(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bmeau
`
`11111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2016/063995 Al
`
`(43) International Publication Date
`28 April2016 (28.04.2016)
`
`(51) International Patent Classification:
`A61K 311506 (2006.01)
`A61P 25120 (2006.01)
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`PCT /JP20 15/080304
`
`21 October2015 (21.10.2015)
`
`English
`
`English
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,AT,AU,AZ,BA,BB,BG,BH,BN,BR,BW,BY,
`BZ,CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LU, L Y, MA, MD, ME, MG,
`MK, MN, fviW, MX, MY, MZ, NA, NG, Nl, NO, NZ, OM,
`PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC,
`SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, v'N, ZA, ZM, ZW.
`us (84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, l\1Z, NA, RW, SD, SL, ST, SZ,
`TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU,
`TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE,
`DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, Sl, SK,
`SM, TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ,
`GW, KM, ML, MR, NE, SN, TD, TG).
`
`(30) Priority Data:
`62/067,443
`
`23 October 2014 (23.10.2014)
`
`(71) Applicant: EISAI R&D MANAGEMENT CO., LTD.
`[JP/JP]; 6-10 Koishikawa, 4-chome, Bunkyo-ku, Tokyo,
`1128088 (JP).
`
`(72) Inventors: MOLINE c\fargaret; c/o Eisai Inc., 100 Tice
`Boulevard Woodcliff Lake, New Jersey 07677 (US).
`P ASTINO Gina; c/o Eisai Inc., 100 Tice Boulevard
`Woodcliff Lake, New Jersey 07677 (US). AKIMOTO
`Yurie; c/o Eisai Co., Ltd., Kawashima Industrial Complex,
`1, Kawashimatakehaya-machi, Kakamigahara-shi, Gifu,
`5016195 (JP).
`
`(74) Agent: SHIGA Masatake; 1-9-2, Marunouchi, Chiyo(cid:173)
`da-ku, Tokyo, 1006620 (JP).
`
`;;;;;;;;;;;;;;; -
`;;;;;;;;;;;;;;; -
`-;;;;;;;;;;;;;;;
`
`;;;;;;;;;;;;;;;
`
`Published:
`
`with international search report (Art. 21 (3))
`
`with amended claims and statement (Art. 19(1))
`
`(54) Title: COMPOSITIONS AND METHODS FOR TREATING INSOMNIA
`
`(57) Abstract: In the present invention, compound such as (lR,2S)-2-(((2,4-dimethylpyrimidin-5-yl)oxy)methyl)-2-(3-fluorophenyl)(cid:173)
`N-(5-fluoropyridin-2-yl) cyclopropanecarboxamide have been found to be potent orexin receptor antagonists, and may be useful in
`the treatment of sleep disorders such as insomnia, as well as tor other therapeutic uses.
`
`Page 1 of 72
`
`EISAI EXHIBIT 1007
`
`

`

`wo 2016/063995
`
`PCT /JP20 15/080304
`
`DESCRIPTION
`
`COMPOSITIONS AND METHODS FOR TREATING INSOMNIA
`
`FIELD OF THE INVENTION
`
`[000 1] The present invention is directed to compositions and methods for treating insomnia. The present
`
`application claims priority on the basis of US Patent Application No. 62/067,443, filed in the United
`
`States on October 23, 2014, the contents of which are incorporated herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Orexin receptors are G-protein coupled receptors found predominately in the brain. Their
`
`endogenous ligands, orexin-A and orexin-B, are expressed by neurons localized in the hypothalamus.
`
`Orexin-A is a 33 amino acid peptide; orexin-B consists of28 amino acids (Sakurai T. et al., Cell, 1998,
`
`92 573-585). There are two subtypes of orexin receptors, orexiri receptor 1 (hereinafter referred to as
`
`OXI) and orexin receptor 2 (hereinafter referred to as OX2); OXI binds orexin-A preferentially, while
`
`OX2 binds both orexin-A and -B. Orexins stimulate food consumption in rats, and it has been suggested
`
`that orexin signaling could play a role in a central feedback mechanism for regulating feeding behavior
`
`(Sakurai et al., supra). It has also been observed that orexins control wake-sleep conditions (Chemelli
`
`R.M. et al., Cell, 1999, 98, 437-451). Orexins may also play roles in brain changes associated with opioid
`
`and nicotine dependence (S.L. Borgland et al., Neuron, 2006, 49, 598-601; C.J. Winrow et al.,
`
`Neuropharmacology, 2010, 58, 185-194), and ethanol dependence (J.R. Shoblock et al.,
`
`Psychopharmacology, 2011, 215, 191-203). Orexins have additionally been suggested to play a role in
`
`some stress reactions (T. Ida et al., Biochem. Biophys. Res. Commun., 2000,270, 318-323). Compound
`
`such as
`
`( 1 R,2S )-2-( ( (2,4-dimethylpyrimidin-5-y l)oxy )me thy 1)-2-(3-fluoropheny 1)-N -( 5-fluoropyridin-2-yl)
`
`cyclopropanecarboxamide (hereinafter referred to as Compound A) have been found to be potent orexin
`
`receptor antagonists, and may be useful in the treatment of sleep disorders such as insomnia, as well as
`
`for other therapeutic uses.
`
`[0003] The Formula of Compound A
`
`1
`
`Page 2 of 72
`
`

`

`wo 2016/063995
`
`PCT I JP2015/080304
`
`[0004] Regarding the hypnotic agent, when an active pharmaceutical ingredient (hereinafter referred to as
`
`API) in a pharmaceutical formulation to be taken a once-a-night dosing is too high a dose, it has the
`
`potential to cause the next-day residual sleepiness, while the single insufficient dose may cause the
`
`patient to wake up during normal sleep period even if the patients are able to fall sleep with the hypnotic.
`
`Therefore, it is difficult to set the proper dose with considering the sensitive balance between easy of
`
`sleep onset and the avoidance of the residual sleepiness, as compared with the considering only the
`
`balance between side effects and efficacy. Furthermore, even if the dose of a certain drug for insomnia,
`
`the physiochemical properties of the API and the pharmacokinetic (hereinafter referred to as PK) profile
`
`after administration of the drug were known, such information would not be applicable to other APis for
`
`insomnia because it would be likely effected by a number of factors, including the mechanism of action,
`
`the route of administration, the rate of absorption, the physiochemical property such as the solubility and
`
`the stability in plasma or other factors of each API.
`
`Indeed, the relationship between the residual
`
`sleepiness and the characteristics of the hypnotic agents is not always consistent (CNS Drugs 2004; 18
`
`(5): 297-328). The relation between PK profile and the sleepiness effect such as the sleep onset or the
`
`residual sleepiness has been unknown yet for compound A.
`
`[0005] There exists a need in the art for more effective methods of treating insomnia to achieve rapid
`
`sleep onset as well as sleep maintenance, throughout the sleep period, but avoid residual sleepiness and/or
`
`the next-day impairment, comprising administrating orally a solid dosage form of a hypnotic agent.
`
`Further, there exists a need in the art for a pharmaceutical composition comprising a hypnotic agent and
`
`at least one pharmaceutically acceptable excipient for the treatment of insomnia to achieve rapid sleep
`
`onset as well as sleep maintenance, throughout the sleep period, but avoid residual sleepiness and/or
`
`..
`
`next-day impairment.
`
`SUMMARY OF THE INVENTION
`
`[0006] It is an object of the present invention to provide methods of treating insomnia comprising
`
`administrating orally a solid dosage form of the drug compound A.
`
`2
`
`Page 3 of 72
`
`

`

`wo 2016/063995
`
`PCT/JP2015/080304
`
`[0007] It is further an object of the present invention to provide a pharmaceutical composition,
`
`comprising a therapeutically effective amount of compound A
`
`[0008] In certain embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose ranging from about 1 mg to about 15 mg.
`
`[0009] In certain embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose ranging from about 2 mg to about 15 mg.
`
`[0010] In certain embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose ranging from about 2 mg to about 10 mg.
`
`[00 11] In certain embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose chosen from about 2, 2.5, 4, 5, 8, 10, or 15 mg.
`
`[00 12] In certain embodiment, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose providing a mean maximum plasma concentration
`
`(Cmax) of from about 3.0 ng/ml to about 7.2 ng/ml for each 1 mg of compound A, after single dose
`
`administration to human subjects.
`
`[0013] In certain embodiment, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose ranging from about 1 mg to about 15 mg, and
`
`wherein said single daily dose achieves a mean maximum plasma concentration (Cmax) of from about 3.0
`
`ng/ml to about 7.2 ng/ml for each 1 mg of compound A, after single dose administration to human
`
`subjects.
`
`[00 14] In certain embodiment, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 1 mg daily dose, and wherein said single dose achieves a mean
`
`3
`
`Page 4 of 72
`
`

`

`wo 2016/063995
`
`PCT/JP2015/080304
`
`maximum plasma concentration (Cmax) within the range of about 80% to about 125% of 5.3 ng/ml, after
`
`single dose administration to human subjects.
`
`[0015] In certain embodiment, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 2.5 mg daily dose, and wherein said single daily dose achieves a
`
`mean maximum plasma concentration (Cmax) within the range of about 80% to about 125% of 16 ng/ml,
`
`after single dose administration to human subjects.
`
`[0016] In certain embodiment, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 5 mg daily dose, and wherein said single daily dose achieves a
`
`mean maximum plasma concentration (Cmax) of within the range of about 80% to about 125% of 23
`
`ng/ml, after single dose administration to human subjects.
`
`[00 17] In certain embodiment, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 10 mg daily dose, and wherein said single daily dose achieves a
`
`mean maximum plasma concentration (Cmax) within the range of about 80% to about 125% of 36 ng/ml,
`
`after single dose administration to human subjects.
`
`[0018] In further embodiments, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose to achieve a mean AUC(0-24) of from about 15.9
`
`ng*hr/ml to about 23.8 ng*hr/ml for each 1 mg of compound A, after single dose administration to human
`
`subjects.
`
`[0019] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 1 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(0-24) within the range of about 80% to about 125% of 17 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0020] In further embodiments, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 2.5 mg daily dose, and wherein said single daily dose achieves a
`
`4
`
`Page 5 of 72
`
`

`

`wo 2016/063995
`
`PCT/JP2015/080304
`
`mean AUC(0-24) within the range of about 80% to about 125% of 57 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0021] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 5 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(0-24) within the range of about 80% to about 125% of 95 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0022] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 10 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(0-24) within the range of about 80% to about 125% of 159 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0023] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose to achieve a mean AUC(O-t) of from about 19.1
`
`ng*hr/ml to about 51.1 ng*hr/ml for each 1 mg of compound A, after single dose administration to human
`
`subjects.
`
`[0024] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single I mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-t) within the range of about 80% to about 125% of 19 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0025] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 2.5 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-t) within the range of about 80% to about 125% of 80 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`(0026] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 5 mg daily dose, and wherein said single daily dose achieves a
`
`5
`
`Page 6 of 72
`
`

`

`wo 2016/063995
`
`PCT /JP2015/080304
`
`mean AUC(O-t) within the range of about 80% to about 125% of 128 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0027] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 10 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-t) within the range of about 80% to about 125% of 284 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0028] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose to achieve a mean AUC(O-inf) of from about 19.8
`
`ng*hr/ml to about 53.1 ng*hr/ml for each 1 mg of compound A, after single dose administration to human
`
`subjects.
`
`[0029] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 1 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-inf) within the range of about 80% to about 125% of 20 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0030] In further embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 2.5 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-inf) within the range of about 80% to about 125% of 80 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0031] In further embodiments, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 5 mg daily dose, and wherein said single daily dose achieves a
`
`mean AUC(O-inf) within the range of about 80% to about 125% of 149 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0032] In further embodiments, the present invention to provide methods oftreating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single 10 mg daily dose, and wherein said single daily dose achieves a
`
`6
`
`Page 7 of 72
`
`

`

`wo 2016/063995
`
`PCT I JP2015/080304
`
`mean AUC(O-inf) within the range of about 80% to about 125% of 311 ng*hr/ml, after single dose
`
`administration to human subjects.
`
`[0033] In certain embodiments, the present invention to provide methods of treating insomnia, comprises
`
`administrating orally a dosage form with a therapeutically effective amount of compound A, wherein said
`
`therapeutically effective amount is single daily dose ranging from about 1 mg to about 15 mg, and
`
`wherein said single daily dose provides a mean plasma compound A concentration of about 20 ng!ml or
`
`less at from 8 to 10 hours after single dose administration to human subjects.
`
`[0034] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose ranging from
`
`about 1 mg to about 15 mg.
`
`[0035] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose to achieve a mean
`
`maximum plasma concentration (Cmax) of from about 3.0 ng!ml to about 7.2 ng!ml for each 1 mg of the
`
`drug, after single dose administration to human subjects.
`
`[0036] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single I mg daily dose, and wherein
`
`said single daily dose achieves a mean maximum plasma concentration (Cmax) within the range of about
`
`80% to about 125% of 5.3 ng!ml, after single dose administration to human subjects.
`
`[0037] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 2.5 mg daily dose, and
`
`wherein said single daily dose achieves a mean maximum plasma concentration (Cmax) within the range
`
`of about 80% to about 125% of 16 ng!ml, after single dose administration to human subjects.
`
`[0038] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 5 mg daily dose, and wherein
`
`said single daily dose achieves a mean maximum plasma concentration (Cmax) within the range of about
`
`7
`
`Page 8 of 72
`
`

`

`wo 2016/063995
`
`PCT I JP2015/080304
`
`80% to about 125% of23 ng/ml, after single dose administration to human subjects.
`
`[0039] In another embodiment, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 10 mg daily dose, and
`
`wherein said single daily dose achieves a mean maximum plasma concentration (Cmax) within the range
`
`of about 80% to about 125% of 36 ng/ml, after single dose administration to human subjects.
`
`[0040] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose providing a mean
`
`AUC(0-24) of from about 15.9 ng*hr/ml to about 23.8 ng*hr/ml for each 1 mg of the drug, after single
`
`dose administration to human subjects.
`
`[0041] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 1 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(0-24) within the range of about 80% to about 125% of 17
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0042] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 2.5 mg daily dose, and
`
`wherein said single daily dose achieves a mean AUC(0-24) within the range of about 80% to about 125%
`
`of 57 ng*hr/ml, after single dose administration to human subjects.
`
`[0043] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 5 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(0-24) within the range of about 80% to about 125% of 95
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0044] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 10 mg daily dose, and
`
`wherein said single daily dose achieves a mean AUC(0-24) within the range of about 80% to about 125%
`
`8
`
`Page 9 of 72
`
`

`

`wo 2016/063995
`
`PCT/JP2015/080304
`
`of 159ng*hr/ml, after single dose administration to human subjects.
`
`[0045] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose providing a mean
`
`AUC(O-t) of from about 19.1 ng*hr/ml to about 51.1 ng*hr/ml for each I mg of the drug, after single dose
`
`administration to human subjects.
`
`[0046] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 1 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(O-t) within the range of about 80% to about 125% of 19
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0047] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 2.5 mg daily dose, and
`
`wherein. said single daily dose achieves a mean AUC(O-t) within the range of about 80% to about 125%
`
`of 80 ng*hr/ml, after single dose administration to human subjects.
`
`[0048] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 5 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(O-t) within the range of about 80% to about 125% of 128
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0049] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 1 0 mg daily dose, and
`
`wherein said single daily dose achieves a mean AUC(O-t) within the range of about 80% to about 125%
`
`of284 ng*hr/ml, after single dose administration to human subjects.
`
`[0050] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose providing a mean
`
`AUC(O-inf) of from about 19.8 ng*hr/ml to about 53.1 ng*hr/ml for each 1 mg of the drug, after single
`
`9
`
`Page 10 of 72
`
`

`

`wo 2016/063995
`
`PCT /JP2015/080304
`
`dose administration to human subjects.
`
`[0051] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 1 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(O-inf) within the range of about 80% to about 125% of 20
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0052] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 2.5 mg daily dose, and
`
`wherein said single daily dose achieves a mean AUC(O-inf) within the range of about 80% to about 125%
`
`of 80 ng*hr/ml, after single dose administration to human subjects.
`
`[0053] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 5 mg daily dose, and wherein
`
`said single daily dose achieves a mean AUC(O-inf) within the range of about 80% to about 125% of 149
`
`ng*hr/ml, after single dose administration to human subjects.
`
`[0054] In further embodiments, the present invention provides an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single 10 mg daily dose, and
`
`wherein said single daily dose achieves a mean AUC(O-inf) within the range of about 80% to about 125%
`
`of 311 ng*hr/ml, after single dose administration to human subjects.
`
`[0055] In certain embodiments, the present invention to provide an oral dosage form for treating insomnia
`
`comprising a therapeutically effective amount of compound A and at least one pharmaceutically
`
`acceptable excipient, wherein said therapeutically effective amount is single daily dose ranging from
`
`about 1 mg to about 15 mg, and wherein said single daily dose provides a mean plasma compound A
`
`concentration of about 20 ng/ml or less at from 8 to 10 hours after single dose administration to human
`
`subjects.
`
`[0056] In certain embodiments, the present invention is directed to an oral pharmaceutical dosage form
`
`comprising a pharmaceutically acceptable excipient and an effective amount of compound A for treating
`
`insomnia, the dosage form providing an dissolution rate of 85 % or more in dissolution medium (0.1
`
`10
`
`Page 11 of 72
`
`

`

`wo 2016/063995
`
`PCT/ JP20 15/080304
`
`mol!L hydrochloric acid containing 0.5% polysorbate 80, 900 mL, 37 ± 0.5°C) within 30 minutes from
`
`the onset of dissolution study using the Apparatus 2 (Paddle Apparatus, paddle speed; 75 rpm) according
`
`to the procedure for immediate-release dosage form in 6.10 Dissolution test of JP16 or <711> Dissolution
`
`ofUSP37.
`
`[0057] In certain embodiments, the present invention is directed to an oral pharmaceutical dosage form
`
`comprising a pharmaceutically acceptable excipient and an effective amount of compound A for treating
`
`insomnia, the dosage form providing an dissolution rate of 85 % or more in dissolution medium (0.1
`
`mol!L hydrochloric acid, 900 mL, 37 ± 0.5°C) within 15 minutes from the onset of dissolution study
`
`using the Apparatus 2 (Paddle Apparatus, paddle speed; 50 rpm) according to the procedure for
`
`immediate-release dosage form in 6.10 Dissolution test ofJP16 or <711> Dissolution ofUSP37.
`
`[0058] In certain embodiments, the present invention is directed to an oral pharmaceutical dosage form
`
`comprising lactose as pharmaceutically acceptable excipient.
`
`[0059] In certain embodiments, the present invention is directed to an oral pharmaceutical dosage form
`
`comprising low-substituted hydroxypropyl cellulose as pharmaceutically acceptable excipient.
`
`[0060] In certain embodiments, the present invention is directed to an oral pharmaceutical dosage form
`
`comprising lactose and low-substituted hydroxypropyl cellulose as pharmaceutically acceptable excipient.
`
`[0061] The method according to the present invention has a potential use of the treatment of insomnia
`
`with easy of sleepiness onset, but the avoidance of residual sleepiness and/or the next-day impairment.
`
`[0062] The pharmaceutical composition according to the present invention has a potential use of an oral
`
`solid dosage for the treatment of insomnia.
`
`DETAILED DESCRIPTION
`
`I. Definitions
`
`[0063] In order the invention described herein may be more fully understood, the following definitions
`
`are provided for the purposes of the disclosure:
`
`[0064] The term "effective amount" means an amount of drug of compound A that is capable of
`
`achieving a therapeutic effect in a human subjective in need thereof.
`
`[0065]The term "drug of compound A" shall mean (lR, 2S)-2-(((2,4-dimetylpyrimidin-5-yl)oxy)
`
`11
`
`Page 12 of 72
`
`

`

`wo 2016/063995
`
`PCT /JP20 15/080304
`
`methyl)-2-(3-fluorophenyl)-N-(5-flu