Pfizer's Fosdagrocorat, PF-04171327 for Rheumatoid Arthritis

Fosdagrocorat, PF-04171327,

CAS 1044535-58-1

(2R,4aS,10aR)-4a-Benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-N-(2-methyl-3-pyridinyl)-4b-(phenylmethyl)-7-(phosphonooxy)-7-(trifluoromethyl)-, (4bS,7R,8aR)-

(2R,4aS,10aR)-4a-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl dihydrogen phosphate

MF C29H30F3N2O5P
Exact Mass: 574.1844

• PF 04171327
• PF-04171327
• UNII-HPI19004QS
• Selective Glucocorticoid Receptor Modulator

phase 2 .Rheumatoid Arthritis

Glucocorticoid receptor modulators

Pfizer

• 03 Sep 2015Phase II development of fosdagrocorat is ongoing
• 01 Jun 2014Pfizer completes a phase II trial in Rheumatoid arthritis in US, Bulgaria, Colombia, the Czech Republic, Germany, Hungary, India, South Korea, Malaysia, Mexico, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Spain and the Ukraine (NCT01393639)
• 30 Sep 2011Phase-II clinical trials in Rheumatoid arthritis in Bulgaria, Colombia, Germany, India, Malaysia, Mexico, Poland, Romania and South Africa (PO)

Fosdagrocorat, also known as PF-04171327, a dissociated agonist of the glucocorticoid receptor (DAGR), a selective high-affinity partial agonist of the GR with potent anti-inflammatory activity at exposures that provide less undesirable effects on bone and glucose metabolism compared with prednisone (pred).

Glucocorticoid receptor modulators are glucocorticoid receptor ligands that are used to treat a variety of conditions because of their powerful anti-inflammatory, antiproliferative and immunomodulatory activity. J. Miner, et al., Expert Opin. Investig. Drugs (2005) 14(12):1527-1545.
Examples of glucocorticoid receptor modulators include dexamethasone, prednisone, prednisolone, RU-486, and as described in WO 2000/66522 and WO 2004/005229.
Treatment with glucocorticoid receptor modulators is often associated with side effects, such as bone loss and osteoporosis.
Identifying a glucocorticoid receptor modulator that is efficacious, potent, and has mitigated side-effects fulfills a medical need.

SYNTHESIS COMING............

PATENT

WO 2008093227/US 20100286214

https://www.google.com/patents/WO2008093227A1?cl=en

SCHEME A

The 1 (/?)-Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²'⁷]trideca-2,4,6-trien-13-one of Formula A-8 was prepared using the protocol described in Scheme A, which is generally disclosed in WO 00/66522. Ph depicts Phenyl. Bn depicts Benzyl. Compound A-1 can be purchased (for example, VOUS and Riverside; CAS No. 4133-35-1 ). Compound A-2 can be prepared as described in Org. Syn. 1971 , 51 , 109-112.

SCHEME B

The (4βS,7R,8αR)-4β-benzyl-7-hydroxy-Λ/-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4b,5,6,7,8α,9,10-octahydrophenanthrene-2-carboxamide was prepared as described in Scheme B.

SCHEME C

 The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme C. Bn depicts benzyl.

SCHEME D

The (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme D. Bn depicts benzyl. Ph depicts phenyl.

SCHEME E

The (2R,4αS, 10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoy[)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate of C-3 was prepared as described in Scheme E. Bn depicts benzyl. Ph depicts phenyl.

Starting Material A-8 is 1(R)~Benzyl-5-bromo-9(S)-hydro-10(R)-hydroxy-10(R)-methyl-tricyclo[7.3.1.0²'⁷]trideca-2,4,6-trien-13-one as depicted by the following formula:

Preparation 1 : (S)-4a-benzyl-7-bromo-2-ethoxy-3,4,4a,9-tetrahydrophenanthrene

Starting Material A-8 (450 g; 1.17 moles) was dissolved in ethanol (4.5 L) at ambient temperature. 21% sodium ethoxide in ethanol (44 mL; 0.12 moles) was added and the mixture was heated to reflux for three hours. Once the Starting Material A-8 was consumed, the reaction mixture was chilled to -25⁰C. Acetyl chloride (250 mL; 3.51 moles) was slowly added to the mixture while the temperature was maintained near -25°C. After the addition was complete, the mixture was warmed to O⁰C and held there until the intermediate enone was consumed. The mixture was slurry at this point. 21 % sodium ethoxide in ethanol (1.31 L; 3.51 moles) was added to the mixture while the temperature was maintained between -5°C and 5⁰C. If the mixture was not basic, more sodium ethoxide was added. The temperature of the mixture was increased to 25°C and then diluted with water (5.9 L). The mixture was filtered and the solid was washed with water (3 X). The title compound (440 g; 85 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.27 (t, 3H), 1.65 (dt, 1 H), 2.06 (d, 1 H), 2.21 (dd, 1 H)₁ 2.49 (m, 1 H), 2.65 (m, 2H), 2.89 (m, 2H), 3.85 (q, 2H), 5.45 (m, 2H), 6.44 (d, 2H), 6.98 (t, 2H), 7.06 (m, 2H), 7.25 (d, 1 H), 7.33 (dd, 1 H).

Preparation 2: (S)-4a-benzyl-7-bromo-2,2-(1,2-ethylenedioxy)-1,2,3,4,4a,9-hexahydrophenanthrene

The (S)-4α-benzyl-7-bromo-2-ethoxy-3,4,4α,9-tetrahydrophenanthrene (1270 g; 3.2 moles; 85 area %, which may be prepared as described in Preparation 1 ) was dissolved in toluene (6.45 L). The ethylene glycol (898 mL; 16.1 moles) and p-toluenesulfonic acid (6.1 g; 0.03 moles) were added and the reaction heated to reflux. Solvent (1 L) was distilled from the mixture and replaced with fresh toluene (1 L). This distillation process was repeated twice more. More p-toluenesulfonic acid (6.1 g) was added each time fresh toluene was added. During the reaction, two intermediates (detected by LC) were formed as the substrate was converted into product. The end point of the reaction was an equilibrium point between the two intermediates and the product. Once the endpoint was reached, the mixture was cooled to ambient temperature. The mixture was washed with 0.5 M NaOH (2 L). The phases separated quickly and both were dark with a small rag layer. The mixture was washed with water (2 L). The phases
separated very slowly. The mixture was dried by azeotropic distillation. Methanol (4 L) was added to the mixture and solvent (4 L) was distilled from the mixture. The methanol addition and solvent distillation were repeated twice more. Methanol was added to the mixture and precipitation occurred a few minutes later. More methanol (4 L) was added to the mixture and then brought to reflux. After 30 minutes, the mixture was cooled to 0⁰C. The mixture was filtered and the solid was washed with chilled methanol (2 X 2L). The solid was dried in a vacuum oven at 65°C. The title compound (882 g; 98 area %) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.71 (m, 2H), 2.06 (m, 2H), 2.31 (dd, 1 H), 2.39 (m, 1 H), 2.68 (d, 1 H), 2.77 (m, 1 H), 2.86 (dd, 1 H), 3.36 (d, 1 H), 3.86 (m, 4H), 5.45 (m, 1 H), 6.50 (m, 2H), 7.00 (m, 4H), 7.37 (dd, 1 H), 7.44 (d, 1 H).

Preparation 3: (S)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate

The (S)-4α-benzyl-7-bromo-2,2-(1 ,2-ethylenedioxy)-1 ,2,3,4,4α,9-hexahydrophenanthrene (719 g; 1.75 moles, which may be prepared as described in Preparation 2) was dissolved in tetrahydrofuran (7.19 L) and chilled to -7O⁰C. The 1.6 M n-butyl lithium in hexane (2270 mL; 2.27 moles) was added at a rate such that the temperature was maintained below -6O⁰C. The mixture held an additional 15 minutes after the addition. Carbon dioxide (108 g; 2.45 moles) was added while the temperature was maintained below -60°C. The mixture held an additional 15 minutes after the addition. The mixture was warmed to ambient temperature. Solvent (7 L) was distilled from the mixture at atmospheric pressure. DMF (7 L) was added to the mixture. The mixture was cooled to ambient temperature. Methyl iodide (152 mL; 2.45 moles) was added and the mixture was held until the reaction was completed (~1 hour). The mixture was heated to 7O⁰C and solvent was distilled by gradually reducing the pressure to 70 mmHg. Once distillation had ceased, the mixture was cooled to room
temperature. Water (6.5 L) was slowly added to the mixture to precipitate the product. The mixture was filtered and the solid washed with water (3 X). The solid was dried on the filter. The crude product (736 g; 74 area %) was obtained as a beige solid. The product was purified by chromatography. 463 g of product was recovered from the chromatography. This material was separated from n-heptane (6130 mL). 394 g of the title compound was recovered. Another 70 g of title compound was recovered from the mother liquor by chromatography. ¹H NMR (DMSO) δ ppm: 1.74 (m, 2H), 2.10 (m, 2H)₁ 2.33 (dd, 1 H), 2.45 (m, 1 H), 2.72 (d, 1 H), 2.79 (m, 1 H), 2.94 (dd, 1 H), 3.40 (d, 1 H), 3.87 (m, 7H), 5.49 (m, 1 H), 6.47 (m, 2H), 6.93 (m, 2H), 7.01 (m, 1 H), 7.42 (d, 1 H), 7.64 (d, 1 H), 7.79 (dd, 1 H).

Preparation 4: (4βS,8α/?)-methyl 4β-benzyl-7,7-(1,2-ethylenedioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (S)-methyl 4β-benzyl-7,7-(1 ,2-ethylenedioxy)-4β,5,6,7,8,10-hexahydrophenanthrene-2-carboxylate (201 g; 0.515 moles, which may be prepared as described in Preparation 3) and 50 ml of ethylene glycol was dissolved in toluene (2.0 L) in an autoclave. To this was added 10 grams of a 5% Pd/C (dry catalyst). The autoclave was then sealed and purged with nitrogen (three cycles) followed by hydrogen (three cycles). The reaction was run for 18 hours with a pressure of 80 psig and temperature of 50 ⁰C. HPLC analysis for completion and selectivity (typical selectivity's are: 95 to 5, Trans to Cis). The suspension was filtered through Celite® to remove the catalyst and the toluene solution is concentrated at 50 ⁰C, under vacuum, to
approximately 200 ml. While still at 50 ⁰C, 1 L of 1-butanol was added and the solution heated to 60 ⁰C, until clear. Upon cooling, the resulting solid title compound was isolated by vacuum filtration (196 grams; 97%; Trans to Cis 95.75 to 4.24). ¹H NMR (300 MHz, CDCI₃) δ ppm: 7.79 (bs, 1 H₁ Ar-H), 7.47 (d, J= 9 Hz, 1 H, Ar-H), 7.13-7.05 (cm, 3H, Ar-H), 6.56-6.53 (cm, 2H, Ar-H), 6.43 (d, J= 9 Hz, 1 H, Ar-H), 4.04-3.93 (cm, 4H, 2-CH₂), 3.89 (s, 3H, CH₃),3.08-3.03 (cm, 3H, CH₂, CH-H), 2.63 (d, J= 15 Hz, CH-H), 2.22-1.72 (cm, 8H, 4-CH₂), 1.57 (cm, 1 H, CH-H).; ¹³CNMR (CDCI₃, δ): 167.7, 149.2, 137.7, 136.4, 131.1 , 130.5, 127.8, 127.7, 127.4, 126.3, 125.5, 108.9, 64.6, 64.5, 52.1 , 40.5, 39.8, 38.3, 35.8, 31.6, 30.3, 27.9, 24.6.

Preparation 5: (4βS,8α/?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

ThΘ (4βS,8αR)-mΘthyl 4β-benzyl-7,7-(1 ,2-ethylenΘdioxy)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (150 g, 382 mmol, which may be prepared as described in Preparation 4) was dissolved in dichloromethane (630 ml). Water (270 ml) was added with stirring followed by trifluoroacetic acid (73 ml. 1150 mmol) via drop funnel over 30 minutes, maintaining the internal temperature below 3O⁰C. After the addition was complete, the reaction was heated at 4O⁰C for 2 hours. In process check indicated incomplete reaction with around 9% (area percent) starting material. The layers were separated and fresh water (270 ml) and trifluoroacetic acid (31 ml) was added. The reaction mixture was heated at 4O⁰C for 1 hour. This process was continued until the starting material was consumed. The organic phase was washed with 5% aqueous sodium bicarbonate (300 ml), water (300 ml) and dried over MgSO₄ and concentrated to dryness to give 126.4 g of the title compound (representing a 95% yield). ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.4 Hz, 1 H), 7.11 (m, 3H), 6.6 (d, J= 5.70 Hz, 2H), 6.45 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 3.80 (m, 2H), 3.04-1.48 (m, 11 H).

Preparation 6: (4βS,7f?,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5_J6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,8αf?)-methyl 4β-benzyl-7-oxo-4β,5,6,7,8_I8α,9,10-octahydrophenanthrene-2-carboxylate (118g, 0.339 mole, which may be prepared as described in Preparation 5) dissolved in dichloromethane was chilled to -5O⁰C. The solution became turbid. 1.0 M Tetrabutylammonium fluoride a solution in THF (3.4 ml, 0.003 mol) was added with no appreciable temperature change. Trifluorotrimethylsilane (79 ml, 0.51 mol) was added over 20 minutes with a color change to bright orange to light red in color. The reaction mixture was held at -50 ⁰C for about 2 hours and then allowed to warm to 0 ⁰C.
Tetrabutylammonium fluoride (340 ml, 0.34 moles) was added very slowly at 0 ⁰C, to the reaction mixture over 45 minutes. An exotherm was observed with gas evolution. The reaction mixture was stirred 10 minutes and HPLC analysis indicated complete desilylialation. Water (1 L) was added to the reaction mixture and with vigorous stirring and allowed to warm to room temperature. The organic layer was washed with water (1 L). The organic layer was concentrated and chromatographed to produce 72 g, 51 % of the title compound, with an additional 32 g of impure product. ¹H NMR (DMSO) δ ppm: 7.70 (s, 1 H), 7.37 (d, J=8.1 Hz, 1 H)₁ 7.09 (m, 3H), 6.5 (dd, J=1.2, 6.6 Hz, 2H), 6.38 (d, J=8.4 Hz, 1 H), 3.80 (s, 3H), 3.80 (m, 2H), 3.09-1.21 (m, 13H).

Preparation 7: (4βS,7/?,8α/?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β₎5,6,7₎8,8α,9,10-octahydrophenanthrene-2-carboxylate (5.0 g; 11.9 mmol, which may be prepared as in Preparation 6) and 5-methyltetrazole (3.6 g; 43.0 mmol) were mixed together in dichloromethane (50 mL) at ambient temperature. Dibenzylphosphoramidite (8.3 mL; 25.1 mmol) was added and the mixture was stirred until the reaction was completed (1 hour). The mixture was chilled to 0⁰C and 30% hydrogen peroxide (10 mL) was added. The reaction was stirred until the oxidation was completed (30 minutes). The aqueous phase was separated from the organic phase. The organic phase was washed with 10% sodium meta-bisulfite (50 ml_). The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 15% ethyl acetate in hexanes. The purified title compound (8.41 g; 94% yield) was obtained as a colorless oil that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.31 (t, 1 H), 1.63-1.92 (m, 3H), 2.05-2.35 (m, 3H), 2.63 (d, 1 H), 2.75-3.16 (m, 4H), 3.80 (s, 3H), 5.13 (m, 4H), 6.43 (d, 1 H), 6.49 (m, 2H), 7.04-7.17 (m, 3H), 7.33-7.42 (m, 12H), 7.71 (d, 1 H).

Preparation 8: dibenzyl (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-o yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yI phosphate

The (4βS,7R,8αf?)-methyl 4β-benzyl-7-(bis(benzyloxy)phosphoryloxy)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (7.9 g; 11.6 5 mmol, which may be prepared as in Preparation 7) and 3-amino-2-picoline (1.3 g; 12.2 mmol) were mixed together in tetrahydrofuran (80 ml_) and chilled to 0°C. The 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (24 ml_; 24.4 mmol) was added while maintaining the temperature below 10⁰C. The mixture was stirred for 30 minutes. Water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic extract was washed with water. The organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography with 70% ethyl acetate in hexanes. The purified title compound (6.79 g; 68% yield) was obtained as a yellow gum that contained 6% ethyl acetate by weight. ¹H NMR (DMSO): δ 1.33 (t, 1 H), 1.66-1.93 (m, 3H), 2.08-2.34 (m, 3H), 2.41 (s, 3H), 2.68 (d, 1 H), 2.76-3.19 (m, 4H), 5.14 (m, 4H), 6.47 (d, 1 H), 6.56 (m, 2H), 7.07-7.19 (m, 3H), 7.20-7.53 (m, 12H), 7.71 (d, 1 H), 7.76 (s, 1 H), 8.32 (d, 1 H), 9.93 (s, 1 H).

Example 1 : (4βS,7/?,8αR)-4β-benzyl-7-hydroxy-W-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7ft,8αR)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 mL; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 mL) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 mL) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 mL). Solvent (230 mL) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1 H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1H), 7.44 (dd, 1H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-i ,2,3,4,4α,9,10,1 Oα-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS, 10αR)-4α-bθnzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2-(trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 70⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1.33 (t, 1 H)₁ 1.69-1.98 (m, 3H), 2.07-2.29 (m, 3H)₁ 2.42 (s, 3H), 2.61-2.80 (m, 2H)₁ 2.93-3.19 (m, 3H)₁ 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

PATENT

WO 2008093236

http://www.google.co.in/patents/WO2008093236A1?cl=en

Example 1 : (4βS,7/?,8α/?)-4β-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-7- (trifluoromethyl)-4β,5,6,7,8,8α,9,10-octahydrophenanthrene-2-carboxamide

The (4βS,7R,8α/?)-methyl 4β-benzyl-7-hydroxy-7-(trifluoromethyl)-4β,5,6_J7,8,δα,9, 10- octahydrophenanthrene-2-carboxylate (10 g; 23.9 mmol, which may be prepared as described in Preparation 6), and 3-amino-2-picoline (2.71 g; 25.1 mmol) were dissolved in toluene (200 ml_). The 1 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (74.1 ml_; 74.1 mmol) was added at a rate such that the temperature was maintained below 35⁰C. There was a mild exotherm and a solid precipitated during the addition. The mixture was held an additional 30 minutes after the addition. Water (250 ml_) was added to the mixture. There was a mild exotherm and the solid dissolved. Ethyl acetate (50 ml_) was added to the mixture to ensure the product did not precipitate. Stirring was stopped to allow the phases to separate. The aqueous phase was removed. The organic phase was washed with water (250 ml_). Solvent (230 ml_) was distilled at atmospheric pressure from the organic phase. The mixture was cooled to ambient temperature. The mixture was filtered and the solid was washed with toluene (2 times) followed by heptane (2 times). The solid was dried in a vacuum oven at 70⁰C. The title compound of the present example (10 g) was obtained as a beige solid. ¹H NMR (DMSO) δ ppm: 1.32 (m, 1H), 1.82 (m, 4H), 2.10 (m, 4H), 2.41 (s, 3H), 2.68 (d, 1 H), 3.08 (m, 3H), 6.00 (s, 1 H), 6.43 (d, 1 H), 6.59 (m, 2H), 7.12 (m, 3H), 7.25 (dd, 1 H), 7.44 (dd, 1 H), 7.71 (dd, 1 H), 7.75 (d, 1 H), 8.31 (dd, 1 H), 9.91 (s, 1 H).

Example 2: (2f?,4αS,10α/?)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1,2,3,4,4α,9,10,10α-octahydrophenanthren-2-yl dihydrogen phosphate

The dibenzyl (2R,4αS,10αR)-4α-benzyl-7-((2-methylpyridin-3-yl)carbamoyl)-2- (trifluoromethyl)-1 ,2,3,4,4a,9,10,10a-octahydrophenanthren-2-yl phosphate (6 g; 7.9 mmol, which may be prepared as described in Preparation 8) was dissolved in methanol (120 ml_). 5% palladium on carbon (63% water) (1.3 g; 0.4 mmol) was added to the mixture. The mixture was treated with hydrogen (50 psi) at room temperature. The reaction stalled with 12% of the monobenzylic intermediate remaining. The mixture was filtered through a pad of Celite®. Fresh catalyst (1.3 g) was added to the solution and resubmitted to the hydrogenation conditions. Once the reaction was completed, the mixture was filtered through a pad of Celite®. The solution was concentrated to about 60 ml_ by distillation and not by using a rotary evaporator. During the distillation a white solid precipitated. The mixture was cooled to ambient temperature. The mixture was filtered and the solid washed with methanol. The solid was dried in a vacuum oven at 7O⁰C. The compound of the present example (3.36 g; 75% yield) was obtained as a white solid and had an LC purity of 98 area %. ¹H NMR (DMSO): δ 1 .33 (t, 1 H), 1 .69- 1.98 (m, 3H), 2.07-2.29 (m, 3H), 2.42 (s, 3H), 2.61 -2.80 (m, 2H), 2.93-3.19 (m, 3H), 3.30 (d, 1 H), 6.50 (d, 1 H), 6.64 (m, 2H), 7.08-7.20 (m, 3H), 7.29 (dd, 1 H), 7.48 (dd, 1 H), 7.75 (dd, 2H), 8.33 (dd, 1 H), 9.96 (s, 1 H).

REFERENCES

https://www.pfizer.com/sites/default/files/product-pipeline/July%2028%202015%20Pipeline%20Update.pdf

https://clinicaltrials.gov/ct2/show/NCT00938587

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Cc1c(cccn1)NC(=O)c2ccc3c(c2)CC[C@H]4[C@]3(CC[C@@](C4)(C(F)(F)F)OP(=O)(O)O)Cc5ccccc5

O=P(O)(O[C@@]1(C(F)(F)F)C[C@@]2([H])CCC3=C(C=CC(C(NC4=CC=CN=C4C)=O)=C3)[C@]2(CC5=CC=CC=C5)CC1)O

MELOXICAM

Meloxicam

351.40, C₁₄H₁₃N₃O₄S_{2, MP 255 °C}

(8E)-8-[hydroxy-[(5-methyl-1,3-thiazol-2-yl)amino]methylidene]-9-methyl-10,10-dioxo-10$l^{6}-thia-9-azabicyclo[4.4.0]deca-1,3,5-trien-7-one;

4-Hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide;

CAS 133687-22-6; Mobec;Mobic (TN);

2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-(5-methylthiazolyl)-, 1,1-dioxide;

The IUPAC name of Meloxicam is (3E)-3-[hydroxy-[(5-methyl-1,3-thiazol-2-yl)amino]methylidene]-2-methyl-1,1-dioxo-1λ6,2-benzothiazin-4-one. With the CAS registry number 71125-38-7, it is also named as 2H-1,2-Benzothiazine-3-carboxamide, 4-hydroxy-2-methyl-N-(5-methylthiazolyl)-, 1,1-dioxide.

Uses of Meloxicam: this chemical is a nonsteroidal anti-inflammatory drug with analgesic and fever reducer effects. And it inhibits cyclooxygenase that can be used as an anti-inflammatory. Additionally, it can be used for the treatment of rheumatoid arthritis and osteoarthritis.

In Europe, where the product has been available since the early 1990s, it is also prescribed and licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs and cats. For many years, both injectable and oral (liquid and tablet) formulations of meloxicam have been licensed for use in dogs, and injectable ones for use in cats. In June 2007, a new oral version of Metacam was licensed in Europe for the long-term relief of pain in cats. As of June 2008, Meloxicam is registered for long term use in cats in Australia, New Zealand, and throughout Europe. 'Metacam oral suspension 1.5 is not approved or recommended (according to the manufacture insert) for use in cats in the U.S.

1H NMR DMSOD6

13C NMR DMSOD6

Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic and fever reducer effects. It is a derivative of oxicam, closely related to piroxicam, and falls in the enolic acid group of NSAIDs.^[2] It was developed by Boehringer-Ingelheim. Meloxicam starts to relieve pain about 30–60 minutes after administration.^[3]

Mechanism of action

Main article: Non-steroidal anti-inflammatory drug

Meloxicam blocks cyclooxygenase (COX), the enzyme responsible for converting arachidonic acid into prostaglandin H₂—the first step in the synthesis of prostaglandins, which are mediators of inflammation. Meloxicam has been shown, especially at its low therapeutic doses, selectively to inhibit COX-2 over COX-1.^[1]

Meloxicam concentrations in synovial fluid range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown,^[2] but it may account for the fact that it performs exceptionally well in treatment of arthritis in animal models.^[4]

Side effects

Meloxicam use can result in gastrointestinal toxicity and bleeding, headaches, rash, and very dark or black stool (a sign of intestinal bleeding). Like other NSAIDs, its use is associated with an increased risk of cardiovascular events such as heart attack and stroke.^[5]It has fewer gastrointestinal side effects than diclofenac,^[6] piroxicam,^[7] naproxen,^[8] and perhaps all other NSAIDs which are not COX-2 selective.^[6] Although meloxicam does inhibit thromboxane A, it does not appear to do so at levels that would interfere withplatelet function.

A pooled analysis of randomized, controlled studies of meloxicam therapy of up to 60 days duration found that meloxicam was associated with a statistically significantly lower number of thromboembolic complications than the NSAID diclofenac (0.2% versus 0.8% respectively) but a similar incidence of thromboembolic events to naproxen and piroxicam.^[9]

Potential serious cardiovascular side effects

Persons with hypertension, high cholesterol, or diabetes are at risk for cardiovascular side effects. Persons with family history of heart disease, heart attack or stroke must tell their treating physician as the potential for serious cardiovascular side effects is significant.^[10][11]

Veterinary use

Meloxicam is also used in the veterinary field, most commonly in dogs and cats, but also sees off-label use in other animals such as cattle and exotics.^[12][13] The U.S. Food and Drug Administration sent a Notice of Violation to the manufacturer for its promotional materials which included promotion of the drug for off-label use.^[14] In the U.S. the drug is indicated for management of pain and inflammation associated with osteoarthritis in dogs only. In Europe, where the product has been available since the early 1990s,^{[citation needed]} it is also prescribed and licensed for other anti-inflammatory benefits including relief from both acute and chronic pain in dogs. Side effects in animals are similar to those found in humans; the principal side effect is gastrointestinal irritation (vomiting, diarrhea and ulceration). Rarer but important side effects include liver and kidney toxicity.

Since 2003, the oral (liquid) formulations of meloxicam have been licensed in the U.S for use in dogs only,^[15] with the January 2005 product insert specifically warning in bold-face type: "Do not use in cats."^[16] An injectable formulation for use in dogs was approved by the FDA in November 2003,^[17] with a formulation for cats, for surgical use only, approved in October 2004.^[18]

In the U.S., per the manufacturer's clinical instructions as of July 2010, injectable meloxicam is indicated in operative use with felines as a single, one-time dose only, with specific and repeated warnings not to administer a second dose.^[19] In June 2007, a new oral version of meloxicam was licensed in Europe for the long-term relief of pain in cats. As of June 2008, meloxicam is registered for long term use in cats in Australia, New Zealand, and throughout Europe. A peer-reviewed journal article cites feline overdose of NSAIDs, including meloxicam, as being a cause of severe kidney damage in cats.^[20]

The pharmacokinetics of meloxicam have been investigated in koalas (Phascolarctos cinereus).^[21]

Meloxicam has been investigated as an alternative to Diclofenac by the RSPB to prevent deaths of vultures.

Preparation of Meloxicam: this chemical can be prepared by Methyl 4-hydroxy-2-methyl-(2H)-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-Amino-5-methylthiazole. The yield is 74 %.

References

1.  Noble, S; Balfour, JA (March 1996). "Meloxicam.". Drugs 51 (3): 424–30; discussion 431–32. doi:10.2165/00003495-199651030-00007. PMID 8882380.
2.  "Meloxicam official FDA information, side effects, and uses". Drugs.com. March 2010. Retrieved 17 March 2010.
3.  Auvinet, B; Ziller, R; Appelboom, T; Velicitat, P (November–December 1995). "Comparison of the onset and intensity of action of intramuscular meloxicam and oral meloxicam in patients with acute sciatica.". Clinical Therapeutics 17 (6): 1078–98.doi:10.1016/0149-2918(95)80086-7. PMID 8750399.
4.  Engelhardt, G; Homma, D; Schlegel, K; Utzmann, R; Schnitzler, C (Oct 1995). "Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance". Inflammation Research 44 (10): 423–433. doi:10.1007/BF01757699. PMID 8564518.
5.  Stamm O, Latscha U, Janecek P, et al. (January 1976). "Development of a special electrode for continuous subcutaneous pH measurement in the infant scalp". Am. J. Obstet. Gynecol. 124 (2): 193–5. PMID 2012.
6.  Hawkey, C; Kahan, A; Steinbrü, K; Alegre, C; Baumelou, E; Bégaud, B; Dequeker, J; Isomäki, H; et al. (Sep 1998). "Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients". Rheumatology 37 (9): 937–945(9).doi:10.1093/rheumatology/37.9.937.
7.  Dequeker, J; Hawkey, C; Kahan, A; Steinbruck, K; Alegre, C; Baumelou, E; Begaud, B; Isomaki, H; et al. (1998). "Improvement in gastrointestinal tolerability of the selective cyclooxygenase (COX)-2 inhibitor, meloxicam, compared with piroxicam: results of the Safety and Efficacy Large-scale Evaluation of COX- inhibiting Therapies (SELECT) trial in osteoarthritis". The British Journal of Rheumatology 37 (9): 946–51.doi:10.1093/rheumatology/37.9.946. PMID 9783758.
8.  Wojtulewski, JA; Schattenkirchner, M; Barceló, P; Le Loët, X; Bevis, PJR; Bluhmki, E; Distel, M. "A Six-Month Double-Blind Trial to Compare the Efficacy and Safety of Meloxicam 7.5 mg Daily and Naproxen 750 mg Daily in Patients with Rheumatoid Arthritis".Rheumatology. 35, Supplement 1: 22–8. doi:10.1093/rheumatology/35.suppl_1.22.
9.  Singh, G; Lanes, S; Steinbrü, G; Triadafilopoulos (2004). "Gastrointestinal tolerability of meloxicam compared to diclofenac in osteoarthritis patients". Am J Med 117 (9): 100–6.doi:10.1016/j.amjmed.2004.03.012. PMID 15234645.
10.  "Medline Plus". Nlm.nih.gov. Retrieved 15 November 2014.
11.  "Drugs.com". Drugs.com. Retrieved 15 November 2014.
12.  Off-label use discussed in: Arnold Plotnick MS, DVM, ACVIM, ABVP, Pain Management using Metacam, and Stein, Robert, Perioperative Pain Management Part IV, Looking Beyond Butorphanol, Sep 2006, Veterinary Anesthesia & Analgesia Support Group.
13.  For off-label use example in rabbits, see Krempels, Dana, Hind Limb Paresis and Paralysis in Rabbits, University of Miami Biology Department.
14.  US FDA Notice of Violation for off-label use promotion, April 2005.
15.  "NADA 141-213: New Animal Drug Application Approval (for Metacam (meloxicam) 0.5 mg/mL and 1.5 mg/mL Oral Suspension)" (PDF). US Food and Drug Administration. April 15, 2003. Retrieved 24 July 2010.
16.  Metacam Client Information Sheet, product description: "Non-steroidal anti-inflammatory drug for oral use in dogs only", and in the "What Is Metacam" section in bold-face type: "Do not use in cats.", January 2005.
17.  "Metacam 5 mg/mL Solution for Injection" (PDF). Fda.gov. Retrieved 15 November2014.
18.  "Metacam 5 mg/mL Solution for Injection, Supplemental Approval" (PDF). Fda.gov. October 28, 2004. Retrieved 15 November 2014.
19.  See the manufacturer's FAQ on its website, and its clinical dosing instructions for cats.
20.  Merola, Valentina, DVM, DABT, and Dunayer Eric, MS, VMD, DABT, The 10 most common toxicoses in cats, Toxicology Brief, Veterinary Medicine, pp. 340–342, June, 2006.
21. Kimble, B.; Black, L. A.; Li, K. M.; Valtchev, P.; Gilchrist, S.; Gillett, A.; Higgins, D. P.; Krockenberger, M. B.; Govendir, M. (2013). "Pharmacokinetics of meloxicam in koalas ( ) after intravenous, subcutaneous and oral administration". Journal of Veterinary Pharmacology and Therapeutics 36 (5): 486–493. doi:10.1111/jvp.12038.PMID 23406022.

External links

• Manufacturer's Official Product Website for the Veterinary formulations
• Manufacturer's United States Division website for the Veterinary formulations
• FDA Metacam
• Meloxicam Side Effects

Meloxicam

Systematic (IUPAC) name
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.
Clinical data
Trade names	Mobic
AHFS/Drugs.com	monograph
MedlinePlus	a601242
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	89%[1]
Protein binding	99.4%[1]
Metabolism	Hepatic (CYP2C9 and 3A4-mediated)[1]
Biological half-life	20 hours[1]
Excretion	Urine and faeces equally[1]
Identifiers
CAS Number	71125-38-7
ATC code	M01AC06
PubChem	CID 5281106
IUPHAR/BPS	7220
DrugBank	DB00814
ChemSpider	10442740
UNII	VG2QF83CGL
KEGG	D00969
ChEBI	CHEBI:6741
ChEMBL	CHEMBL599
PDB ligand ID	MXM (PDBe, RCSB PDB)
Chemical data
Formula	C14H13N3O4S2
Molar mass	351.403 g/mol

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