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RPC1063

(S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile ……..any error report amcrasto@gmail.com

COMPD IS  I-S

X=-OH AND Y = CN  ………any error report amcrasto@gmail.com

(S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile

Receptos, Inc. INNOVATOR

WO 2011060389

THIS IS COMPD RPC1063  as above.ignore rest

RPC1063 is a novel, differentiated sphingosine 1-phosphate 1 receptor (S1P1) selective modulator exhibiting picomolar potency that is effective in rodent models of both multiple sclerosis (MS) and inflammatory bowel disease (IBD), and possesses an excellent safety profile in non-clinical toxicology studies. Receptos has completed a Phase 1 study with RPC1063 which tested single ascending doses, multiple ascending doses and dose titration regimens in healthy volunteers. The Phase 1 results confirmed optimal pharmacokinetic, pharmacodynamic and safety features, which provide supportive data for the differentiation strategy for RPC1063 as a potential best-in-class second generation S1P1 receptor modulator.

A Phase 2/3 study has been initiated to study RPC1063 in the indication of relapsing multiple sclerosis (RMS). RPC01-201, designed to demonstrate the clinical efficacy of RPC1063 in patients suffering from RMS, is a Phase 2/3 placebo-controlled (Phase 2) and active comparator-controlled (Phase 3) trial, and is the first of two planned pivotal studies for RPC1063 in RMS. Receptos anticipates initiating a second Phase 2 study with RPC1063 in ulcerative colitis in 2012.

A compound discovered and synthesized in The Scripps Research Institute (TSRI) labs of Professors Hugh Rosen and Edward Roberts has provided positive results for safety and efficacy in Phase 2 clinical trials for relapsing multiple sclerosis, according to Receptos, the biopharmaceutical company developing the drug for approval by the US Food and Drug Administration.

“The Rosen and Roberts laboratories are very gratified to see these direct improvements in the lives of patients and families dealing with this debilitating illness,” said Rosen. “These data support our labs’ approach at TSRI—that discovery of fundamental mechanisms in chemical biology provides the foundation for intelligent intervention in disease processes. Meeting the needs of patients and their families is our high calling in biomedical science.”

The drug candidate, RPC1063, was first discovered at TSRI from work in the National Institutes of Health (NIH) Molecular Libraries Initiative. The randomized, double-blind Phase 2 study assessed the efficacy, safety and tolerability of two orally administered doses of RPC1063 against placebo in 258 patients with relapsing multiple sclerosis across 77 sites in 13 countries. There was a highly statistically significant 86 percent reduction in MRI measures of disease activity.

A Phase 3 trial—a randomized, double-blind study involving 1,200 patients with relapsing multiple sclerosis—was launched in December 2013.

On June 9th, 2014 Receptos announced that a portion of its Phase 2 results in relapsing multiple sclerosis (RMS) met the primary endpoint of reducing MRI brain lesion activity. News of being a potential best in class profile has caused RCPT shares to shoot up 50% in a matter of two days. Detailed results of the RADIANCE trial are expected to be presented in coming months.
The MS market is valued at around $16B, but faces competition from existing products (below). Positioning a successful therapy will prove to be difficult even if FDA approval is attained. With Phase 3 initiation just announced, RPC1063 is years away from the market.

Given the competitive landscape and Receptos’ top line results, the company may be seen as a potential takeover target by the investing community. For example, Teva’s Copaxone lost US market exclusivity May 2014 and has patents expiring in May 2015 in most of the rest of the world. As a result of generics, Teva expects to take a $550M hit during 2014. A therapy such as RPC1063 could minimize these losses in the upcoming future.

SYNTHESIS

http://www.google.com/patents/WO2011060389A1?cl=en

Scheme 1:

Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) RuCl(p-cymene)[(R,R)-Ts-DPEN], HC0₂H- TEA complex; (iii) NH₂OH*HCl, Na₂C0₃ or TEA, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.

Scheme 2:

Reagents: (i) DPPA, DBU, toluene; (ii) PG = protecting group e.g. Boc: Pd/C, H₂, Boc₂0, TEA, MeOH; (iii) NH₂OH*HCl, NaHC0₃, EtOH; (iv) HOBt, EDC, benzoic acid, DMF (v) deprotection e.g. 4M HC1 in dioxane; (vi) (a) R’-LG or R”-LG, where LG represents a leaving group, K₂C0₃, CH₃CN; (b) R’-C0₂H or R²-C0₂H, HOBt, EDC, DMF or R^l-COCl or R²-COCl, TEA, DCM; (c) R -S0₂C1 or R³-S0₂C1, TEA, DCM (d) R²-CHO, HOAc, NaB¾ or NaCNBH₃ or Na(OAc)₃BH, MeOH; (e) R¹– OCOC1 or R²-OCOCl, DIEA, DMF; (f) HN(R⁵R⁵), CDI, TEA, DCM; (g) ¾NS0₂NH₂, Δ, dioxane; (h) dimethyloxirane, Δ, EtOH; (vii) (a) If R’ or R” = H, then reactions (vi)(a-d) can be performed; (b) If R’ or R” contains an ester then (i) hydrolysis NaOH, EtOH or (ii) reduction NaBFL,, MeOH can be performed; (c) If R’ or R” contains an acid then couplings HN(R⁵R⁵), HOBt, EDC, DMF can be performed; (d) If R’ or R” contains an appropriate activated alkene then Michael additions HN(R⁵R⁵), DMF can be performed.

The (R)-enantiomer was prepared in the same manner outlined in Scheme 2 starting from (5)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile.

Scheme 3:

Reagents: (i) Sodium borohydride, ethanol, silica gel; (ii) PG = protecting group e.g. TBDMS chloride, imidazole; (iii) 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi( 1,3,2- dioxaborolane), PdCl₂(dppf).CH₂Cl₂, potassium acetate, dioxane.

Scheme 4:

Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) For racemic material: Sodium borohydride, ethanol, silica gel; For (/?)-indanol: 0S)-(-)-2-methyl-CBS- oxazaborolidine, BH₃-DMS, toluene; For (5)-indanol: (R)-(+)-2-methyl-CBS- oxazaborolidine, BH₃-DMS, toluene; (iii) NH₂OH*HCl, Na₂C0₃ or TEA, EtOH.

Scheme 5:

Reagents: (i) Oxalylchloride, DCM; (ii) Ethanolamine, Et₃N, DCM; (iii) SOCl₂, DCM, KOH, MeOH (iv) N-Bromosuccinimide, azoisobutyronitrile, DCM; (v) Protected (e.g. TBDMS) 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro- lH-inden-l-ol, K₂C0₃, Pd(PPh₃)₄, DME, H₂0; (vi) deprotection e.g. TBAF, THF; (vii) SOCl₂, DCM; (viii) R’-NH₂ or R”-NH₂, DLPEA, DMA.

Scheme 6:

W

Reagents: (i) (R)-2-methylpropane-2-sulfinamide, Ti(OEt)₄, toluene; (ii) NaB¾, THF; (iii) 4N HC1 in dioxane, MeOH; (iv) Boc₂0, TEA, DCM; (v) 4,4,4′,4′,5,5,5′,5′- octamethyl-2,2′-bi(l,3,2-dioxaborolane), PdCl2(dppf).CH₂Cl_2> potassium acetate, dioxane; (vi) 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile, K₂C0₃, Pd(PPh₃)₄, DME, H₂0; (vii) 4N HC1 in dioxane; (viii) (a) R’-LG or R”-LG, where LG represents a leaving group, K₂C0₃, CH₃CN; (b) R¹-C0₂H or R²-C0₂H, HOBt, EDC, DMF or R’-COCl or R²-COCl, TEA, DCM; (c) R’-SOaCl or R³-S0₂C1, TEA, DCM (d) R²– CHO, HOAc, NaB¾ or NaCNBH₃ or Na(OAc)₃BH, MeOH; (e) R’-OCOCl or R²– OCOC1, DIEA, DMF; (f) HN(R⁵R⁵), CDI, TEA, DCM; (g) H₂NS0₂NH₂, Δ, dioxane; (h) dimethyloxirane, Δ, EtOH; (ix) (a) If R’ or R” = H, then reactions (viii)(a-d) can be performed; (b) If R’ or R” contains an ester then (i) hydrolysis NaOH, EtOH or (ii) reduction NaBFLt, MeOH can be performed; (c) If R’ or R” contains an acid then couplings HN(R⁵R⁵), HOBt, EDC, DMF can be performed; (d) If R’ or R” contains an appropriate activated alkene then Michael additions HN(R⁵R⁵), DMF can be performed. [0255] The (5)-enantiomer can be prepared using (5)-2-methylpropane-2-sulfinamide in step (i).

[0256] Scheme 7:

Reagents: (i) HOBt, EDC, 2-(3,4-diethoxyphenyl)acetic acid, DMF; (ii) S0C1₂, DCM; (iii) R’-NH₂, DIPEA, DMA.

[0257] Scheme 8:

Reagents: (i) Zn(CN)₂, Pd(PPh₃)₄, NMP; (ii) (R)-2-methylpropane-2-sulfinamide, Ti(OEt)₄, toluene; (iii) NaB¾, THF; (iv) 4M HC1 in dioxane, MeOH; (v) PG = protecting group e.g. Boc₂0, TEA, DCM; (vi) NH₂OH*HCl, TEA, EtOH; (vii) R’- halide, NaH, DMF.

Reagents: (i) (a) HOBt, EDC, 2-(3,4-diethoxyphenyl)acetic acid, DMF (b) deprotection e.g. 4N HCl in dioxane; (ii) (a) R’-LG, where LG represents a leaving group, K₂C0₃, CH₃CN; (b) if R’ contains an ester then (a) followed by NaOH, EtOH; (c) R’-C0₂H, HOBt, EDC, DMF or R’-COCl, TEA, DCM; (d) R’-S0₂C1, TEA, DCM (e) R’-CHO, HOAc, NaBFL or NaCNBH₃ or Na(OAc)₃BH, MeOH.

[0259] The (5)-enantiomer can be prepared using protected (/?)-l-amino-N-hydroxy-2,3 dihydro-lH-indene-4-carboximidamide in step (i).

Scheme 10:

Reagents: (i) HOBt, EDC, 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid, DMF; (ii) 2N HCL in ether, DCM.

[0261] Scheme 11:

Reagents: (i) PG = protecting group e.g. Boc₂0, DMAP, ACN; (ii) NH₂OH*HCl, Na₂C0₃, EtOH; (iii) HOBt, EDC, benzoic acid, DMF; (iv) deprotection e.g. 4N HCl in dioxane.

Scheme 12:

Reagents: (i) NH₂OH*HCl, Na₂C0₃, EtOH; (ii) HOBt, EDC, benzoic acid, DMF. [0263] Scheme 13:

Reagents: (i) NH₂OH*HCl, Na₂C0₃, EtOH; (ii) HOBt, EDC, 3-cyano-4- isopropoxybenzoic acid, DMF.

[0264] Scheme 14:

Reagents: (i) PG= protecting group e.g. tert-butylchlorodimethylsilane, TEA, DCM; (ii) Zn(CN)₂, Pd(PPh₃)₄, NMP; (iii) NH₂OH*HCl, Na₂C0₃, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.

Selected compounds and their corresponding analytical data is shown in Table 1, where the LCMS data was collected using Method 2 (see General Methods). The enantiomeric purity was determined for key intermediates and selected final compounds and is presumed from the synthesis for the remaining compounds. TABLE 1

see compd 2

TABLE 2

 

Experimental Procedures

[0266] 5-oxo-5, 6, 7, 8-tetrahydronaphthalene-l-carbonitrile (INT-1)

[0267] To a stirred solution of 5-bromo-3,4-dihydronaphthalen-l(2H)-one (9.95g, 44.2 mmol) in NMP (50 mL) was added Zn(CN)₂ (10.38 g, 88.4 mmol). The mixture was degassed twice by bubbling N₂ through the solution for 30 min then evacuated. Pd(Ph₃)₄ (0.5g, 0.44 mmol) was added and the mixture was heated to 110°C under N₂. After 5h, the mixture was cooled to room temperature and poured onto ice (600 mL), using water (300 mL) to complete the transfer. After the ice had melted, the solution was filtered and the resulting solid was collected, suspended in DCM, and filtered again. The solid was collected, washed with water, and purified by column chromatography (EA/ hex) to provide 6.9 g (91%) of 5-oxo-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-1 as a white solid. LCMS- ESI (m/z) calculated for C_nH₉NO: 171.2; found 172.1 [M+H]⁺, t_R = 2.95 min. Ή NMR (400 MHz, CDCI3) 6 8.26 (dd, J = 7.9, 1.4 Hz, 1H), 7.82 (dd, J = 7.6, 1.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 3.20 (t, J = 6.1 Hz, 2H), 2.72 (dd, J = 7.2, 6.1 Hz, 2H), 2.30 – 2.17 (m, 2H). ^I3C NMR (101 MHz, CDC1₃) δ 196.22, 147.39, 137.18, 133.39, 131.59, 127.19, 116.93, 112.94, 38.48, 28.05, 22.28.

[0268] (R)-5-hydroxy-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile (INT-2)

 

[0269] To a stirred solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-1 (3.0 g, 17.5 mmol) in 5:1 HC0₂:NEt₃ (24 mL) was added RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.13 g, 0.26 mmol). The mixture was stirred at 30°C for 15 h then partitioned between EA and H₂0. The combined organic layers were dried over Na₂S0₄ and chromatographed (EA/ hex) to provide 2.99 g (99%) of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l -carbonitrile INT-2 as a white solid. LCMS-ESI (m/z) calculated for CnHnNO: 173.2; found 174.1 [M+H]⁺, 156.1 [Μ-Ν¾]⁺, t_R = 2.60 min. Ή NMR (400 MHz, CDC1₃) δ 7.71 (d, J = 7.8 Hz, 1H), 7.54 (dt, J = 8.7, 4.4 Hz, 1H), 7.34 – 7.26 (m,lH), 4.85 – 4.71 (m, 2H), 3.48 (s, 1H), 3.13 – 2.96 (m, lH), 2.90 (ddd, J = 17.7, 7.8, 5.6 Hz, 1H), 2.15 – 1.95 (m, 2H), 1.97 – 1.76 (m, 2H). Chiral HPLC: (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile was eluted with 5% IPA / hexane: 99.1% ee, t_R = 15.3 min.

[0270] (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-3 was prepared in an analogous fashion using INT-1 and RuCl(p-cymene)[(S,S)-Ts-DPEN]. Chiral HPLC: 99.4% ee, t_R for the (S)-enantiomer = 17.99 min.

[0271] General Procedure 1. Preparation of Amide Oximes

[0272] To (R)- or (S)-cyanides (1 eq) in EtOH (0.56 M) was added hydroxylamine hydrochloride (3 eq) and either NaHC0₃ or TEA (3 eq) and the reaction mixture heated at 85°C for 1-2 h. The organic soluble amide oximes were isolated by removal of the solvent and partitioning between water and DCM. The water soluble amide oximes were chromatographed or used directly in the cyclization. Pure amide oximes can be obtained by recrystallization from alcoholic solvents.

[0273] (R)-N,5-dihydroxy-5,6, 7,8-tetrahydronaphthalene-l-carboximidamide (INT-4)

[0274] Prepared using General Procedure 1. To a stirring solution of (R)-5-hydroxy-5 ,6,7,8- tetrahydronaphthalene-l-carbonitrile INT-2 (79.1 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (34.9 mg, 0.50 mmol) and sodium bicarbonate (42.2 mg, 0.50 mmol). The mixture was heated at 70°C for 18 h. The product was purified by chromatography (MeOHV DCM) to provide 27.3 mg (29%) (R)-N,5-dihydroxy-5,6,7,8- tetrahydronaphthalene-l-carboximidamide INT-4 as a white solid. LCMS-ESI (m/z) calculated for CuHnNO: 173.2; found 174.1 [M+H]⁺, 156.1 [M-NH ]⁺, t_R = 2.60 min.(S)- N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-l-carboximidamide ENT-5 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT -3.

[0275] General Procedure 2. Cyclization to Oxadiazole Amines

[0276] A solution of the appropriate acid (1 eq), HOBt (1.3 eq), and EDC (1.3 eq) in DMF

(0.08 M in acid) was stirred at room temperature under an atmosphere of N₂. After the complete formation of the HOBt- acid complex (1-3 h), the (R)- or (S)-amide oxime (1.1 eq) was added to the mixture. After complete formation of the coupled intermediate (ca. 0.5- 2 h), the mixture was heated to 75-95°C until the cyclization was complete (8-12 h). The reaction mixture was diluted with saturated NaHC0₃ and extracted with EA. The combined organic extracts were dried, concentrated, and could be purified by chromatography (EA/hexanes), preparative HPLC or recrystallization.

[0277] (R)-5-(3-(5-hydroxy-5, 6, 7,8-tetrahydronaphthalen-l-yl)-l,2,4-oxadiazol-5-yl)-2- isopropoxybenzonitnle (Compound 1)

 

[0278] Prepared using General Procedure 2. To a stirring solution of 3-cyano-4- isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy- 5,6,7, 8-tetrahydronaphthalene-l-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90°C for 15 h. The mixture was diluted with EA and washed with NaHC0₃. The combined organic layers were dried, concentrated, chromatographed (EA/ hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l- yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m z) calculated for C₂₂H₂₁N₃0₃: 375.4; found 376.1 [M+H]⁺, t_R = 3.73 min. 1H NMR (400 MHz, CDC1₃) δ 8.42 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 8.9, 2.2 Hz, 1H), 7.97 (dd, J = 7.7, 1.3 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.91 – 4.83 (m, 1H), 4.79 (dq, J = 12.0, 6.0 Hz, 1H), 3.20 (dt, J = 17.8, 5.4 Hz, 1H), 3.01 (dt, J = 13.3, 6.4 Hz, lH), 2.13 – 1.81 (m, 4H), 1.79 (d, J = 7.2 Hz, 1H), 1.47 (d, J = 5.6 Hz, 6H). ¹³C NMR (101 MHz, CDC1₃) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)-l,2,4-oxadiazol-5-yl)- 2-isopropoxybenzonitrile was eluted with 10% IPA / hexane: 99.4% ee, tR = 40.85 min.

[0279] (S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile 2 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8- tetrahydronaphthalene-l-carbonitrile INT-5. Chiral HPLC: 99.1% ee, t_R for the (S)- enantiomer = 38.19 min.