-iS-iS^-dimethyl-l pyrazol-l-yl)phenyl)-4-((>?)-3-(2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethyl)pyrrolidin-l- yl)butanoic acid.

PAPER

Organic & Biomolecular Chemistry (2016), 14(25), 5992-6009

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c6ob00496b#!divAbstract

Synthesis and determination of absolute configuration of a non-peptidic α_vβ₆ integrin antagonist for the treatment of idiopathic pulmonary fibrosis

Abstract

A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).

3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-
naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1a) FREE FORM

off-white solid: LCMS (System A) RT= 0.86 min,100%,

ES+ve m/z 488 (M+H)+;

[]D20 = + 46 (c 1.00 in EtOH);

Analytical HPLC onChiralpak AD column (250 mm  4.6 mm) eluting with 30% EtOH-heptane (containing 0.1%
isopropylamine), flow-rate = 1 mL/min, detecting at 235 nm, RT=12.5 min, 100% (other
diastereoisomer not present RT=9.6 min);

1H NMR δ (CDCl3; 600 MHz) 7.42 – 7.37 (m,1H), 7.31 (d, J=1.5 Hz, 1H), 7.29 (d, J=0.9 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 7.21 (d, J=7.3Hz, 1H), 6.31 (d, J=7.3 Hz, 1H), 5.99 (s, 1H), 3.55 (br. s., 1H), 3.60 – 3.52 (m, 1H), 3.45 (t,
J=5.4 Hz, 2H), 3.27 (t, J=10.6 Hz, 1H), 3.09 (br. s.,1H), 2.93 – 2.86 (m, 1H), 2.82 (d, J=10.1Hz, 1H), 2.86 – 2.75 (m, 2H), 2.72 (t, J=6.2 Hz, 1H), 2.74 – 2.67 (m, 2H), 2.75 (d, J=9.0 Hz,1H), 2.61 – 2.50 (m, 1H), 2.31 (s, 3H), 2.29 (s, 3H), 2.33 – 2.26 (m, 1H), 2.24 – 2.11 (m, 1H),1.94 – 1.86 (m, 2H), 1.94 – 1.84 (m, 1H), 1.78 – 1.66 (m, 1H), 1.65 – 1.51 (m, 1H);

13CNMR δ (CDCl3, 151 MHz) 177.7, 153.6, 150.6, 149.0, 144.4, 140.3, 139.6, 139.3, 129.4,
126.2, 123.7, 123.2, 117.4, 109.7, 107.0, 63.3, 56.7 , 54.5, 44.1, 40.9, 40.0, 36.9, 35.5, 32.8,
30.3, 25.8, 19.9, 13.5, 12.5;

νmax (neat) 3380, 1670, 1588, 1384, 797, 704 cm–1;

HRMS (ESI)calcd for C29H38N5O2 (M+H)+ 488.3020, found 488.3030.

REFERENCES

///////////////GSK 3008348, phase 1, idiopathic pulmonary fibrosis, GSK, Niall Andrew ANDERSON, Brendan John FALLON, John Martin Pritchard, Integrin alphaV antagonists

Next talk in #MEDI 1st time disclosures is Simon MacDonald of @GSK on a treatment for idiopathic pulmonary fibrosis

PF 2562

CAS 1609258-91-4

MF C₁₉ H₁₇ N₅ O

Jennifer Elizabeth Davoren

Principal Scientist at Pfizer

SYNTHESIS

• Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors which are expressed in many regions of the brain. D1 mRNA has been found, for example, in the striatum and nucleus accumbens. See e.g., Missale C, Nash S R, Robinson S W, Jaber M, Caron M G “Dopamine receptors: from structure to function”, Physiological Reviews 78:189-225 (1998). Pharmacological studies have reported that D1 and D5 receptors (D1/D5), namely D1-like receptors, are linked to stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors, namely D2-like receptors, are linked to inhibition of cAMP production.
• Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. For example, D1 receptors are involved in different types of memory function and synaptic plasticity. See e.g., Goldman-Rakic P S et al., “Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction”, Psychopharmacology 174(1):3-16 (2004). Moreover, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer’s dementia, Parkinson’s disease (PD), Huntington’s chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, Tourette’s syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g., Goulet M, Madras B K “D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys”, Journal of Pharmacology and Experimental Therapy 292(2):714-24 (2000); Surmeier D J et al., “The role of dopamine in modulating the structure and function of striatal circuits”, Prog. Brain Res. 183:149-67 (2010).
  New or improved agents that modulate (such as agonize or partially agonize) D1 are needed for developing new and more effective pharmaceuticals to treat diseases or conditions associated with dysregulated activation of D1, such as those described herein.

PATENT

US 20140128374

Example 6

4-[4-(4,6-Dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine (6)

Step 1. Synthesis of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (C31)

Cesium carbonate (1.03 g, 3.16 mmol) and palladium(II) acetate (24 mg, 0.11 mmol) were added to a solution of C28 (225 mg, 1.05 mmol) and P3 (250 mg, 1.05 mmol) in 1,4-dioxane (10 mL) in a sealable reaction vessel, and the solution was purged with nitrogen for 10 minutes. Di-tert-butyl[3,4,5,6-tetramethyl-2′,4′,6-tri(propan-2-yl)biphenyl-2-yl]phosphane (97%, 104 mg, 0.210 mmol) was added, and the reaction mixture was briefly purged with nitrogen. The vessel was sealed and the reaction mixture was stirred at 100° C. for 3 hours. After cooling to room temperature, the mixture was filtered through Celite and the filter pad was washed with ethyl acetate; the combined filtrates were concentrated in vacuo and purified via silica gel chromatography (Eluents: 20%, then 50%, then 100% ethyl acetate in heptane). The product was obtained as an off-white solid. Yield: 272 mg, 0.655 mmol, 62%. LCMS m/z 416.5 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.99 (s, 1H), 8.11 (d, J=0.6 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.25-7.27 (m, 2H, assumed; partially obscured by solvent peak), 7.20-7.24 (m, 1H), 7.10 (d, J=8.4 Hz, 1H), 5.73 (dd, J=9.4, 2.5 Hz, 1H), 4.04-4.10 (m, 1H), 3.74-3.82 (m, 1H), 2.49-2.59 (m, 1H), 2.28 (s, 6H), 2.08-2.21 (m, 2H), 2.04 (s, 3H), 1.66-1.84 (s, 3H).

Step 2. Synthesis of 4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-1H-pyrazolo[4,3-c]pyridine (6)

C31 (172 mg, 0.414 mmol) was dissolved in 1,4-dioxane (5 mL) and dichloromethane (5 mL), and cooled to 0° C. A solution of hydrogen chloride in 1,4-dioxane (4 M, 1.04 mL, 4.16 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 45 hours. After removal of solvent in vacuo, the residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The aqueous layer was extracted twice with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, affording the product as an off-white solid. Yield: 130 mg, 0.392 mmol, 95%. LCMS m/z 332.3 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 8.20 (br s, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.28-7.30 (m, 1H), 7.23-7.27 (m, 1H), 7.16 (dd, J=6.0, 1.0 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 2.28 (s, 6H), 2.05 (s, 3H).

Preparation P8

6-(4-Hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (P8)

Step 1. Synthesis of 1-(4-methoxy-2-methylphenyl)propan-2-one (C8)

Four batches of this experiment were carried out (4×250 g substrate). Tributyl(methoxy)stannane (400 g, 1.24 mol), 1-bromo-4-methoxy-2-methylbenzene (250 g, 1.24 mol), prop-1-en-2-yl acetate (187 g, 1.87 mol), palladium(II) acetate (7.5 g, 33 mmol) and tris(2-methylphenyl)phosphane (10 g, 33 mmol) were stirred together in toluene (2 L) at 100° C. for 18 hours. After cooling to room temperature, the reaction mixture was treated with aqueous potassium fluoride solution (4 M, 400 mL) and stirred for 2 hours at 40° C. The resulting mixture was diluted with toluene (500 mL) and filtered through Celite; the filter pad was thoroughly washed with ethyl acetate (2×1.5 L). The organic phase from the combined filtrates was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 5% ethyl acetate in petroleum ether) provided the product as a yellow oil. Combined yield: 602 g, 3.38 mol, 68%. LCMS m/z 179.0 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.05 (d, J=8.3 Hz, 1H), 6.70-6.77 (m, 2H), 3.79 (s, 3H), 3.65 (s, 2H), 2.22 (s, 3H), 2.14 (s, 3H).

Step 2. Synthesis of 1-(4-methoxy-2-methylphenyl)propane-1,2-dione (C9)

C8 (6.00 g, 33.7 mmol) and selenium dioxide (7.47 g, 67.3 mmol) were suspended in 1,4-dioxane (50 mL) and heated at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through Celite; the filtrate was concentrated in vacuo. Silica gel chromatography (Eluent: 10% ethyl acetate in heptane) afforded the product as a bright yellow oil. Yield: 2.55 g, 13.3 mmol, 39%. LCMS m/z 193.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.6 Hz, 1H), 6.81 (br d, half of AB quartet, J=2.5 Hz, 1H), 6.78 (br dd, half of ABX pattern, J=8.7, 2.6 Hz, 1H), 3.87 (s, 3H), 2.60 (br s, 3H), 2.51 (s, 3H).

Step 3. Synthesis of 6-(4-methoxy-2-methylphenyl)-5-methylpyrazin-2(1H)-one (C10)

C9 (4.0 g, 21 mmol) and glycinamide acetate (2.79 g, 20.8 mmol) were dissolved in methanol (40 mL) and cooled to −10° C. Aqueous sodium hydroxide solution (12 N, 3.5 mL, 42 mmol) was added, and the resulting mixture was slowly warmed to room temperature. After stirring for 3 days, the reaction mixture was concentrated in vacuo. The residue was diluted with water, and 1 N aqueous hydrochloric acid was added until the pH was approximately 7. The aqueous phase was extracted with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was slurried with 3:1 ethyl acetate/heptane, stirred for 5 minutes, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: ethyl acetate) provided the product as a tan solid that contained 15% of an undesired regioisomer; this material was used without further purification. Yield: 2.0 g. LCMS m/z 231.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.14 (d, J=8.2 Hz, 1H), 6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H).

Step 4. Synthesis of 6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (C11)

C10 (from the previous step, 1.9 g) was dissolved in N,N-dimethylformamide (40 mL). Lithium bromide (0.86 g, 9.9 mmol) and sodium bis(trimethylsilyl)amide (95%, 1.91 g, 9.89 mmol) were added, and the resulting solution was stirred for 30 minutes. Methyl iodide (0.635 mL, 10.2 mmol) was added and stirring was continued at room temperature for 18 hours. The reaction mixture was then diluted with water and brought to a pH of approximately 7 by slow portion-wise addition of 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed several times with water, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Gradient: 75% to 100% ethyl acetate in heptane) afforded the product as a viscous orange oil. Yield: 1.67 g, 6.84 mmol, 33% over two steps. LCMS m/z 245.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.03 (br d, J=8 Hz, 1H), 6.85-6.90 (m, 2H), 3.86 (s, 3H), 3.18 (s, 3H), 2.08 (br s, 3H), 2.00 (s, 3H).

Step 5. Synthesis of P8

To a −78° C. solution of C11 (1.8 g, 7.37 mmol) in dichloromethane (40 mL) was added a solution of boron tribromide in dichloromethane (1 M, 22 mL, 22 mmol). The cooling bath was removed after 30 minutes, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was cooled to −78° C., and methanol (10 mL) was slowly added; the resulting mixture was slowly warmed to room temperature. The reaction mixture was concentrated in vacuo, methanol (20 mL) was added, and the mixture was again concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL) and water (200 mL) and the aqueous layer was brought to pH 7 via portion-wise addition of saturated aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water and with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a light tan solid. Yield: 1.4 g, 6.0 mmol, 81%. LCMS m/z 231.1 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.87-6.89 (m, 1H), 6.85 (br dd, J=8.2, 2.5 Hz, 1H), 3.22 (s, 3H), 2.06 (br s, 3H), 2.03 (s, 3H).

Step 1. Synthesis of 5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine (C27)

1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (5 g, 6 mmol) was added to a degassed mixture of 2-(4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (30 g, 120 mmol), 5-bromo-4,6-dimethylpyrimidine (22.5 g, 120 mmol), and potassium phosphate (76.3 g, 359 mmol) in 1,4-dioxane (300 mL) and water (150 mL). The reaction mixture was heated at reflux for 4 hours, whereupon it was filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: ethyl acetate in petroleum ether) provided the product as a brown solid. Yield: 25 g, 110 mmol, 92%. LCMS m/z 229.3 [M+H⁺]. ¹H NMR (300 MHz, CDCl₃) δ 8.95 (s, 1H), 6.94 (d, J=8.2 Hz, 1H), 6.87-6.89 (m, 1H), 6.84 (dd, J=8.3, 2.5 Hz, 1H), 3.86 (s, 3H), 2.21 (s, 6H), 1.99 (s, 3H).

Step 2. Synthesis of 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol (C28)

Boron tribromide (3.8 mL, 40 mmol) was added drop-wise to a solution of C27 (3.0 g, 13 mmol) in dichloromethane (150 mL) at −70° C. The reaction mixture was stirred at room temperature for 16 hours, then adjusted to pH 8 with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 60% to 90% ethyl acetate in petroleum ether) afforded the product as a yellow solid. Yield: 1.2 g, 5.6 mmol, 43%. LCMS m/z 215.0 [M+H⁺]. ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.80 (dd, J=8.3, 2.5 Hz, 1H), 2.24 (s, 6H), 1.96 (s, 3H).

//////////////PF 2562, non-catechol dopamine 1 receptor agonist, PFIZER, Jennifer Elizabeth Davoren, Amy Beth Dounay, Ivan Viktorovich Efremov, David Lawrence Firman Gray, Scot Richard Mente, Steven Victor O’Neil, Bruce Nelsen Rogers, Chakrapani Subramanyam, Lei Zhang, 1609258-91-4

Now at #MEDI 1st time disclosures David Gray of @pfizer on a non-catechol dopamine 1 receptor agonist #ACSSanFran

Cc1ncnc(C)c1c2ccc(cc2C)Oc4nccc3nncc34

Tamibarotene

тамибаротен , تاميباروتان , 他米巴罗汀 ,

94497-51-5  CAS

• Molecular FormulaC₂₂H₂₅NO₃
• Average mass351.439 Da

4-(((5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)amino)carbonyl)benzoic Acid, Tamibarotene

Tamibarotene , a small molecule retinoic acid receptor alpha (RARα) agonists developed by Nippon Shinyaku, was approved in Japan for the treatment of acute promyelocytic leukemia (APL) in 2005. Recently, the drug was in clinical development for the treatment of acute myeloid leukemia (AML), myelodysplasia, pediatric solid tumor, and steroid-refractory

Tamibarotene (brand name: Amnolake), also called retinobenzoic acid, is orally active, synthetic retinoid, developed to overcome all-trans retinoic acid (ATRA) resistance, with potential antineoplastic activity against acute promyelocytic leukaemia (APL) .^[1] It is currently marketed only in Japan and early trials have demonstrated that it tends to be better tolerated than ATRA.^[2] It has also been investigated as a possible treatment for Alzheimer’s disease, multiple myeloma and Crohn’s disease.^[2][3]

Synthesis

The tetralin-based compound tamibarotene (7) has been tested as an agent for treating leukaemias.

Reaction of the diol (1) with hydrogen chloride affords the corresponding dichloro derivative (2). Aluminum chloride mediated Friedel–Crafts alkylation of acetanilide with the dichloride affords the tetralin (3). Basic hydrolysis leads to the primary amine (4). Acylation of the primary amino group with the half acid chloride half ester from terephthalic acid (5) leads to the amide (6). Basic hydrolysis of the ester grouping then affords (7).^[4]

PAPER

Synthesis of Tamibarotene via Ullmann-Type Coupling

Xuefei Bao, Xuejun Qiao, Changshun Bao, Yuting Liu, Xuan Zhao, Yi Lu, and Guoliang Chen^*

Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00089

An effective process was developed for the preparation of tamibarotene via an Ullmann-type coupling in a nonpressurized l-proline/DMSO system. Notable features were the telescoping of reactions, avoiding environmentally hazardous materials, and an acceptable overall yield. The safe scalable process was validated on a 1 kg scale.

Mp 223–225 °C (lit.   SEE BELOW  mp 231–232 °C); ¹H NMR (400 MHz, chloroform-d) δ 8.22 (d, J = 7.7 Hz, 2H), 7.97 (d, J = 7.7 Hz, 2H), 7.80 (s, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 1.70 (s, 4H), 1.31 (s, 6H), 1.29 (s, 6H); MS (ESI) m/z: 350.0 [M – H]⁻

…Journal of Medicinal Chemistry (1988), 31 (11), 2182-92

PAPER

Journal of Medicinal Chemistry (1988), 31 (11), 2182-92

PAPER

Chem. Pharm. Bull. 61(8) 846–852 (2013)

https://www.jstage.jst.go.jp/article/cpb/61/8/61_c13-00356/_pdf

References

Tamibarotene

Names
IUPAC name 4-[(1,1,4,4-tetramethyltetralin-6-yl)carbamoyl]benzoic acid
Identifiers
CAS Number	94497-51-5
3D model (Jmol)	Interactive image
Beilstein Reference	3564473
ChEBI	CHEBI:32181
ChemSpider	97231
DrugBank	DB04942
IUPHAR/BPS	2648
PubChem CID	108143
UNII	08V52GZ3H9
InChI[show]
SMILES[show]
Properties
Chemical formula	C22H25NO3
Molar mass	351.45 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////Tamibarotene, тамибаротен , تاميباروتان , 他米巴罗汀 , 

CC1(C)CCC(C)(C)C2=C1C=CC(NC(=O)C1=CC=C(C=C1)C(O)=O)=C2

BLU-285

CAS 1703793-34-3

• Molecular FormulaC₂₆H₂₇FN₁₀
• Average mass498.558 Da

• Originator Blueprint Medicines
• Class Antineoplastics; Skin disorder therapies; Small molecules
• Mechanism of Action Platelet-derived growth factor alpha receptor modulators; Proto oncogene protein c-kit inhibitors

• Orphan Drug Status Yes – Systemic mastocytosis; Gastrointestinal stromal tumours
• Phase I Gastrointestinal stromal tumours; Solid tumours; Systemic mastocytosis
• 04 Dec 2016 Proof-of-concept data from phase I trial in Systemic mastocytosis presented at the 58^thAnnual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)
• 03 Dec 2016 Pharmacodynamics data from preclinical studies in Systemic mastocytosis presented at the 58^th Annual Meeting and Exposition of the American Society of Hematology (ASH-Hem-2016)
• 03 Dec 2016 Preliminary pharmacokinetic data from a phase I trial in Systemic mastocytosis presented at the 58th Annual Meeting and Exposition of the American Society of Hematology (ASH Hem-2016)

BLU 285

(S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 44) WO2015057873

Yulian Zhang,

ΚΓΓ and PDGFR.

The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization and activation of downstream signaling pathways. KIT mutations generally occur in the DNA encoding the juxtumembrane domain (exon 11). They also occur, with less frequency, in exons 7, 8, 9, 13, 14, 17, and 18. Mutations make KIT function independent of activation by SCF, leading to a high cell division rate and possibly genomic instability. Mutant KIT has been implicated in the pathogenesis of several disorders and conditions including systemic mastocytosis, GIST (gastrointestinal stromal tumors), AML (acute myeloid leukemia), melanoma, and seminoma. As such, there is a need for therapeutic agents that inhibit ΚΓΓ, and especially agents that inhibit mutant ΚΓΓ.Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. A PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance. As such, there is a need for agents that target this mutation.

CONTD………..

PATENT

WO 2015057873

Example 7: Synthesis of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, 1 -f\ [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine and (S)- 1 – (4- fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (Compounds 43 and 44)

Step 1 : Synthesis of (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f] [ 1 ,2,4] triazin-4-yl)piperazin- 1 -yl)pyrimidin-5-yl)methanone:

4-Chloro-6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/] [l,2,4]triazine (180 mg, 0.770 mmol), (4-fluorophenyl)(2-(piperazin-l-yl)pyrimidin-5-yl)methanone, HC1 (265 mg, 0.821 mmol) and DIPEA (0.40 mL, 2.290 mmol) were stirred in 1,4-dioxane (4 mL) at room temperature for 18 hours. Saturated ammonium chloride was added and the products extracted into DCM (x2). The combined organic extracts were dried over Na₂S0₄, filtered through Celite eluting with DCM, and the filtrate concentrated in vacuo. Purification of the residue by MPLC (25- 100% EtOAc-DCM) gave (4-fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (160 mg, 0.331 mmol, 43 % yield) as an off-white solid. MS (ES+) C₂5H₂₂FN₉0 requires: 483, found: 484 [M + H]⁺.

Step 2: Synthesis of (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-p razol-4-yl)p rrolo[2, l- ] [l,2,4]triazin-4- l)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide:

(S)-2-Methylpropane-2-sulfinamide (110 mg, 0.908 mmol), (4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methanone (158 mg, 0.327 mmol) and ethyl orthotitanate (0.15 mL, 0.715 mmol) were stirred in THF (3.2 mL) at 70 °C for 18 hours. Room temperature was attained, water was added, and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0- 10% MeOH-EtOAc) gave (5,Z)-N-((4-fluorophenyl)(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)methylene)-2- methylpropane-2-sulfinamide (192 mg, 0.327 mmol, 100 % yield) as an orange solid. MS (ES+) C2₉H₃iFN₁₀OS requires: 586, found: 587 [M + H]⁺.

Step 3: Synthesis of (_lS’)-N-(l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4- l)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-

(_lS’,Z)-N-((4-Fluorophenyl)(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2,l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0 °C for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0 °C continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (x2). The combined organic extracts were washed with brine, dried over Na₂S0₄, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (_lS’)-N-(l-(4-fluorophenyl)-l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l- ] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5 % yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C₃oH₃₅FN₁₀OS requires: 602, found: 603 [M + H]⁺.

Step 4: Synthesis of l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2,l-f\ [ 1 ,2,4] triazin-4- l)piperazin- 1 -yl)pyrimidin-5-yl)ethanamine:

(S)-N- ( 1 – (4-Fluorophenyl)- 1 -(2- (4- (6-( 1 -methyl- 1 H-pyrazol-4-yl)pyrrolo [2,1-/] [l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol) was stirred in 4 M HCl in 1,4-dioxane (1.5 mL)/MeOH (1.5 mL) at room temperature for 1 hour. The solvent was removed in vacuo and the residue triturated in EtOAc to give l-(4-fluorophenyl)- l-(2-(4-(6-(l -methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine, HCl (110 mg, 0.206 mmol, 103 % yield) as a pale yellow solid. MS (ES+) C₂₆H₂₇FN₁₀ requires: 498, found: 482 [M- 17 + H]+, 499 [M + H]⁺.

Step 5: Chiral separation of (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine and (5)-1-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-1 -yl)pyrimidin- -yl)ethanamine:

The enantiomers of racemic l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl- lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (94 mg, 0.189 mmol) were separated by chiral SFC to give (R)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-

pyrazol-4-yl)pyrrolo[2, l-/][l,2,4]triazin-4-yl)piperazin- l-yl)pyrimidin-5-yl)ethanamine (34.4 mg, 0.069 mmol, 73.2 % yield) and (_lS^,)-l-(4-fluorophenyl)- l-(2-(4-(6-(l-methyl-lH-pyrazol-4-yl)pyrrolo[2, l-/] [l,2,4]triazin-4-yl)piperazin-l-yl)pyrimidin-5-yl)ethanamine (32.1 mg, 0.064 mmol, 68.3 % yield). The absolute stereochemistry was assigned randomly. MS (ES+)

C₂₆H₂₇FN₁₀ requires: 498, found: 499 [M + H]⁺.

/////////BLU-285,  1703793-34-3, PHASE 1,  Brian Hodous, BlueprintMeds,  KIT & PDGFRalpha inhibitors, Orphan Drug Status

Fc1ccc(cc1)[C@](C)(N)c2cnc(nc2)N3CCN(CC3)c4ncnn5cc(cc45)c6cn(C)nc6

Next in 1st time disclosures Brian Hodous of @BlueprintMeds will talk about KIT & PDGFRalpha inhibitors #ACSSanFran

The Food and Drug Administration (FDA) has approved several quinazoline derivatives for clinical use as anticancer drugs. These include gefitinib, erlotinib, lapatinib, afatinib, and vandetanib (Fig.1) [43]. Gefitinib (Iressa®) was approved by the FDA in 2003 for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in patients after failure of both platinum-based and/or docetaxel chemotherapies. In 2004, erlotinib (Tarceva®) was approved by the FDA for treating NSCLC. Furthermore, in 2005, the FDA approved erlotinib in combination with gemcitabine for treatment of locally advanced, unrespectable, or metastatic pancreatic cancer. Erlotinib acts as a reversible tyrosine kinase inhibitor. Lapatinib (Tykreb®) was approved by the FDA in 2012 for breast cancer treatment. It inhibits the activity of both human epidermal growth factor receptor-2 (HER2/neu) and epidermal growth factor receptor (EGFR) pathways. Vandetanib (Caprelsa®) was approved by the FDA in 2011 for the treatment of metastatic medullary thyroid cancer. It acts as a kinase inhibitor of a number of cell receptors, mainly the vascular endothelial growth factor receptor (VEGFR), EGFR, and rearranged during transfection (RET)-tyrosine kinase (TK). Afatinib (Gilotrif®) was approved by the FDA in 2013 for NSCLC treatment. It acts as an irreversible covalent inhibitor of the receptor tyrosine kinases (RTK) for EGFR and erbB-2 (HER2).

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

Abstract

An insight into the therapeutic potential of quinazoline derivatives as anticancer agents

Dr. Shagufta Waseem

ASSISTANT PROFESSOR – CHEMISTRY

Biography

Office No.: C42

Phone: Tel. Ext. 1331

Email: shagufta.waseem@aurak.ac.ae

Biography

Dr. Shagufta joined the American University of Ras Al Khaimah as an Assistant Professor of Chemistry in the School of Arts and Sciences in August 2014. Prior to joining AURAK, Dr. Shagufta worked as an Adjunct Assistant Professor of Chemistry at the University of Modern Sciences, Dubai and American University of Ras Al Khaimah, UAE.

Dr. Shagufta also worked as a Postdoctoral Researcher Associate at the Department of Chemistry and Biochemistry, Oklahoma University, USA. She developed the noble drug delivery system for breast cancer drugs using carbon nanotubes and acquired the significant experience in nanotechnology and synthetic organic chemistry. She was appointed as a Postdoctoral Research Fellow and Visiting Scientist at Leiden/Amsterdam Centre for Drug Research (LACDR), Leiden, The Netherlands. Her research interest was In silico prediction and clinical evaluation of the cardiotoxicity of drug candidates. She was focused to identify chemical substructures as ‘chemical alerts’ that interact with this hERG channel.  Dr. Shagufta received a Ph.D. under the prestigious CSIR-JRF and SRF research fellowship in Chemistry from Central Drug Research Institute (CDRI)/Lucknow University, India in 2008, her PhD research work was in the field of estrogens and antiestrogens, design and synthesis of steroidal and non-steroidal tissue selective estrogen receptor modulators (SERMs) for breast cancer, 3D-QSAR CoMFA and CoMSIA studies and analysis of pharmaceutical important molecules.

Dr. Shagufta has published 20 articles in peer-reviewed International journals of Royal Society of Chemistry, Elsevier, Wiley and Springer. Dr. Shagufta teaches courses such as General chemistry, Organic Chemistry, Chemistry in Everyday Life, and Spectroscopy along with laboratory courses.

Research and Publication

Research Interest-Dr. Shagufta 

Organic Chemistry, Medicinal Chemistry focused on Breast Cancer and Osteoporosis, Heterogeneous catalysis and Nanotechnology.

Publications- Dr. Shagufta 

1. Irshad Ahmad and Shagufta. 2015. Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer. European Journal of Medicinal Chemistry, 102, 375-386.

2. Irshad Ahmad and Shagufta. 2015. Sulfones: An important class of organic compounds with diverse biological activities. International Journal of Pharmacy and Pharmaceutical Sciences, 7 (3), 19-27.

3. Priyanka Singh, Subal Kumar Dinda, Shagufta, Gautam Panda. 2013. Synthetic approach towards trisubstituted methanes and a chiral tertiary α-hydroxyaldehyde, possible intermediate for tetrasubstituted methanes. RSC Adv.(Royal Society of Chemistry) 3, 12100-12103. [ISSN: 2046-2069] 

4. Donna J. Nelson, Shagufta, Ravi Kumar. 2012. Characterization of a tamoxifen-tethered single-walled carbon nanotube conjugate by using NMR spectroscopy. Anal. Bioanal. Chem.[Springer] 404:771–776. [ISSN: 1618-2642]

5. Donna J. Nelson, Ravi Kumar, Shagufta. 2012. Regiochemical reversals in nitrosobenzene reactions with carbonyl compounds – α-aminooxy ketone versus α-hydroxyamino ketone products. Eur. J. Org. Chem.(Wiley-VCH) 6013-6020. [ISSN: 1099-0690]

6. Munikumar R. Reddy, Elisabeth Klaasse, Shagufta, Adriaan P. IJzerman, Andreas Bender. 2010. Validation of an in silico hERG model and its applications to the virtual screening of commercial compound databases. Chem. Med. Chem. (Wiley-VCH)5: 716-729. [ISSN: 1860-7187] 

7. Shagufta, Dong Guo, Elisabeth Klaasse, Henk de Vries, Johannes Brussee, Lukas Nalos, Martin B Rook, Marc A Vos, Marcel AG van der Heyden and Adriaan P. IJzerman. 2009. Exploring the chemical substructures essential for hERG K+ channel blockade by synthesis and biological evaluation of dofetilide analogues. Chem. Med. Chem.(Wiley-VCH) 4:1722-1732. [ISSN: 1860-7187]

8. Shagufta, Ritesh Singh and Gautam Panda. 2009, Synthetic studies towards steroid-amino acid hybrids. Indian Journal of Chemistry.(Indian Science) 48B: 989-995. [ISSN: 0975-0983]

9. Maloy K. Parai, Shagufta, Ajay K. Srivastava, Matthias Kassack, Gautam Panda. 2008. An unexpected reaction of phosphorous tribromide on chromanone, thiochromanone, 3,4-dihydro-2H-benzo[b]thiepin-5-one, 3,4-dihydro-2H-benzo[b]oxepin-5-one and tetralone derived allylic alcohols: a case study. Tetrahedron (Elsevier)64: 9962-9976. [ISSN: 0040-4020]

10. Gautam Panda, Maloy Kumar Parai, Sajal Kumar Das, Shagufta, Manish Sinha, Vinita Chaturvedi, Anil K. Srivastava, Anil N. Gaikwad, Sudhir Sinha. 2007. Effect of substituents on diarymethanes for antitubercular activity. European Journal of Medicinal Chemistry (Elsevier) 42: 410-419. [ISSN: 0223-5234]

11. Shagufta and Gautam Panda. 2007. A new example of a steroid-amino acid hybrid: Construction of constrained nine membered D-ring steroids. Organic and Biomolecular Chemistry (Royal Society of Chemistry) 5 : 360- 366. [ISSN 1477-0539]

12. Shagufta, Ashutosh Kumar, Gautam Panda and Mohammad Imran Siddiqi. 2007. CoMFA and CoMSIA 3D-QSAR analysis of diaryloxy methano phenanthrene derivatives as anti- tubercular agents. Journal of Molecular Modeling (Springer) 13: 99-107. [ISSN:0948-5023]

13. Shagufta, Ajay Kumar Srivastava, Ramesh Sharma, Rajeev Mishra, Anil K. Balapure, Puvvada S. R. Murthy and Gautam Panda. 2006. Substituted phenanthrenes with basic amino side chains: A new series of anti-breast cancer agents. Bioorganic and Medicinal Chemistry (Elsevier) 14: 1497-1505. [ISSN: 0968-0896]

14. Shagufta, Ajay Kumar Srivastava and Gautam Panda. 2006. Isomerization of allylic alcohols into saturated carbonyls using phosphorus tribromide. Tetrahedron Letters (Elsevier) 47: 1065-1070. [ISSN: 0040-4039]

15. Gautam Panda, Jitendra K. Mishra, Shagufta, T. C. Dinadayalane and G. Narahari Sastry & Devendra S Negi. 2006. Hard-soft acid-base (HSAB) principle and difference in d-orbital configurations of metals explain the regioselectivity of nucleophilic attack to a carbinol in Friedel-Crafts reaction catalyzed by Lewis and protonic acids. Indian Journal of Chemistry (Indian Science)45B: 276-287. [ISSN: 0975-0983]

16. Shagufta, Maloy Kumar Parai and Gautam Panda. 2005. A new strategy for the synthesis of aryl- and heteroaryl-substituted exocyclic olefins from allyl alcohols using PBr3. Terahedron Letters (Elsevier) 46: 8849-8852. [ISSN: 0040-4039]

17. Shagufta, Resmi Raghunandan, Prakash R. Maulik and Gautam Panda. 2005. Convenient phosphorus tribromide induced syntheses of substituted 1-arylmethylnaphthalenes from 1-tetralone derivatives. Tetrahedron Letters (Elsevier) 46: 5337-5341. [ISSN: 0040-4039]

18. Gautam Panda, Shagufta, Anil K. Srivastava and Sudhir Sinha. 2005. Synthesis and antitubercular activity of 2-hydroxy-aminoalkyl derivatives of diaryloxy methano phenanthrenes. Bioorganic and Medicinal Chemistry Letters (Elsevier) 15: 5222-5225. [ISSN: 0960-894X]

19. Sajal Kumar Das, Shagufta, and Gautam Panda. 2005. An easy access to unsymmetric trisubstituted methane derivatives (TRSMs). Tetrahedron Letters (Elsevier) 46: 3097-3102. [ISSN: 0040-4039]

20. Shagufta, Jitendra Kumar Mishra, Vinita Chaturvedi, Anil K. Srivastava, Ranjana Srivastava and Brahm S. Srivastava. 2004. Diaryloxy methano phenanthrenes: a new class of antituberculosis agents. Bioorganic and Medicinal Chemistry (Elsevier) 12: 5269-5276. [ISSN: 0968-0896]

Dr. Irshad Ahmad

ASSOCIATE PROFESSOR – CHEMISTRY

Biography

Office No.: C21

Phone: Tel. Ext. 1270

Email: iahmad@aurak.ac.ae

Biography

Dr. Irshad Ahmad joined the American University of Ras Al Khaimah in spring 2011 as an Assistant Professor of Chemistry. He received the master’s degree in chemistry from Jiwaji University in 1999. Subsequently acquired significant pharmaceutical industrial experience and developed cardio-selective beta-blocker drug molecule. He joined Central Salt and Marine Chemical Research Institute and Bhavnagar University under the sponsored project of DST and CSIR as a senior research fellow and received his PhD degree in chemistry in 2006. Subsequently, he accepted an invited scientist position in Korea Research Institute of Chemical Technology, South Korea and contributed his expertise in the field of Nanotechnology. Dr. Irshad is a recipient of prestigious European fellowships (NWO-Rubicon & FCT) and he joined Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, The Netherlands as a NWO Rubicon fellow (Netherlands Organization for Scientific Research, the Dutch Science Foundation), he acquired expertise in the field of supramolecular chemistry.

Afterward, he moved to the Leibniz Institute for Surface Modification, Leipzig, Germany under the Deutsche Forschungsgemeinschaft Grant. Dr. Irshad developed “Novel ultra-fast metathesis catalyst” for the production of high quality alternating copolymers. Subsequently Dr. Irshad, joined Department of Chemistry and Biochemistry, Stephenson Life Science Research Center, University of Oklahoma, USA as a postdoctoral research associate.  He developed strategies for the novel environmentally friendly reactions for the production of value added chemicals from biomass.

Dr. Irshad specialized in the area of chemistry, bridging the traditional disciplines of inorganic, organic and bio-organic chemistry. He contributed US and European patent for green and clean technology development. He has published peer-reviewed international research articles in the American Chemical Society (ACS), Royal Society of Chemistry (RSC) Cambridge, Elsevier Science, Wiley, and Springer journals. He has presented his research at several scientific conferences worldwide and received awards.

Research and Publication

Research Interest:

Asymmetric catalysis, Biotechnology, Metathesis, Material science, Nanotechnology, Pharmaceutical, Renewable energy and Supramolecular chemistry

Book:

Asymmetric Homogeneous and Heterogeneous Catalysts: An Approach to the Synthesis of Chiral Drug Intermediates by Scholars Press, Germany. 2013, ISBN: 978-3-639-51138-3

Membership:   

• American Chemical Society (ACS), USA
• The Royal Society of Chemistry, Cambridge, UK

Patents:

• United States Patent 7,235,676, H. Khan, S. H. R. Abdi, R. I. Kureshy, S. Singh, I. Ahmad, R. V. Jasra, P. K. Ghosh, ‘Catalytic process for the preparation of epoxides from alkenes.

• Patent Cooperation Treaty (PCT) WO/2005/095370, N. H. Khan, S. H. R. Abdi, R. I. Kureshy, S. Singh, I. Ahmad, R. V. Jasra, P. K. Ghosh. An improved catalytic process for the preparation of epoxides from alkenes.

• European Patent EP 1732910 A1, N. H. Khan, S. H. R. Abdi, R. I. Kureshy, S. SinghA, I. Ahmad, R. V. Jasra, P. K. Ghosh, An improved catalytic process for the preparation of epoxides from alkenes. 

Publications:

• Pramoda, U. Gupta, I. Ahmad, R. Kumar, C.N.R. Rao, Assemblies of Covalently Cross-linked Nanosheets of MoS₂ and of MoS₂-RGO: Synthesis and Novel Properties, Journal of Materials Chemistry A, 4, 2016, 8989.

• Shagufta, I. Ahmad, Recent insight into the biological activities of synthetic xanthone derivatives, European Journal of Medicinal Chemistry, 116, 2016, 267.

• Ahmad, Shagufta, Recent Development in Steroidal and Non-steroidal Aromatase Inhibitors for the Chemoprevention of Estrogen dependent Breast Cancer, European Journal of Medicinal Chemistry, 102, 2015, 375.

• Ahmad, Shagufta, Sulfones: An important class of organic compounds with diverse biological activities, International Journal of Pharmacy and Pharmaceutical Sciences, 7, 3, 2015, 19.

• Kumar, K. Gopalakrishnan, I. Ahmad, and C. N. R. Rao, BN-Graphene Composites Generated by Covalent Cross-Linking with Organic Linkers, Advanced Functional Materials, 25, 37, 2015, 5910.

• Kumar, D. Raut, I. Ahmad,   U. Ramamurty,   T. K. Maji and   C. N. R. Rao. Functionality preservation with enhanced mechanical integrity in the nanocomposites of the metal–organic framework, ZIF-8, with BN nanosheets, Materials Horizons, 1, 2014, 513.

• R. Buchmeiser, I. Ahmad, V. Gurram and P. S. Kumar, Pseudo-Halide and Nitrate Derivatives of Grubbs and Grubbs_Hoveyda Initiators: Some Structural Features Related to the Alternating Ring-Opening Metathesis Copolymerization of Norborn-2-ene with Cyclic Olefins, Macromolecule, 44 (11), 2011, 4098.

• Ahmad, G. Chapman and K. M. Nicholas, Sulfite-Driven, Oxorhenium-Catalyzed Deoxydehydration of Glycols, Organometallics, 30 (10), 2011, 2810.

• Vkuturi, G. Chapman, I. Ahmad, K. M. Nicholas, Rhenium-Catalyzed Deoxydehydration of Glycols by Sulfite, Inorganic Chemistry, 49, 2010, 4744.

• I. Kureshy, I. Ahmad, K. Pathak, N. H. Khan, S. H. R. Abdi, H. C. Bajaj, Solvent- free microwave synthesis of aryloxypropanolamines by ring opening of aryloxy epoxides, Research Letters in Organic Chemistry, 2009, Article ID 109717, doi:10.1155/2009/109717.

• I. Kureshy, I. Ahmad, K. Pathak, N. H. Khan, S. H. R. Abdi, R. V. Jasra, Sulfonic acid functionalized mesoporous SBA-15 as an efficient and recyclable catalyst for the synthesis of chromenes from chromanols, Catalysis Communications 10, 2009, 572.

• Pathak, I. Ahmad, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, R. V. Jasra, The synthesis of silica-supported chiral BINOL: Application in Ti-catalyzed asymmetric addition of diethylzinc to aldehydes, Journal of Molecular Catalysis A-Chemical 280, 2008, 106.

• Kluwer, I. Ahmad, J. N. H. Reek, Improved synthesis of monodentate and bidentate 2- and 3-pyridylphosphines, Tetrahedron Letter 48, 2007, 2999.

• Pathak, I. Ahmad, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, R. V. Jasra, Oxidative Kinetic Resolution of racemic Secondary Alcohols catalyzed by recyclable Dimeric Mn(III) salen catalysts, Journal of Molecular Catalysis A-Chemical 274, 2007, 120.

• I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Easily Recyclable Chiral Polymeric Mn (salen) Complex for Oxidative Kinetic resolution of Racemic Secondary Alcohols, Chirality, 19, 2007, 352.

• Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra, Enantioselective phenylacetylene addition to aromatic aldehydes and ketones catalyzed by recyclable polymeric Zn(II) salen complex, Chirality, 19, 2007, 1.

• I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Chiral Mn (III) salen complexes covalently bonded on modified MCM-41 and SBA-15 as efficient catalysts for enantioselective epoxidation of non- functionalized alkenes, Journal of Catalysis A-Chemical, 238, 2006, 134.

• Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra Enantioselective addition of diethylzinc to aldehydes using immobilized chiral BINOL-Ti complex on ordered mesoporous silicas, Tetrahedron: Asymmetry,17, 2006, 1506.

• I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, K. Pathak, R. V. Jasra, Encapsulation of chiral MnIII (salen) complex in ordered mesoporous silicas: An approach Towards heterogenizing asymmetric Epoxidation catalysts for non-Functionalized alkenes, Tetrahedron: Asymmetry 16, 2005, 3562.

• I. Kureshy, I. Ahmad, N. H. Khan, S. H. R. Abdi, S. Singh, P. H. Pandia, R. V. Jasra, New immobilized chiral Mn(III) salen complexes on pyridine N-Oxide Modified MCM-41as effective catalysts for epoxidation of nonfunctionalized Alkenes, Journal of Catalysis A- Chemical 235 , 2005, 28.

• Pathak, A. P. Bhatt, S. H. R. Abdi, R. I. Kureshy, N. H. Khan, I. Ahmad, R. V. Jasra Enantioselective addition of diethylzinc to aldehydes using immobilized chiral BINOL-Ti complex on ordered mesoporous silicas, Tetrahedron: Asymmetry,17, 2006, 1506.

• I. Kureshy, S. Singh, N. H. Khan, S. H. R. Abdi, I. Ahmad, A. Bhatt, R. V. Jasra, Improved catalytic activity of homochiral dimeric cobalt salen hydrolytic kinetic resolution of terminal racemic epoxides, Chirality, 17, 2005, 1.

• I. Kureshy, S. Singh, N. H. Khan, S. H. R. Abdi , I. Ahmad, .Bhatt, R. V. Jasra, Environment friendly protocol for enantioselective epoxidation of non-functionalized Alkenes catalyzed by recyclable homochiral dimeric Mn(III)salen complexes with hydrogen peroxide and UHP adduct as Oxidants, Catalysis Letters, 107, 2005, 127.

• I. Kureshy, N. H. Khan, S. H. R. Abdi, I. Ahmad, S. Singh, and R. V. Jasra, Dicationic chiral Mn (III) Salen complex exchange in the interlayers of Montmorillonite clay: a heterogeneous enantioselective catalyst for epoxidation of non-functionalised alkenes, Journal of Catalysis, 221, 2004, 234.

• I. Kureshy, N. H. Khan, S. H. R. Abdi, S. Singh, I. Ahmad, R. V. Jasra, Catalytic asymmetric epoxidation of non-functionalised alkenes using polymeric Mn(III)Salen as catalysts and NaOCl as oxidant, Journal of Molecular Catalysis A-Chemical, 218, 2004, 141.

• I. Kureshy, N.H. Khan, S.H. R. Abdi, A. P. Vyas, I. Ahmad, S. Singh, R. V. Jasra, Enantioselective Epoxidation of Non-Functionalised Alkenes catalysed by recyclable new Homo Chiral Dimeric Mn(III) Salen complexes, Journal of Catalysis, 224, 2004, 229.

• I. Kureshy, N. H. Khan, S. H. R. Abdi, I. Ahmad, S. Singh, and R. V. Jasra, Immobilization of dicationic Mn(III) salen in the interlayers of montmorrillonite Clay for enantioselective epoxidation of non-functionalised alkenes, Catalysis Letters, 91, 2003, 207.

Selected International Events:

• Applied Nanotechnology and Nanoscience International Conference (ANNIC), November 9-11, 2016, Barcelona, SPAIN.

• 2^nd International Conference on Smart Material Research (ICSMR), September 22-24, 2016, Istanbul, TURKEY.

• Emirates Foundation’s Think Science Competition, April 17-19, 2016, World Trade Center, Dubai, UAE.

• SSL Visiting Fellow 2013-15 at the International Centre for Materials Science, JNCASR, SSL, Bangalore, INDIA.

• Global Conference on Materials Sciences (GC-MAS-2014), November 13-15, 2014, Antalya, TURKEY.

• 5^th Annual International Workshop on Advanced Material (IWAM 2013), organized by Ras Al Khaimah Center for Advance Materials (RAK CAM), Feb. 24-26, 2013 at Al Hamra Fort Hotel, Ras Al Khaimah, UAE.

• Internal Quality Assurance in Higher Education Institutions workshop organized by the Commission for Academic Accreditation (CAA)- 2nd May 2011, Alghurair University campus, Dubai, UAE.

• 45^th American Chemical Society (ACS) Midwest Regional meeting, Oct. 27-30, 2010, Wichita, Kansas, USA.

• 55^th Annual American Chemical Society (ACS) PentaSectional Meeting- Biofuel, April 10, 2010, organized by American Chemical Society (ACS), Norman, Oklahoma, USA.

• 18^th International Symposium on Olefin Metathesis and Related Chemistry (ISOM XVIII), Organized by the Leibniz-Institute for Surface modification (IOM), August 2-7, 2009, Leipzig, GERMANY.

• 16^th International Symposium on Homogeneous Catalysis (ISHC-XVI), July 6-11, 2008, Organized by the Institute of Chemistry of Organometallic Compounds (ICCOM) of the Italian Research Council (CNR) held in Florence, ITALY.

• European IDECAT Summer School on Computational Methods for Catalysis and Materials Science, 15-22 September 2007, Porquerolles, FRANCE.

• 8^th Netherland’s Catalysis and Chemistry Conference (NCCC), March 5-7, 2007, Noordwijkerhout, The NETHERLANDS.

• 7^th International Symposium on Catalysis Applied to Fine Chemicals organized by German Catalysis Society and Dechema. Oct 23-27, 2005, Bingen -Mainz, GERMANY.

• 1^st Indo- German Conference on Catalysis-A Cross Disciplinary Vision, February 6-8, 2003, Indian Institute of Chemical Technology (IICT), Hyderabad, INDIA.

see rinku.thomas@aurak.ac.ae

NVP-LXS196

CAS 1874276-76-2

3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide

• 3-Amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide

Michael Joseph Luzzio

Julien Papillon,

Michael Scott Visser

SYNTHESIS

Uveal melanoma (UM) is the most common cancer of the eye in adults (Singh AD. et al., Ophthalmology. 201 1 ; 1 18: 1881-5). Most UM patients develop metastases for which no curative treatment has been identified so far. The majority of UM tumors have mutations in the genes GNAQ (guanine nucleotide-binding protein G(q) subunit alpha) and GNA11 (guanine nucleotide-binding protein G(q) subunit 1 1 ), which encode for small GTPases (Harbour JW. Pigment Cell Melanoma Res. 2012;25: 171-81). Both of these mutations lead to activation of the protein kinase C (PKC) pathway. The up-regulation of PKC pathway has downstream effects which leads to constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway that has been implicated in causing uncontrolled cell growth in a number of proliferative diseases.

Whilst anti-proliferative effects have been observed with certain PKC pathway inhibitors, no sustained MAPK pathway inhibition has been observed. Thus far, PKC inhibitors (PKCi) have had limited efficacy as single agents in patients (Mochly-Rosen D et al., Nat Rev Drug Discov. 2012 Dec;1 1 (12):937-57). Moreover, inhibition of PKC alone was unable to trigger cell death in vitro and/or tumor regression in vivo (Chen X, et al., Oncogene. 2014;33:4724-34).

The protein p53 is a transcription factor that controls the expression of a multitude of target genes involved in DNA damage repair, apoptosis and cell cycle arrest, which are all important phenomena counteracting the malignant growth of tumors. The TP53 gene is one of the most frequently mutated genes in human cancers, with approximately half of all cancers having inactivated p53. Furthermore, in cancers with a non-mutated TP53 gene, typically the p53 is functionally inactivated at the protein level. One of the mechanisms of p53 inactivation is through its interaction with human homolog of MDM2 (Mouse double minute 2) protein. MDM2 protein functions both as an E3 ubiquitin ligase, that leads to proteasomal degradation of p53, and an inhibitor of p53 transcriptional activation. Therefore, MDM2 is an important negative regulator of the p53 tumor suppressor. MDM2 inhibitors can prevent interaction between MDM2 and p53 and thus allow the p53 protein to exert its effector functions. Whilst TP53 mutations are not common in UM, there are reports suggesting the p53 pathway is inactivated by either high expression of MDM2 protein or downregulation of the PERP protein in UM patients.

A combination of an MDM2 inhibitor (Nutlin-3) has been shown to act synergistically with reactivation of p53 and induction of tumor cell apoptosis (RITA) and Topotecan to cause growth inhibition in UM cell lines (De Lange J. et al., Oncogene. 2012;31 :1 105-16). However, Nutlin-3 and Topotecan delayed in vivo tumor growth only in a limited manner.

PATENT

WO 2017029588

PATENT

WO 2016020864

Example 9: 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)- 6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

Synthesis of tert-butyl (4-meth l-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of 3-fluoro-2-nitropyridine (11.2 g, 81 mmol) in dioxane (200 mL) was added tert-butyl (4-methylpiperidin-4-yl)carbamate (26 g, 121 mmol). Huenig’s Base (28.3 mL,

162 mmol) was added and the mixture was heated to 85 °C for 18 hrs. The reaction was cooled to RT and concentrated to give a brown solid. The solids were washed with 200 mL of 4: 1 heptane:EtOAc. Slurry was concentrated to half volume and filtered to collect (26.2 g, 78 mmol, 96%) brown solid. LC-MS (Acidic Method): ret.time= 1.46 min, M+H = 337.4

Step 2: Synthesis of tert-butyl (4-meth l-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate

To a solution of tert-butyl (4-methyl-l-(2-nitropyridin-3-yl)piperidin-4-yl)carbamate (11.6 g, 37.2 mmol) in ethyl acetate (200 mL). 10% Pd-C (3.48 g) was added and stirred under H₂ balloon pressure at RT for 4h. A small amount of MgS0₄ was added to the reaction and then the reaction mixture was filtered through a pad of cellite, then washed with ethyl acetate (100 mL) and the filtrate was concentrated to afford a brown solid (8.54 g, 27.9 mmol, 85%). LC-MS (Acidic Method): ret.time= 0.91 min, M+H = 307.4.

Step 3: Synthesis of tert-butyl (l-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-meth lpiperidin-4-yl)carbamate

To a solution of 3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxylic acid in dimethyl formamide (125 mL) was added ((lH-benzo[d][l,2,3]triazol-l- yl) oxy)

tris(dimethylamino) phosphonium hexafluorophosphate(V) (1.8g, 4.24 mmol) and 4-methylmorpholine (1 mL, 9.79 mmol). Reaction stirred at RT for 40 minutes. Tert-butyl (l-(2-aminopyridin-3-yl)-4-methylpiperidin-4-yl) carbamate in dimethylformamide (25 mL) was added and reaction stirred for 16 hrs at RT. The reaction mixture was diluted with EtOAc and was washed with NaHC03(aq) (3 x 200mL) and brine (lx 200mL). The organic phase was dried with Na₂S0₄, filtered and concentrated. The crude product was taken up in acetonitrile (30 mL) and mixture was allowed to stand at RT for a period of time. Yellow solid collected by filtration (1.39g, 74%). LC-MS (Acidic Method): ret.time= 1.13 mm, M+H = 573.3.

Step 4: Synthesis of 3-amino-N-(3-(4-amino-4-methylpiperidin-l-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide

A solution of tert-butyl (l-(2-(3-amino-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamido)pyridin-3-yl)-4-methylpiperidin-4-yl)carbamate (l -39g, 2.06 mmol) in dichloromethane (10 mL) was cooled to 0 °C. 2,2,2-trifluoroacetic acid (2.4 ml, 31 mmol) was added dropwise to the solution. The mixture was allowed to warm to 22 °C and stirred for 4 hrs. Reaction mixture was concentrated to remove DCM and excess TFA. A red oil was produced, which was taken up in 100 mL CHCI₃/IPA 3: 1 and saturated aq. NaHCC was added to neutralize the solution. The mixture was then stirred at 22°C for 16 hrs. The mixture transfered to separatory funnel and aqueous layers were washed with CHCI₃/IPA 3: 1 (3X 100 mL). Combined organic phases were dried with Na₂S0₄, filtered and concentrated to afford a yellow solid. The crude product was recrystallized from acetonitrile. A yellow solid was collected by filtration (0.82g, 83%). LC-MS (Acidic Method ): ret.time= 0.75 mm, M+H = 473.2. 1H NMR (400 MHz, Methanol-^) δ 8.92 (dd, J = 5.1, 1.4 Hz, 1H), 8.68 (s, 1H), 8.47 – 8.27 (m, 1H), 8.12 (dd, J = 4.9, 1.6 Hz, 1H), 7.83 – 7.50 (m, 2H), 7.18 (dd, J = 7.9, 4.9 Hz, 1H), 3.02 – 2.65 (m, 4H), 1.54 – 1.24 (m, 4H), 0.74 (s, 3H).

REFERENCES

Visser, M.; Papillon, J.; Fan, J.; et al.
NVP-LXS196, a novel PKC inhibitor for the treatment of uveal melanoma
253rd Am Chem Soc (ACS) Natl Meet (April 2-6, San Francisco) 2017, Abst MEDI 366

//////////////NVP-LXS196, NVP-LXS 196, 1874276-76-2, Michael Joseph Luzzio, Julien Papillon,Michael Scott Visser, NOVARTIS, PKC inhibitor,  uveal melanoma

FC(F)(F)c1cccnc1c2cnc(N)c(n2)C(=O)Nc3ncccc3N4CCC(C)(N)CC4

http://sanfrancisco2017.acs.org/i/803418-253rd-american-chemical-society-national-meeting-expo/289

Michael Visser of @Novartis talking now in 1st time disclosures about a PKC inhibitor to treat uveal melanoma #ACSSanFran

Synthesis will be updated watch this space………..

CONTD……….

contd…………….

Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

Gregory R. Ott^*†, Mangeng Cheng^†, Keith S. Learn^†, Jason Wagner^†, Diane E. Gingrich^†, Joseph G. Lisko^†, Matthew Curry^†, Eugen F. Mesaros^†, Arup K. Ghose^†, Matthew R. Quail^†, Weihua Wan^†, Lihui Lu^†, Pawel Dobrzanski^†, Mark S. Albom^†, Thelma S. Angeles^†, Kevin Wells-Knecht^†, Zeqi Huang^†, Lisa D. Aimone^†, Elizabeth Bruckheimer^‡, Nathan Anderson^‡, Jay Friedman^‡, Sandra V. Fernandez^§, Mark A. Ator^†, Bruce A. Ruggeri^†, and Bruce D. Dorsey^†

^† Teva Branded Pharmaceutical Products R&D, 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States

^‡ Champions Oncology, Inc., One University Plaza, Suite 307, Hackensack, New Jersey 07601, United States

^§ Thomas Jefferson University, 233 South 10th Street, 1002 BLSB, Philadelphia, Pennsylvania 19107, United States

J. Med. Chem., 2016, 59 (16), pp 7478–7496

DOI: 10.1021/acs.jmedchem.6b00487

*Telephone: 1-610-738-6861. E-mail: gregory.ott@tevapharm.com.

Development of a Process Route to the FAK/ALK Dual Inhibitor TEV-37440

Shawn P. Allwein^*† , Dale R. Mowrey†, Daniel E. Petrillo†, James J. Reif†, Vikram C. Purohit†, Karen L. Milkiewicz†, Roger P. Bakale†, Michael A. Christie†, Mark A. Olsen‡, Christopher J. Neville‡, and Gregory J. Gilmartin‡

^†Chemical Process Research & Development, ^‡Analytical Development, Teva Pharmaceuticals, 383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00070

*E-mail: shawn.allwein@tevapharm.com.

The development of a scalable route to TEV-37440, a dual inhibitor of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), is presented. The medicinal chemistry route used to support this target through nomination is reviewed, along with the early process chemistry route to support IND (inversigational new drug) enabling activities within CMC (Chemistry, Manufacturing, and Controls). The identification and development of an improved route that was performed in the pilot plant to supply early phase clinical supplies are discussed. Details surrounding the use of a novel ring expansion, a selective nitration through a para-blocking group strategy, a single-pot amination–hydrogenation, a diastereomeric salt resolution, a through-process step to avoid a hazardous intermediate, and a practical formation of a trihydrochloride dihydrate salt are disclosed.

///////////////////TEV-37440, TEV 37440, CEP-37440, CEP 37440

CNC(=O)c5ccccc5Nc1nc(ncc1Cl)Nc3ccc2C[C@H](CCCc2c3OC)N4CCN(CC4)CCO

Metopimazine

RP-9965, EXP-999, NG-101

l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide

• Isonipecotamide, 1-[3-[2-(methylsulfonyl)phenothiazin-10-yl]propyl]- (7CI,8CI)
• 1-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]isonipecotamide
• 2-Methylsulfonyl-10-[3-(4-carbamoylpiperidino)propyl]phenothiazine

• EXP 999
• Metopimazine
• RP 9965
• Vogalene
• metopimazine (gastroparesis), Neurogastrx

Sanofi (Originator)
Teva

Treatment of Nausea and Vomiting, APPROVED

Dopamine D3 receptor antagonist; Dopamine D2 receptor antagonist

Gastroprokinetic

Metopimazine (INN) is a phenothiazine antiemetic.

Metopimazine is an established antiemetic that has been approved and marketed for many years in Europe for the treatment of acute conditions. The compound does not cross the blood-brain-barrier, and is therefore free from central side effects, and is not associated with cardiovascular side effects

In May 2016, preclinical data were presented at the 2016 DDW in San Diego, CA. In rats, po NG-101 and domperidone did not penetrate the brain at therapeutically relevant concentrations, unlike metoclopramide. In dogs, the amplitude and frequency of antral contractions were increased by NG-101, whereas in rats, po metopimazine resulted in an increase in gastric emptying of solid foods. The blood-brain barrier was not readily crossed and there was no interaction with 5-HT3 or 5-HT4 receptors by NG-101 unlike metoclopramide and domperidone, respectively

In July 2014, preclinical data were published. Metopimazine at 1mg/kg increased gastric motility in hound dogs. In studies in rodents, metopimazine at 3 and 10 mg/kg increased gastric emptying by 18 and 40%, respectively, compared with vehicle control

There is an increasing demand for antiemetic agents because of the most troublesome adverse effects of chemotherapy-induced nausea and emesis during cancer treatment.

However, the objective of complete prevention of emesis in all patients remains elusive. Therefore, there is a great demand for both development of (i) new antiemetic agents and (ii) new manufacturing processes for existing antiemetic agents. Metopimazine is an existing dopamine D₂-receptor antagonist with potent antiemetic properties. It is chemically known as l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide , which belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs) with interesting biological and pharmacological activities.

Recently, it has been found that Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high emetogenic noncisplatin-based chemotherapy.It has been used in France for many years for the prevention and treatment of nausea and vomiting under the brand name of Vogalene

In 1959, the first synthesis and manufacture process of Metopimazine  was reported by Jacob et al.The synthesis starts from the protection of 2-(Methylsulfanyl)-10H-phenothiazine..Jacob, R. M.; Robert, J. G. German Patent No. DE1092476, 1959.

Later, in 1990, Sindelar et al. reported a modified process , which starts from synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone..Sindelar, K.; Holubek, J.; Koruna, I.; Hrubantova, M.; Protiva, M. Collect. Czech. Chem. Commun. 1990, 55, 1586– 1601, DOI: 10.1135/cccc19901586

In 2010, Satyanarayana Reddy et al. reported a modified synthetic route which starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of 2-(methylsulfanyl)-10H-phenothiazine ..Satyanarayana Reddy, M.; Eswaraiah, S.; Satyanarayana, K. Indian Patent No. 360/CHE/2010 A, Aug 19, 2011.

Synthesis of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4- carboxamide (1)-Metopimazine: Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.

1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4 Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96 (m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, – CH2-).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

MS m/z (ESI): 446.21 (M+H)+.

SYNTHESIS

PATENT

IN 201641043070

IN 2013CH05689

IN 2013CH00361

IN 2010CH00360

DE 1092476/US 3130194

PAPER

A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D₂-Receptor Antagonist

Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth, Madhusudana Rao Gajula^*, and Kumar Pramod^*

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00052

*E-mail: pramodkumar@microlabs.in. Tel: 0811 0415647, ext. 245. Mobile No.: +91 9008448247., *E-mail: gmadhusudanrao@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00052

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Synthesis of 1-(3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide (1), Metopimazine

 

Metopimazine

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	A04AD05 (WHO)
Identifiers
IUPAC name[show]
CAS Number	14008-44-7
PubChem CID	26388
ChemSpider	24584
UNII	238S75V9AV
ChEMBL	CHEMBL398615
ECHA InfoCard	100.034.367
Chemical and physical data
Formula	C22H27N3O3S2
Molar mass	445.6 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C

//////////////Metopimazine, Dopamine D₂-Receptor Antagonist, 14008-44-7, sanofi, teva, RP-9965, Nausea and Vomiting, EXP-999, NG-101, metopimazine, gastroparesis, Neurogastrx

NC(=O)C1CCN(CC1)CCCN2c4ccccc4Sc3ccc(cc23)S(C)(=O)=O

USA Viewership touched 3 lakhs on New Drug Approvals

https://newdrugapprovals.org/

Total 16.9 lakhs in 213 countries

BMS 986205

CAS: 1923833-60-6

Phase 1 cancer

BMS-986205, ONO-7701,  F- 001287

• Molecular Formula C₂₄H₂₄ClFN₂O
• Average mass 410.912 Da

• Originator Bristol-Myers Squibb
• Class Antineoplastics
• 01 Feb 2016 Phase-I/II clinical trials in Cancer (Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (PO) (NCT02658890)
• 31 Jan 2016 Preclinical trials in Cancer in USA (PO) before January 2016
• 01 Jan 2016 Bristol-Myers Squibb plans a phase I/IIa trial for Cancer (Late-stage disease, Combination therapy, Second-line therapy or greater) in USA, Australia and Canada (PO) (NCT02658890)

Hilary Beck

EX Principal Investigator, Company NameFLX Bio, Inc., 

CURRENTLY Director, Medicinal Chemistry at IDEAYA Biosciences, IDEAYA Biosciences, The University of Texas at Austin

Brian Wong

Chief Executive Officer at FLX Bio, Inc.

Bristol-Myers Squibb, following its acquisition of Flexus Biosciences, is developing BMS-986205 (previously F- 001287), the lead from an immunotherapy program of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors for the potential treatment of cancer. In February 2016, a phase I/IIa trial was initiated .

BMS-986205 (ONO-7701) is being evaluated at Bristol-Myers Squibb in phase I/II clinical trials for the oral treatment of adult patients with advanced cancers in combination with nivolumab. Early clinical development is also ongoing at Ono in Japan for the treatment of hematologic cancer and for the treatment of solid tumors.

In April 2017, data from the trial were presented at the 108th AACR Annual Meeting in Washington DC. As of February 2017, the MTD had not been reached, but BMS-986205 plus nivolumab treatment was well tolerated, with only two patients discontinuing treatment due to DLTs. The most commonly reported treatment-related adverse events (TRAEs) were decreased appetite, fatigue, nausea, diarrhea, and vomiting. Grade 3 TRAEs were reported in three patients during the combination therapy; however, no grade 3 events were reported during BMS-986205 monotherapy lead-in. No grade 4 or 5 TRAEs were reported with BMS-986205 alone or in combination with nivolumab

Indoleamine 2,3-dioxygenase (IDO; also known as IDOl) is an IFN-γ target gene that plays a role in immunomodulation. IDO is an oxidoreductase and one of two enzymes that catalyze the first and rate-limiting step in the conversion of tryptophan to N-formyl-kynurenine. It exists as a 41kD monomer that is found in several cell populations, including immune cells, endothelial cells, and fibroblasts. IDO is relatively well-conserved between species, with mouse and human sharing 63% sequence identity at the amino acid level. Data derived from its crystal structure and site-directed mutagenesis show that both substrate binding and the relationship between the substrate and iron-bound dioxygenase are necessary for activity. A homolog to IDO (ID02) has been identified that shares 44% amino acid sequence homology with IDO, but its function is largely distinct from that of IDO. (See, e.g., Serafini P, et al, Semin. Cancer Biol, 16(l):53-65 (Feb. 2006) and Ball, H.J. et al, Gene, 396(1):203-213 (Jul. 2007)).

IDO plays a major role in immune regulation, and its immunosuppressive function manifests in several manners. Importantly, IDO regulates immunity at the T cell level, and a nexus exists between IDO and cytokine production. In addition, tumors frequently manipulate immune function by upregulation of IDO. Thus, modulation of IDO can have a therapeutic impact on a number of diseases, disorders and conditions.

A pathophysiological link exists between IDO and cancer. Disruption of immune homeostasis is intimately involved with tumor growth and progression, and the production of IDO in the tumor microenvironment appears to aid in tumor growth and metastasis. Moreover, increased levels of IDO activity are associated with a variety of different tumors (Brandacher, G. et al, Clin. Cancer Res., 12(4): 1144-1151 (Feb. 15, 2006)).

Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard treatment regimens show highly variable degrees of long-term success because of the ability of tumor cells to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastasis. Recent advances in the treatment of cancer and cancer-related diseases, disorders and conditions comprise the use of combination therapy incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Under most scenarios, immunotherapy is associated with less toxicity than traditional chemotherapy because it utilizes the patient’s own immune system to identify and eliminate tumor cells.

In addition to cancer, IDO has been implicated in, among other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (e.g. , rheumatoid arthritis). Thus, suppression of tryptophan degradation by inhibition of IDO activity has tremendous therapeutic value. Moreover, inhibitors of IDO can be used to enhance T cell activation when the T cells are suppressed by pregnancy, malignancy, or a virus (e.g., HIV). Although their roles are not as well defined, IDO inhibitors may also find use in the treatment of patients with neurological or neuropsychiatric diseases or disorders (e.g., depression).

Small molecule inhibitors of IDO have been developed to treat or prevent IDO-related diseases. For example, the IDO inhibitors 1-methyl-DL-tryptophan; p-(3-benzofuranyl)-DL-alanine; p-[3-benzo(b)thienyl]-DL-alanine; and 6-nitro-L-tryptophan have been used to modulate T cell-mediated immunity by altering local extracellular concentrations of tryptophan and tryptophan metabolites (WO 99/29310). Compounds having IDO inhibitory activity are further reported in WO 2004/094409.

In view of the role played by indoleamine 2,3-dioxygenase in a diverse array of diseases, disorders and conditions, and the limitations (e.g., efficacy) of current IDO inhibitors, new IDO modulators, and compositions and methods associated therewith, are needed.

In April 2017, preclinical data were presented at the 108th AACR Annual Meeting in Washington DC. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively

In April 2017, preclinical data were presented at the 253rd ACS National Meeting and Exhibition in San Francisco, CA. BMS-986205 showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. A good pharmacokinetic profile was seen at oral and iv doses in rats, dogs and monkeys. The compound showed good oral exposure and efficacy in in vivo assays

Preclinical studies were performed to evaluate the activity of BMS-986205, a potent and selective optimized indoleamine 2, 3-dioxygenase (IDO)- 1inhibitor, for the treatment of cancer. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. BMS-986205 was also found to be potent when compared with IDO-1from other species (human < dog equivalent monkey equivalent mouse > rat). In cell-free systems, incubation of inhibitor lead to loss of heme absorbance of IDO-1 which was observed in the presence of BMS-986205 (10 microM), while did not observed with epacadostat (10 microM). The check inhibitory activity and check reversibility (24 h after compound removal) of BMS-986205 was found to be < 1 and 18% in M109 (mouse) and < 1 and 12% SKOV3 (human) cells, respectively. In human whole blood IDO-1, human DC mixed lymphocyte reaction and human T cells cocultured with SKOV3 cells- cell based assays, BMS-986205 showed potent cellular effects (inhibition of kynurenine and T-cell proliferation 3H-thymidine) with IC50 values of 2 to 42 (median 9.4 months), 1 to 7 and 15 nM, respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively. In vivo human-SKOV3 and hWB-xenografts, IC50 values of BMS-986205 were 3.4 and 9.4 NM, respectively. The ADME of BMS-986205 at parameters iv/po dose was 0.5/2, 0.5/1.5 and 0.5/1.2 mg/kg, respectively; iv/clearance was 27, 25 and 19 ml, min/kg, respectively; iv Vss was 3.8, 5.7 and 4.1 l/kg, respectively; t1/2 (iv) was 3.9, 4.7 and 6.6 h, respectively; fraction (po) was 64, 39 and 10%, respectively. At the time of presentation, BMS-986205 was being evaluated in combination with nivolumab.

The chemical structure and preclinical profile was presented for BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide), a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.

BMS-986158: a BET inhibitor for cancerAshvinikumar Gavai of Bristol Myers Squibb (BMS) gave an overview of his company’s research into Bromodomian and extra-terminal domain (BET) as oncology target for transcriptional suppression of key oncogenes, such as MYC and BCL2. BET inhibition has been defined as strong rational strategy for the treatment of hematologic malignancies and solid tumors. From crystal-structure guided SAR studies, BMS-986158, 2-{3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol, was chosen as a potent BET inhibitor, showing IC50 values for BRD2, BRD3 and BRD4 activity of 1 nM; it also inhibited Myc oncogene (IC50 = 0.5 nM) and induced chlorogenic cancer cell death. In vitro the compound also displayed significant cytotoxicity against cancer cells.  When administered at 0.25, 0.5 and 1 mg/kg po, qd to mice bearing human lung H187 SCLC cancer xenograft, BMS-986158 was robust and showed efficacy as a anticancer agent at low doses. In metabolic studies, it showed t1/2 of 36, 40 and 24 min in human, rat and mice, respectively, and it gave an efflux ratio of 3 in Caco-2 permeability assay. In phase 1/II studies, BMS-986158 was well tolerated at efficacious doses and regimens, and drug tolerable toxicity at efficacy doses and regimens. Selective Itk inhibitors for inflammatory disordersThe development of highly selective Itk inhibitors for the treatment of diseases related to T-cell function, such as inflammatory disorders, was described by Shigeyuki Takai (Ono Pharmaceutical). Inhibitory properties of a hit compound, ONO-8810443, were modified via X-ray structure and Molecular Dynamics stimulation to get ONO-212049 with significant kinase selectivity (140-fold) against Lck, a tyrosine kinase operating upstream of Itk in the TCR cascade. Further modifications identified final lead compound ONO-7790500 (N-[6-[3-amino-6-[2-(3-methoxyazetidin-1-yl)pyridin-4-yl]pyrazin-2-yl]pyridin-3-yl]-1-(3-methoxyphenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxamide), which selectively inhibited Itk (IC50 = < 0.004 microM) over Lck (IC50 = 9.1 microM; SI 2000-fold) and suppressed Jurkat T-cell proliferation (IC50 = 0.014 microM). This compound suppressed alphaCD3/CDP28 CD4+T-cell stimulation (IC50 = 0.074 microM) with selectivity over PMA/Ionomycin (IC50 = > 10 microM). ONO-7790500 also exhibited in vivo IL-2 inhibitory properties (62% inhibition at 30 mg/kg po) in mice. In pharmacokinetic studies in balb/c mice, the compound administered orally (10 mg/kg) showed a Cmax of 1420 ng/ml, AUClast of 11,700 ng*h/ml, t1/2 of 5.3 h and oral bioavailability of 68%. Administration iv at 0.3 mg/kg gave an AUC last of 610 ng*h/ml, t1/2 of 3.8 h, Vss of 1260 ml/kg and Cl of 5.1 ml/min/kg. ADMET data showed ONO-7790500 did not have relevant activity in cytochromes and hERG channels (IC50 > 10 microM) in toxicological studies, and gave a PAMPA value of 5.0 x 10(-6) cm/s. Fused imidazole and pyrazole derivatives as TGF-beta inhibitorsDual growth and differentiation factor-8 (GDF-8; also known as myostatin) and TGF-beta inhibitors were described. Both targets belong to TGF-beta superfamily consisting of a large group of structurally related cell regulatory proteins involved in fundamental biological and pathological processes, such as cell proliferation or immunomodulation. Myostatin (GDF8) is a negative regulator negative regulator of skeletal muscle growth and has also been related to bone metabolism. Investigators at Rigel Pharmaceuticals found that compounds designed to be GDF-8 inhibitors were able to inhibit TGF-beta as well, this could be an advantage for the treatment of diseases associated with muscle and adipose tissue disorders, as well as potentially immunosuppressive disorders. Jiaxin Yu from the company described  new fused imidazole derivatives, of which the best compound was 6-[2-(2,4,5-Trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]quinoxaline. This compound was very potent at TGF-beta Receptor Type-1 (ALK5) inhibition with an IC50 value of 1nM. In an in vivo mouse assay this compound showed good activity at 59.7 mg/kg, po, and good plasma exposure; inhibition of GDF-8 and TGFbeta growth factors was 90 and 81.6 %, respectively.Rigel’s Ihab Darwish described a series of fused pyrazole derivatives, with the best compound being 6-[2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridine. This compound showed an IC50 of 0.06 and 0.23 microM for GDF-8 and TGFbeta, respectively, in the pSMAD (MPC-11) signaling inhibition test. The compound had a good pharmacokinetic profile, with 40% of bioavailability in mice after a 5-mg/kg po dose. An iv dose of 1 mg/kg showed t1/2 of 0.7 h and Vss of 1.0 l/h/kgDiscovery of selective inhibitor of IDO BMS-986205 for cancerIndoleamine-2,3-dioxygenase (IDO)-1 enzyme initiates and regulates the first step of the kynurenine pathway (KP) of tryptophan metabolism, and evidence has shown that overexpression of IDO-1 in cancer tumors is a crucial mechanism facilitating tumor immune evasion and persistence. The chemical structure and preclinical profile of BMS-986205 was presented by Aaron Balog from BMS. BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide),  is a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.Three further reports have been published from this meeting .The website for this meeting can be found at https://www.acs.org/content/acs/en/meetings/spring-2017.html.

SYNTHESIS

1 Wittig  NaH

2 REDUCTION H2, Pd, AcOEt, 4 h, rt, 50 psi

3 Hydrolysis HCl, H2O, Me2CO, 2 h, reflux

4  4-Me-2,6-(t-Bu)2-Py, CH2Cl2, overnight, rt

5 SUZUKI AcOK, 72287-26-4, Dioxane, 16 h, 80°C

6  Heck Reaction,  Suzuki Coupling, Hydrogenolysis of Carboxylic Esters, Reduction of Bonds, HYDROGEN

7 Et3N, THF, rt – -78°C , Pivaloyl chloride, 15 min, -78°C; 1 h, 0°C ,THF, 0°C – -78°C, BuLi, Me(CH2)4Me, 15 min, -78°C, R:(Me3Si)2NH •Na, THF, 10 min, -50°C , HYDROLYSIS,  (PrP(=O)O)3, C5H5N, AcOEt, 5 min, rt

Patent

WO2016073770

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=289DBE79BEFC6ADC558C89E7A74B19DB.wapp2nB?docId=WO2016073770&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 19

(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

Example 19 : (i?)-N-(4-chlorophenyl)-2-(cz5-4-(6-fluoroquinolin-4- yl)cyclohexyl)propanamide

[0277] Prepared using General Procedures K, B, E, L, M, N, and O. General Procedure L employed 2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid (mixture of

diastereomers), and ( ?)-2-phenyl-oxazolidinone. General Procedure M employed the cis product and iodomethane. The auxiliary was removed following General Procedure N and the desired product formed employing General Procedure O with 4-chloroaniline.

Purified using silica gel chromatography (0% to 100% ethyl acetate in hexanes) to afford Example 19. 1H NMR of czs-isomer (400 MHz; CDC1₃): δ 9.14 (s, 1H), 8.70 (d, J= 4.6 Hz, 1H), 8.06 (dd, J= 9.2 Hz, J= 5.6 Hz, 1H), 7.58-7.64 (m, 3H), 7.45 (ddd, J= 9.3 Hz, J= 7.8 Hz, J= 2.7 Hz, 1H), 7.19-7.24 (m, 2H), 7.15 (d, J= 4.6Hz, 1H), 3.16-3.26 (m, 1H), 2.59-2.69 (m, 1H), 2.08-2.16 (m, 1H), 1.66-1.86 (m, 7H), 1.31-1.42 (m, 1H), 1.21 (d, J= 6.8Hz, 3H) ppm. m/z 411.2 (M+H)⁺.

REFERENCES

23-Feb-2015
Bristol-Myers Squibb To Expand Its Immuno-Oncology Pipeline with Agreement to Acquire Flexus Biosciences, Inc
Bristol-Myers Squibb Co; Flexus Biosciences Inc

17-Dec-2014
Flexus Biosciences, a Cancer Immunotherapy Company Focused on Agents for the Reversal of Tumor Immunosuppression (ARTIS), Announces $38M Financing
Flexus Biosciences Inc

2015106thApril 21Abs 4290
Potent and selective next generation inhibitors of indoleamine-2,3-dioxygenase (IDO1) for the treatment of cancer
American Association for Cancer Research Annual Meeting
Jay P. Powers, Matthew J. Walters, Rajkumar Noubade, Stephen W. Young, Lisa Marshall, Jan Melom, Adam Park, Nick Shah, Pia Bjork, Jordan S. Fridman, Hilary P. Beck, David Chian, Jenny V. McKinnell, Maksim Osipov, Maureen K. Reilly, Hunter P. Shunatona, James R. Walker, Mikhail Zibinsky, Juan C. Jaen

2017108thApril 04Abs 4964
Structure, in vitro biology and in vivo pharmacodynamic characterization of a novel clinical IDO1 inhibitor
American Association for Cancer Research Annual Meeting
John T Hunt, Aaron Balog, Christine Huang, Tai-An Lin, Tai-An Lin, Derrick Maley, Johnni Gullo-Brown, Jesse Swanson, Jennifer Brown

2017253rdApril 05Abs MEDI 368
Discovery of a selective inhibitor of indoleamine-2,3-dioxygenase for use in the therapy of cancer
American Chemical Society National Meeting and Exposition
Aaron Balog

April 2-62017
American Chemical Society – 253rd National Meeting and Exhibition (Part IV) – OVERNIGHT REPORT, San Francisco, CA, USA
Casellas J, Carceller V

Juan Jaen

Jordan Fridman

Chief Scientific Officer at FLX Bio, Inc.

Rekha Hemrajani

Chief Operating Officer at FLX Bio, Inc

Max Osipov

////////////////PHASE 1, BMS 986205, 1923833-60-6, BMS-986205, ONO-7701,Bristol-Myers Squibb,  Antineoplastics,  F- 001287

 C[C@H]([C@H]1CC[C@@H](C2=CC=NC3=CC=C(F)C=C23)CC1)C(NC4=CC=C(Cl)C=C4)=O

Wrapping up #MEDI‘s 1st time disclosures is Aaron Balog of @bmsnews talking about an IOD-1 inhibitor to treat cancer #ACSSanFran

The U.S. Food and Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

“Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.

Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to Kalydeco. When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated.

Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Cystic fibrosis is a rare disease that affects about 30,000 people in the United States.Kalydeco is indicated for patients aged 2 and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3 percent of the cystic fibrosis population, impacting approximately 900 patients. Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.

Common side effects of Kalydeco include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Kalydeco is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts. Co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of Kalydeco, which may diminish effectiveness, and is therefore not recommended.

Kalydeco is manufactured for Boston-based Vertex Pharmaceuticals Inc.

Tegafur

Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, 29(11), PG 3181-90

Tegafur (INN, BAN, USAN) is a chemotherapeutic prodrug of 5-flourouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU.^[1]

Medical uses

As a prodrug to 5-FU it is used in the treatment of the following cancers:^[2]

• Stomach (when combined with gimeracil and oteracil)
• Breast (with uracil)
• Gallbladder
• Lung (specifically adenocarcinoma, typically with uracil)
• Colorectal (usually when combined with gimeracil and oteracil)
• Head and neck
• Liver (with uracil)^[3]
• Pancreatic

It is often given in combination with drugs that alter its bioavailability and toxicity such as gimeracil, oteracil or uracil.^[2] These agents achieve this by inhibiting the enzyme dihydropyrimidine dehydrogenase (uracil/gimeracil) or orotate phosphoribosyltransferase (oteracil).^[2]

Adverse effects

The major side effects of tegafur are similar to fluorouracil and include myelosuppression, central neurotoxicity and gastrointestinal toxicity (especially diarrhoea).^[2] Gastrointestinal toxicity is the dose-limiting side effect of tegafur.^[2] Central neurotoxicity is more common with tegafur than with fluorouracil.^[2]

Pharmacogenetics

The dihydropyrimidine dehydrogenase (DPD) enzyme is responsible for the detoxifying metabolism of fluoropyrimidines, a class of drugs that includes 5-fluorouracil, capecitabine, and tegafur.^[4] Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency.^[4][5] Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome.^[4][5]

Mechanism of action

It is a prodrug to 5-FU, which is a thymidylate synthase inhibitor.^[2]

Pharmacokinetics

It is metabolised to 5-FU by CYP2A6.^[6][7]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.^{[§ 1]}

The interactive pathway map can be edited at WikiPathways: “FluoropyrimidineActivity_WP1601”.

MASS SPECTRUM

1H NMR

IR

13C NMR

RAMAN

Synthesis

Substances Referenced in Synthesis Path

SYN1

CN 106397416

SYN 2

Advanced Synthesis & Catalysis, 356(16), 3325-3330; 2014

PATENTS

CN 106397416

CN 104513230

CN 103159746

PATENT

CN 102285972

tegafur is a derivative of 5-fluorouracil, and in 1967, Hiller of the former Soviet Union synthesized tegafur (SA Hiller, RA Zhuk, M. Yu. Lidak, et al. Substituted Uracil [ P, British Patent, 1168391 (1969)). In 1974, it was listed in Japan. China was successfully developed by Shandong Jinan Pharmaceutical Factory in 1979. Its present origin is Shanghai and Shandong provinces and cities. The anti-cancer effect of tegafur is similar to that of 5-fluorouracil and is activated in vivo by 5-fluorouracil through liver activation. Unlike 5-fluorouracil, tegafur is fat-soluble, has good oral absorption, maintains high concentrations in the blood for a long time and easily passes through the blood-brain barrier. Clinical and animal experiments show that tegafur on gastrointestinal cancer, breast cancer is better, the role of rectal cancer than 5-fluorouracil good, less toxic than 5-fluorouracil. Teflon has a chemotherapy index of 2-fold for 5-fluorouracil and only 1 / 4-1 / 7 of toxicity. So the addition of fluoride is widely used in cancer patients with chemotherapy.

[0003] The first synthesis of tegafur is Hiller ([SA Hiller, RA Zhuk, Μ. Yu. Lidak, et al. Substituted Uracil [P], British Patent, 1168391 (1969)]. 5-fluorouracil or 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-Fu, 1) and 2-chlorotetrahydrofuran (Thf-Cl), and it is reported that this synthesis must be carried out at low temperature (- 20 to -40 ° C), because Thf-Cl is unstable, and excess Thf-Cl results in a decomposition reaction, thereby reducing the yield of Thf-Fu.

[0004] Earl and Townsend also prepared 1_ (tetrahydro-2-furyl) uracil using Thf-Cl and 2,4-bis (trimethylsilyl) uracil, and then using trifluoromethyl fluorite to product Fluorination. Mitsugi Yasurnoto reacts with the Friedel-Crafts catalyst in the presence of 2,4-bis (trimethylsilyl) -5-fluorouracil (Me3Si-U, 1) 2-acetoxytetrahydrofuran (Thf-OAc, 2) (Kazu Kigasawa et al., 2-tert-Butoxy), & lt; RTI ID = 0.0 & gt;, & lt; / RTI & gt; (K. Kigasawa, M. Hiiragi, K. ffakisaka, et al. J. Heterocyclic Chem. 1977, 14: 473-475) was reacted with 5-Fu at 155-160 ° C. Reported in the literature for the fluoride production route there are the following questions: 1, high energy consumption. In the traditional synthesis method, in order to obtain the product, the second step of the reaction needs to continue heating at 160 ° C for 5-6 hours, high energy consumption; 2, difficult to produce, low yield: 5-fluorouracil as a solid powder The reaction needs to be carried out at a high temperature (160 ° C), which requires the use of a high boiling solvent N, N-dimethylformamide (DMF). But it is difficult to completely remove the fluoride from the addition of fluoride, because DMF can form hydrogen bonds with the fluoride molecules, difficult to separate from each other; 3, in order to unreacted 5-fluorouracil and tegafur separation and recycling , The use of carcinogenic solvent chloroform as a extractant in the conventional method to separate 5-fluorouracil and tegafur. However, the main role of chloroform on the central nervous system, with anesthesia, the heart, liver, kidney damage; the environment is also harmful to the water can cause pollution. Therefore, the use of volatile solvent chloroform, even if the necessary measures to reduce its volatilization, will still cause harm to human health and the environment; 4, low yield. Since both NI and N-3 in the 5-fluorouracil molecule react with 2-tert-butoxytetrahydrofuran, the addition of tegafur is also the addition of 1,3-bis (tetrahydro-2-furyl) -5 – Fluorouracil. Therefore, the improvement of the traditional production process of tegafur is a significant and imminent task.

Example 1 (for example, the best reaction conditions):

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 10. 0 mg CuCl2, microwave irradiation 250W at 25 ° C reaction 0. 6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), and microwave irradiation at 400 ° C for 100 ° C. After distilling off the low boiling solvent, the oil was obtained. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give 1.34349 g of product. Melting point: 160-165 ° C. The yield was 75%.

[0011] Example 2

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 3.8 g (100 mmol) of ethanol were added to a single-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 5mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cool to room temperature, add 1.95 g (15 mmol) of 5-fluorouracil (5-Fu), microwave irradiation 400W, reaction temperature 60 ° C under the reaction pool. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give the product 0. 46 g. Melting point: 160-165 ° C. The yield was 15%.

[0012] Example 3

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 15 ml of tetrahydrofuran (THF). And then weighed 20mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1301: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give the product 1.81 g. Melting point: 160-165 ° C. The yield was 61%.

[0013] Example 4

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran and 19 g (500 mmol) of ethanol were added to a single-necked flask. To this was added 20 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 2001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give product U6g. Melting point: 160-165 ° C. The yield was 43%.

[0014] Example 5

Weigh 3,5 g (50 mmol) of 2,3-dihydrofuran and 9.5 g (250 mmol) of ethanol were added to a single-necked flask. To this was added 30 ml of tetrahydrofuran (THF). And then weighed IOmg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 6001, reaction temperature 1001: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from absolute ethanol to give 1.15 g of product. Melting point: 160-165 ° C. The yield was 38%.

[0015] Example 6

Weigh 3.5 g (50 mmol) of 2,3-dihydrofuran, 1.9 g (50 mmol) of ethanol was added to a one-necked flask. To this was added 25 ml of tetrahydrofuran (THF). And then weighed 15mg CuCl2, microwave irradiation 250W at 25 ° C for 0.6h. Cooled to room temperature, add 1.95 g (15 to 01) 5-fluorouracil (5 call 11), microwave irradiation 5001, reaction temperature 1101: reaction lh. The low boiling solvent was distilled off to give an oil. Rinsed with ether to give a white solid which was recrystallized from anhydrous ethanol to give product 2.10 g. Melting point: 160-165 ° C. The yield was 70%.

Paper

A novel protocol for preparation of tegafur (a prodrug of 5-fluorouracil) is reported. The process involves the 1,8-diazabicycloundec-7-ene-mediated alkylation of 5-fluorouracil with 2-acetoxytetrahydrofuran at 90 °C, followed by treatment of the prepurified mixture of the alkylation products with aqueous ethanol at 70 °C. The yield of the two-step process is 72%.

Synthesis of Tegafur by the Alkylation of 5-Fluorouracil under the Lewis Acid and Metal Salt-Free Conditions

Aleksandra Zasada, Ewa Mironiuk-Puchalska, and Mariola Koszytkowska-Stawińska^* 

Faculty of Chemistry, Warsaw University of Technology, ul. Noakowskiego 3, 00-664 Warszawa, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00103

*E-mail: mkoszyt@ch.pw.edu.pl.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00103

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00103/suppl_file/op7b00103_si_001.pdf

Tegafur, a prodrug of 5-fluorouracil (5-FUra), was discovered in 1967. The compound features high lipophilicity and water solubility compared to 5-FUra. Tegafur is used as a racemate since no significant difference in antitumor activity of enantiomers was observed.

The prodrug is gradually converted to 5-FUra by metabolism in the liver. Hence, a rapid breakdown of the released 5-FUra in the gastrointestinal tract is avoided.(6) In injectable form, tegafur provoked serious side effects, such as nausea, vomiting, or central nervous system disturbances.

The first generation of oral formulation of tegafur , UFT) is a combination of tegafur and uracil in a fixed molar ratio of 1:4, respectively. The uracil slows the metabolism of 5-FUra and reduces production of 2-fluoro-α-alanine as the toxic metabolite. UFT was approved in 50 countries worldwide excluding the USA.

S-1 is the next generation of oral formulation of tegafur.(7) It is a combination of tegafur, gimeracil, and oteracil in a fixed molar ratio of 1:0.4:1, respectively.

Gimeracil inhibits the enzyme responsible for the degradation of 5-FUra. Oteracil prevents the activation of 5-FUra in the gastrointestinal tract, thus minimizing the gastrointestinal toxicity of 5-FUra. S-1 is well-tolerated, but its safety can be influenced by schedule and dose, similar to any other cytotoxic agent. Since common side effects of S-1 can be managed with antidiarrheal and antiemetic medications, the drug can be administered in outpatient settings. S-1 was approved in Japan, China, Taiwan, Korea, and Singapore for the treatment of patients with gastric cancer.

In 2010, the Committee for Medicinal Products for Human Use (CHMP), a division of the European Medicines Agency (EMA), recommended the use of S-1 for the treatment of adults with advanced gastric cancer when given in a combination with cisplatin. Currently, S-1 has not been approved by the FDA in the United States.

There is a great interest in further examination of S-1 as an anticancer chemotherapeutic. Currently, 23 clinical trials with S-1 has been registered in National Institutes of Health (NIH). Combinations of S-1 and other anticancer agents have been employed in a majority of these trials.

5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (Tegafur)

δ_H 1.89–2.10 (m, 3H), 2.38–2.45 (m, 1H), 3.97–4.01 (q-like m, 1H), 4.20–4.24 (dq-like m), 5.97–5.98 (m, 1H), 7.41 (d, ³J_HF 6.1), 9.21 (bs, 1H, NH).

δ_C 23.82, 32.90, 70.26, 87.58, 123.63 (d, ²J_CF 33.89), 140.33 (d, ¹J_CF 237.20) 148.66, 156.9 (d, ²J_CF 26.81).

HRMS m/z calcd for C₈H₁₀N₂O₃F [M – H]⁺ 201.0670, found 201.0669.

Elemental analysis. Found C%, 46.42; H%, 4.45; N%, 13.35. Calcd for 3(C₈H₉N₂O₃F)·H₂O: C%, 46.61; H%, 4.73; N%, 13.59.

References

1

• El Sayed, YM; Sadée, W (1983). “Metabolic activation of R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil (ftorafur) to 5-fluorouracil by soluble enzymes”. Cancer Research. 43 (9): 4039–44. PMID 6409396.
• 2
• Sweetman, S, ed. (14 November 2011). “Martindale: The Complete Drug Reference”. Pharmaceutical Press. Retrieved 12 February 2014.
• 3
• Ishikawa, T (14 May 2008). “Chemotherapy with enteric-coated tegafur/uracil for advanced hepatocellular carcinoma.” (PDF). World Journal of Gastroenterology : WJG. 14 (18): 2797–2801. doi:10.3748/wjg.14.2797. PMC 2710718 . PMID 18473401.
• 4
• Caudle, KE; Thorn, CF; Klein, TE; Swen, JJ; McLeod, HL; Diasio, RB; Schwab, M (December 2013). “Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing.”. Clinical pharmacology and therapeutics. 94 (6): 640–5. doi:10.1038/clpt.2013.172. PMC 3831181 . PMID 23988873.
• 5
• Amstutz, U; Froehlich, TK; Largiadèr, CR (September 2011). “Dihydropyrimidine dehydrogenase gene as a major predictor of severe 5-fluorouracil toxicity.”. Pharmacogenomics. 12 (9): 1321–36. doi:10.2217/pgs.11.72. PMID 21919607.
• 6
• Nakayama, T; Noguchi, S (January 2010). “Therapeutic usefulness of postoperative adjuvant chemotherapy with Tegafur-Uracil (UFT) in patients with breast cancer: focus on the results of clinical studies in Japan.” (PDF). The Oncologist. 15 (1): 26–36. doi:10.1634/theoncologist.2009-0255. PMC 3227888 . PMID 20080863.
• 7

Matt P, van Zwieten-Boot B, Calvo Rojas G, Ter Hofstede H, Garcia-Carbonero R, Camarero J, Abadie E, Pignatti F (October 2011). “The European Medicines Agency review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the treatment of advanced gastric cancer when given in combination with cisplatin: summary of the Scientific Assessment of the Committee for medicinal products for human use (CHMP).” (PDF). The Oncologist. 16 (10): 1451–1457. doi:10.1634/theoncologist.2011-0224. PMC 3228070 . PMID 21963999.

1. (1) Hirose, Takashi; Oncology Reports 2010, V24(2), P529-536 
2. (2) Fujita, Ken-ichi; Cancer Science 2008, V99(5), P1049-1054 
3. (3) Tahara, Makoto; Cancer Science 2011, V102(2), P419-424 
4. (4) Chu, Quincy Siu-Chung; Clinical Cancer Research 2004, V10(15), P4913-4921 
5. (5) Tominaga, Kazunari; Oncology 2004, V66(5), P358-364 
6. (6) Peters, Godefridus J.; Clinical Cancer Research 2004, V10(12, Pt. 1), P4072-4076 
7. (7) Kim, Woo Young; Cancer Science 2007, V98(10), P1604-1608 
8.  Hillers, Solomon; Puti Sinteza i Izyskaniya Protivoopukholevykh Preparatov 1970, VNo. 3, P109-12 
9.  Grishko, V. A.; Trudy Kazakhskogo Nauchno-Issledovatel’skogo Instituta Onkologii i Radiologii 1977, V12, P110-14 
10. Ootsu, Koichiro; Takeda Kenkyushoho 1978, V37(3-4), P267-77 
11.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
12. Yabuuchi, Youichi; Oyo Yakuri 1971, V5(4), P569-84 
13.  Germane, S.; Eksperimental’naya i Klinicheskaya Farmakoterapiya 1970, (1), P85-92 
14.  JP 56046814 A 1981

MORE

1. AIST: Integrated Spectral Database System of Organic Compounds. (Data were obtained from the National Institute of Advanced Industrial Science and Technology (Japan))
2.  ACD-A: Sigma-Aldrich (Spectral data were obtained from Advanced Chemistry Development, Inc.)
3. Nomura, Hiroaki; Chemical & Pharmaceutical Bulletin 1979, V27(4), P899-906 
4. Sakurai, Kuniyoshi; Chemical & Pharmaceutical Bulletin 1978, V26(11), P3565-6 
5. Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, V29(11), P3181-90
6. Lukevics, E.; Zhurnal Obshchei Khimii 1981, V51(4), P827-34 
7.  Needham, F.; Powder Diffraction 2006, V21(3), P245-247 
8. 1. Nomura, Hiroaki; Chemical & Pharmaceutical Bulletin 1979, V27(4), P899-906 
   2. Sakurai, Kuniyoshi; Chemical & Pharmaceutical Bulletin 1978, V26(11), P3565-6 
   3.  “Drugs – Synonyms and Properties” data were obtained from Ashgate Publishing Co. (US) 
   4.  Miyashita, Osamu; Chemical & Pharmaceutical Bulletin 1981, V29(11), P3181-90 
   5.  “PhysProp” data were obtained from Syracuse Research Corporation of Syracuse, New York (US)
   6.  Lukevics, E.; Zhurnal Obshchei Khimii 1981, V51(4), P827-34 
   7.  Lukevics, E.; Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija 1982, (3), P317-20 
   8. Kruse, C. G.; Recueil des Travaux Chimiques des Pays-Bas 1979, V98(6), P371-80 
   9. Lukevics, E.; Latvijas PSR Zinatnu Akademijas Vestis, Kimijas Serija 1981, (4), P492-3
   10.  Kametani, Tetsuji; Heterocycles 1977, V6(5), P529-33
   11.  Kametani, Tetsuji; Journal of Heterocyclic Chemistry 1977, V14(3), P473-5 
   12. Hillers, S.; GB 1168391 1969 

Tegafur

Clinical data
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: D
Routes of administration	Oral
ATC code	L01BC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)
Pharmacokinetic data
Biological half-life	3.9-11 hours
Identifiers
IUPAC name[show]
Synonyms	5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione
CAS Number	17902-23-7
PubChem CID	288216
ChemSpider	254191
UNII	1548R74NSZ
KEGG	D01244
ChEMBL	CHEMBL20883
ECHA InfoCard	100.038.027
Chemical and physical data
Formula	C8H9FN2O3
Molar mass	200.16 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] FC=1C(=O)NC(=O)N(C=1)[C@@H]2OCCC2

///////////TEGAFUR

FC1=CN(C2CCCO2)C(=O)NC1=O

PRESENTING 2 MOLECULES………..I AM NOT SURE WHICH IS TITLE MOLECULE

EMAIL ME amcrasto@gmail.com

2-[(3R)-3alpha-Aminopiperidino]-3-(2-butynyl)-5-(4-methyl-2-quinazolinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-4-one

CAS 1428445-40-2

REF Bioorganic & Medicinal Chemistry (2013), 21(7), 1749-1755.

NEXT ONE………………

CAS 1415912-31-0

TILOGLIPTIN

HWH-ZGC-2-143

Guangzhou Institutes of Biomedicine and Health

Chia Tai Tianqing Pharmaceutical Group Co Ltd;

Non-insulin dependent diabetes

Dipeptidyl peptidase IV inhibitor (oral, type 2 diabetes),

DPP-IV inhibitors (oral, type 2 diabetes), Guangzhou Institutes of Biomedicine and Health/Jiangsu Chia Tai Tianqing Pharmaceutical ; HWH-ZGC-2-143 ;

Novel polymorphic forms of thiadiazole derivatives, preferably aglucin, sitagliptin, saxagliptin, vildagliptin, levaratine, useful for treating type II diabetes. Guangzhou Institutes of Biomedicine and Health , in collaboration with Jiangsu Chia Tai Tianqing Pharmaceutical , is investigating tilogliptin , an oral dipeptidyl peptidase IV inhibitor and a pyrrolopyrimidine analog, for treating type 2 diabetes.

As of June 2017, Centaurus BioPharma is developing diabetes therapy, CT-1006 and CT-1005 (in preclinical development) for treating diabetes mellitus.

See WO2016019868, claiming novel citric acid salt of 8-((R)-3-amino-piperidin-1-yl)-1-([1,2,5]-thiadiazolo [3,4-b] pyridine-5methyl)-7-(2-butyn-1-yl)-3-methyl-xanthine, coassigned to Lianyungang Runzhong Pharmaceutical .

PATENT

WO2016019868

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016019868

PATENT

WO 2017088790

Centaurus BioPharma Co Ltd; Chia Tai Tianqing Pharmaceutical Group Co Ltd

N[C@@H]1CCCN(C1)C5=Nc4ccn(Cc3nc2ccccc2c(C)n3)c4C(=O)N5CC#CC

N[C@@H]1CCCN(C1)c5nc4c(C(=O)N(Cc2ccc3nsnc3n2)C(=O)N4C)n5CC#CC