Supplemental Information for: METABOLISM OF RAMELTEON IN HUMAN LIVER MICROSOMES AND CORRELATION WITH...

Supplemental Information for: METABOLISM OF RAMELTEON IN HUMAN LIVER

MICROSOMES AND CORRELATION WITH THE EFFECT OF FLUVOXAMINE ON RAMELTEON

PHARMACOKINETICSby R. Scott Obach and Tim F. Ryder

Drug Metabolism and Disposition

Figures S1a-S8d: Mass spectral and NMR spectral data for ramelteon metabolites

100 150 200 250 300m/z

200000

400000

600000

200000

400000

600000

800000

1000000

500000

1000000

282261305

283262153 171 230204190 242 307216204

161 187169 242133 260205140105 218126187

159204161133 175143117 252 274

NL: 1.39E620091125a-12#3384-3426 RT: 36.65-37.04 AV: 5 F: ITMS + c ESI Full ms [150.00-360.00]

NL: 1.07E620091125a-12#3382-3428 RT: 36.65-37.04 AV: 5 F: ITMS + c ESI d Full ms2 260.17@cid22.00 [60.00-275.00]

NL: 6.73E520091125a-12#3379-3430 RT: 36.61-37.08 AV: 6 F: ITMS + c ESI d Full ms3 260.21@cid22.00 204.12@cid22.00 [50.00-420.00]

MS2dau 260

MS3dau 204

Figure S-1a; Ramelteon

m/z 204

m/z 187

m/z 159

Ramelteon NMR Assignments

0.99,10.1

2.06,28.5

3.09,36.8

1.93, 1.43,32.8

4.51, 4.42,70.6 3.16,

3.06,27.9

6.89,122.7

6.52,106.5

2.79,2.65,29.9

2.17,1.71,31.2

3.12,41.5

158.9122.2

COSY: Black ArrowsHMBC: Red Arrows

Figure S-1b

1H NMR Spectrum of RamelteonFigure S-1c

COSY NMR Spectrum of RamelteonFigure S-1d

HSQC NMR Spectrum of RamelteonFigure S-1e

HMBC NMR Spectrum of RamelteonFigure S-1f

100 150 200 250 300m/z

200000

400000

600000

500000

1000000

298277299278224153 250204171 191 260

161 204187 230104 133 240 276156159

161204

187 230169

133 240229157 258199112 281159

131141144129 160

NL: 1.71E320091125a-12#2993-3034 RT: 32.50-32.79 AV: 3 F: ITMS + c ESI d Full ms4 276.21@cid22.00 159.17@cid22.00 159.09@cid22.00 [50.00-330.00]

MS2dau 276

MS3dau 258

MS4dau 159

Figure S-2a; Metabolite A

1.94,20.9

3.93,67.1

3.13,36.5

1.94, 1.48,32.7

4.51, 4.45,70.4 3.20,

3.06,27.7

6.89,122.7

6.52,106.5

2.79,2.66,29.9

2.19,1.73,31.1

3.09,41.5

COSY: Black Arrows

Figure S-2b; Metabolite A

1H NMR Spectrum

Figure S-2c; Metabolite A

COSY NMR Spectrum

Figure S-2d; Metabolite A

HSQC NMR Spectrum

Figure S-2e; Metabolite A

Figure S-3a; Metabolite B

100 150 200 250 300m/z

100000

150000

100000

150000

259 276 299153 171 190 260215 230 277195 249202

185 240171159 258213131 223140123104185

202159173131 186155 203117

MS2dau 258

MS3dau 202

0.99,9.4

2.07,28.3

5.94,100.7

6.91,122.6

2.18,1.71,31.2

3.09,41.1

6.53,106.5

1.91, 1.43,32.7

3.09,36.9

3.22,35.9

2.79,2.66,29.8

HO 7.17, 7.09

COSY: Black Arrows

Figure S-3b; Metabolite B

1H NMR Spectrum

Figure S-3c; Metabolite B

1H NMR Spectrum Showing Diastereomeric Mixture

Hydroxyl Proton 1

Hydroxyl Proton 2

Extra coupling of the aromatic doublets

Methine

Figure S-3d; Metabolite B

COSY NMR Spectrum

Figure S-3e; Metabolite B

HSQC NMR Spectrum

Figure S-3f; Metabolite B

100 150 200 250 300m/z

100000

150000

100000

200000

300000

100000

200000

300000

400000258

298259153 299260190171 230215202 269255 283

185 240171159 258213 223131 140185

202159173131 155 267108

Figure S-4a; Metabolite C

MS2dau 258

MS3dau 202

0.98,10.0

2.05,28.2

4.46,4.20,78.8

7.03,124.8

2.17,1.74,31.0

3.28,41.0

6.59,107.4

2.00, 1.53,32.7

3.10,36.9

5.36,68.9

2.80,2.67,29.9

COSY: Black Arrows

Figure S-4b; Metabolite C

1H NMR Spectrum

Figure S-4c; Metabolite C

COSY NMR Spectrum

Figure S-4d; Metabolite C

HSQC NMR Spectrum

Figure S-4e; Metabolite C

100 150 200 250 300m/z

100000

200000

300000276

277298274153 171 278230190 256238215209 308

258189177 203159149 229 276140 247110 129 286157 185

167142129

183115 186

Figure S-5a; Metabolite D

MS2dau 276

MS3dau 185

COSY: Black Arrows

1.87, 1.41

4.51, 4.45,

3.20,3.06,

6.43,6.03

2.72,2.62?

2.14,1.65

Figure S-5b; Metabolite D

1H NMR Spectrum

Figure S-5c; Metabolite D

1H NMR Spectrum Showing the Ratio of Regioisomers

New Aromatic Singlet Together integrate to about 1

Figure S-5d; Metabolite D

COSY NMR Spectrum

Figure S-5e; Metabolite D

100 150 200 250 300m/z

100000

150000

200000

250000

298259159153 299171 190 260230 274215195 249 290159

185240202 215160 258230141133110 149

129117 160157

Figure S-6a; Metabolites E and F

MS2dau 258

MS3dau 159

1.88, 1.37

4.54,4.45,

2.07,1.93

2.04, 1.50

5.01,4.86

2.50,1.49

5.11, 4.96

COSY: Black Arrows

Figure S-6b; Metabolites E and F

1H NMR Spectrum

Figure S-6c; Metabolites E and F

1H NMR Spectrum Shows Diastereomeric Mixture

Hydroxyl Proton 1

Methine 1Hydroxyl Proton 2

Methine 2

Figure S-6d; Metabolites E and F

COSY NMR Spectrum

Figure S-6f; Metabolites E and F

100 150 200 250 300m/z

100000

274185 298

259153 190171 275230215 260 299195 249

159 202 240215104 258173 229138121 269185

167142129 183115 186 208 249

Figure S-7a; Metabolite G

MS2dau 258

MS3dau 185

0.95,9.7

2.01,28.1

4.50,4.45,70.6

6.89,123.1

2.18,1.71,39.9

6.60,107.4

1.89,1.75,38.7

3.06,34.7

3.19,3.27,27.1

2.79,2.66,28.1

COSY: Black Arrows

Figure S-7b; Metabolite G

1H NMR Spectrum

Figure S-7c; Metabolite G

COSY NMR Spectrum

Figure S-7d; Metabolite G

HSQC NMR Spectrum

Figure S-7e; Metabolite G

No Methine

100 120 140 160 180 200 220 240 260 280 300m/z

258275153 185171 190 296230 291259238151 215 305

200185157 228104 257171 274238131 145121183

238157 200 211155 228171 239199133108 257117

Figure S-8a; Metabolite H

MS2dau 274

MS3dau 256

2.05, 1.46

4.70,4.65,

2.76,2.36

COSY: Black Arrows

Figure S-8b; Metabolite H

1H NMR Spectrum

Figure S-8c; Metabolite H

COSY NMR Spectrum

Figure S-8d; Metabolite H

Supplemental Information for: METABOLISM OF RAMELTEON IN HUMAN LIVER MICROSOMES AND CORRELATION WITH...

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