(ll) INTERNATIONAL t\)1PLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`
`International Bureau • . 11111111111111111111mrn 1111110111~011mn111111n11m11
`PCT
`
`(43) IntemationaJ Publication Date
`11 August 2005 (11.08.2005)
`
`(10) IntemationaJ Publication Number
`WO 2005/072740 A2
`
`(74) Agent: TAKASHIMA, Hajlme; ·Meiji Yasuda Seimei
`Osaka Midosuji Bldg.,, 1-1, Fushimimachi 4-chome,,
`Chuo-ku, Osaka-shi, Osaka, 5410044 (JP).
`·
`
`(81) Designated Slates (IUl/ess olherwi~e indicated, for every
`kind of national protection available): AB, AG, AL, AM;
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ,.CA, CH; CN,
`CO, CR. CU, CZ. DB, DK. DM, DZ. EC, EE, EO, ES, FI.
`GB, GD, GB, GH, GM, HR, HU, ID, Il., IN, IS, JP. KB,
`KO, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SB, SO, SK, SL,SY, TJ, TM,
`TN, 'Ill. TT, TZ, UA, UG, US, UZ. VC, VN, W, ZA, ZM,
`ZW.
`
`(84) Designated States (Mnkss otherwise indicated, for t!Very
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ. TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BB, BG, CH, CY, CZ. DE, DK, BE, BS, FI.
`FR, GB, GR, HU, IE, IS, ff, LT, LUi MC, NL, PL, PT; RO,
`SE, SI, SK, TR), OAPI (BP, BJ, CP. CG, Cl, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international sean:h reporr and to be repllhllshed
`upon receipt of 11uu reporr
`
`For two-lener codes and other abbreviations, refer 10 the "Guid(cid:173)
`ance Notes on Codes and Abbnviation.s" appearing at the begin(cid:173)
`ning of each regMlar lssire of the PCT Ga~ne.
`
`(Sl) lnternaUonal Patent Classl6cation1: A61K 3VS383,
`31150, 31140, 311235, 31fl0, 311436, A61P 3104
`
`(21) lntcrnaUonal Applicadon Number:
`PCT/JP200S/001643
`
`(22) lntemaUonal Filing Date: 28 January 2005 (28.01.2005)
`
`(25) Filing Language:
`
`(2') Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`2004-024812
`60/598,037
`
`30 Janumy 2004 (30.01.2004)
`JP
`2 August 2004 (02.08.2004) US
`
`-
`
`(71) Applicants (for all designated States e;ccept US): JAPAN
`
`nato-ku, Tokyo, 1058422 (JP). Amgen SF, LLC [US/US];
`
`;;;;;;;;;;;
`
`913201799 (US).
`
`(72) Inventors; and
`
`-
`
`[JP/JP]; c/o Centtal Pharmaceutical Research Institute of
`
`= TOBACCO INC. [JP/JP]; 2-1, Toranomon 2-chome, Mi-
`==
`= One Amgen Center Drive, Thousand Oaks, California,
`-_
`= (75) lnventors/AppUcants (for US only): OGAWA, Nobuya
`= Japan Tobacco Inc., 1-1, MW11Saki-cho, Te.katsuld-shi,
`
`Osaka, 5691125 (JP). OKUMA, Chlhlro [JP/JP]; c/o
`Central Phannaceutical Research Institute of Japan To-
`bacco Inc., 1-1, Murasaki-cho, Takatsuki-shi, Osaka,
`5691125 (JP). FURUKAWA, Noboru [JP/JPJ; c/o Central
`Pharmaceutical Research Institute of Japan Tobacco Inc.,
`l-l, Mnrasalci-cho, Takatsuki-shi, Osaka, 5691125 (JP).
`
`-
`_
`-
`- -
`;;;;;;;;;;;;;
`-
`
`-----
`
`M < = ~
`t-=
`= M
`
`I(cid:173)
`N
`
`-....-~~~----~~~-~~~~~~~~~~~~----~~~~~~~~~~~~~
`
`~ (54) Title: ANORECllC
`
`(57) Abstract: The present invention relates to an anorectic containing a compound having a DGAT inhibitory activity (OOATI
`O inhibitory activity) OT a prodrug thereof OT a pharmaceutically acceptable salt thereof as an active ingredient The present invention
`::> provides an anti-obesity drug which is an anorectic that does not directly act on the ccnlral nervous system and is satisfactory in
`~ terms of activity, and a therapeutic strategy for preventing or treating obesity.
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`Description
`
`ANORECTIC
`
`Technical. Field
`
`The present invention relates to an anorecti<: action
`5 of a compound having a DGAT (diacylglycerol acyltransferase)
`
`inhibitory activity (e.g. , DGATl inhibitory activity) ..
`
`Moreover, the present invention relates to a combined use of
`
`such DGAT inhibitors (e.g., DGATl inhibitor) and various
`
`drugs.
`
`10
`
`Background Art
`
`It is known that various ·intracerebral neural
`
`activities and neurotransmitters are involved in the control
`
`of appetite in human and animals. These neural activities
`
`are affected by biochemical, neurological or endoc~ine
`
`15
`
`signals that occur in the process of nutritive digestion,
`
`absorption, metabolism and storage.
`
`Sugars and lipids themselves as. nutrients, or
`
`metabolites in fat, muscule and liver cause biochemical
`
`signals that act promotively or suppressively on cerebrai
`
`20 nerve activities involved in appetite.
`
`It is also known that endocrine signals (e.g. , CCK r:
`
`GLPl, Enterostatin, ApoAIV etc.) or neural signals via
`
`chemical receptors of the gastrointestinal tract or from
`
`enteric plexus, during the process of diges~ion and
`25 absorption of sugars and lipids, affect gastrointestinal
`
`functions and cerebral nerve activities.
`
`Moreover, it is known that fat tissue, which i.s a fat
`
`storage organ, produces endocrine or biochemical signals,
`
`such as leptin, adiponectin and free fatty acid, along with
`
`30
`
`storage and consumption of fat. These signals alone or
`
`cooperative combinations of signals are considered to affect
`
`the central nervou:;i system which controls appetite.
`
`The DGATl inhibitor is expected to inhibit absorption
`
`of fat by suppressing re-synthesis of triglyceride in the
`
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`gastrointestinal tract, and changes the above-mentioned
`
`signals that affect function of the gastrointestinal. tract
`
`or brain.
`
`In addition, the DGATl inhibitor is expected to
`5 change biochemical or endocrine signals from fat tissue by
`
`suppressing re-synthesis of triglyceride in the fat tissue.
`
`Furthermore, it has been reported that DGATl
`
`deficient mice show an accelerated sensitivity of brain
`
`function to leptin which is an anti-obese factor: derived
`
`lO
`
`from fat tissue. Therefore, a similar effect is expected
`
`by the administration of a DGATl inhibitor.
`
`In the meantime, as a compound having a DGAT
`
`inhibitory activity, the following compounds are known.
`
`The following compound has been disclosed to have a
`15 DGAT inhibitory activity (e.g., W02004/47755, published
`after the priority date of the present application).
`
`R6
`Rs
`'N'
`
`:~(·· L'-wi_fL
`~N-Z~
`
`2
`
`2)m.
`-w
`
`(l)
`
`This reference discloses inhibition of .DGAT. However,
`
`disclosure of anorectic action resulting from the
`20 inhibition of DGAT as in the present application is not
`
`contained at all.
`
`For example, the followi~g compound has been
`disclosed to have a DGAT inhibitory activity (e .. g .. , JP-A(cid:173)
`HS-213985) .
`
`25
`
`R
`
`b-CO-SCoA
`N H
`.
`
`(3)
`
`This reference discloses inhibition of ACAT and DGAT.
`
`However, disclosure of anorectic action resulting from 'the
`inhibition of DGAT as in the present application is not
`
`2
`
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`.contained at all.
`Similarly, the following compound has been disclosed
`
`PCT/JP200S/001643
`
`to have a DGAT inhibitory activity (e.g., JP-A-HB-182496).
`OH
`0
`
`0
`
`(4)
`
`5
`
`This reference discloses inhibition of DGAT~ However,
`disclosure of anorectic action resulting from the
`inhibition of DGAT as in the present application is not
`contained at all.
`Moreover, the following compound has been disclose~
`10 to have a DGAT inhibitory activity (e.g., W000/58491}.
`
`Me
`
`OH
`
`OH
`
`Me ~OH
`
`OH
`
`0
`
`(5)
`
`This reference discloses inhibition 9f DGAT. However,
`disclosure of anorectic action.resulting from the
`inhibition of DGAT as in the present application is not
`15 contained at all.
`
`Moreover, the following compound has been disclosed
`to have a DGAT inhibitory activity (e.g., JP-A.:..2004-67635).
`
`Rl'''rN
`
`n-
`
`S
`
`~ .. A_A
`
`0
`
`(6)
`
`N
`H
`
`This reference discloses inhibition of DGAT. However,
`
`3
`
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`disclosure of anorectic action resulting from the
`
`inhibition of DGAT as in the present application is not
`
`contained at all.
`
`As a compound having an anorectic action, ApoB
`5 secretion/MTP (Microsomal Triglyceride Transfer ·Protein)
`inhibitors have been disclosed (e.g., JP-A-2001-iB1209).
`
`As such compound, for example, the following formula has
`
`been disclosed.
`
`m ,...L
`
`N
`
`N
`H
`
`lO Specifically, the following compounds have been disclosed.
`CP3
`
`CF3
`
`~
`
`0
`~
`0 ~l':J : CHg
`N~
`H
`
`and
`
`However, this reference does not disclose that these
`compounds have a DGAT inhibitory activity ..
`In addition, the reference discloses that similar
`
`15
`
`compounds have been disclosed to have a suppressive action
`on fat absorption from small intestine, but does not
`
`.disclose that t~ese compounds have a DGAT inhibitory
`activity (e.g., JP-A-2001-172180).
`
`20
`
`While the development of anti-obesity drugs· is
`currently ongoing, they are not satisfactory in terms of
`activity. The development of anorectic agents to prevent
`
`or treat .obesity is also ongoing. However, since most of
`these anorectic agents directly act on the central nervous
`
`4
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`system and side effects are· worried, the development of
`
`anorectic agents that do not directly act on the center has
`
`been strongly desired.
`
`The problem to be solved by the presen~ invention is
`5 provision of an anti-obesity drug which is an anorectic
`
`agent that does not directly act on the central nervous
`
`system and is satisfactory in terms of activity, and a·
`
`therapeutic strategy for preventing or treating obesity.
`D~sc1osure Of ~he Invent~on
`
`10
`
`In view of the above-mentioned problem, the present
`
`inventors have intensively studied in an attempt to search'
`
`a useful anorecti.c and surprisingly found that a compound
`
`having a DGAT inhibitory activity (e.g., DGATl inhibitory
`
`activity) has a remarkable anorectic activity, ,whi.ch.
`15 resulted in the completion of the present invention.
`
`More particularly, the invention provides the
`
`following [1]-[33].
`[lJ An anorectic comprising, as an active ingredient, a
`
`compound having a DGAT (diacylglycerol acyltransferase)
`
`20
`
`inhibitory activity or a prodrug thereof or a
`
`pharmaceutically acceptable salt thereof.
`[2] The anorectic of the above-mentioned [1], wherein the
`compound having a DGAT.inhibitory activity is a compound
`
`represented by the following formula (1):
`
`25
`
`30
`
`wherein
`x
`
`is C(R1
`) or N,
`wherein R1 is· a hydrogen atom, a C1-e alkyl group,
`a C2-e alkenyl group, a C2-e alkynyl group, a C1-e
`
`5
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`fluoroalkyl group, an aryl group, an aryl Ci-4
`alkyl group, C(O)Ra, C02R8 or C(O)NR8 Rb, wherein Ra
`·· and Rb are the same or different and each is a
`hydrogen atom, a C1-e alkyl group, a C2-e alkenyl
`
`5
`
`group, a Cz-e alkynyl group, a C1-s fluoroalkyl
`
`y
`
`10
`
`z
`15 wi
`
`20 wz
`
`group, an aryl group or an aryl Ci-4 alkyl group;
`is c (R1
`) , c (R2) (R2
`} , N or N (R2 } ,
`wherein R1 is as defined above and each .R2 is
`independently a hydrogen atom, a C1-e alkyl group,
`a C2- 8 alkenyl group~ a C2-e alkynyl group, a · C1.:.e
`, C (0) NR8 Rb, ~n ·
`fluoroalkyl group, C (0) Ra, C02R 8
`aryl group or an aryl C1 - 4 alkyl group, wherein R 8
`and Rb are as defined above;
`is 0 or S;
`is an optionally substituted C3-s cycloalkylene
`group, an optionally substituted C3-s
`heterocycloalkylene group, an optionally
`substituted arylene group or an optionally
`substituted heteroarylene group;
`is an optionally substituted C3-e cycloalkyl gro.up,
`an optionally substituted C3-e heterocycloalkyl
`group, an optionally substituted aryl group or an
`optionally substituted heteroaryl group;
`
`25
`
`is a -single bond, a C1-4 alkylene group, ·a Cz-4
`alkenylene group, 0, C(O}N(R8
`) or N(R8 )C-(O),
`
`30
`
`m
`
`wherein Ra is as defined above;
`is a single bond, O, a C1 ~ alkylene group, a C~4
`alkenylene group, a Ci-4 heteroalkylene group,
`) or N(R8 }C(O}, wherein R8 is as·defined
`
`C(O)N(R8
`
`above;
`
`is 0 or 1;
`when m is 1 and L2 is a single bond, a substituent
`of W2 may form, together with a substituent of W1 ,
`a 5 to 7-membered ring that is condensed with W1
`
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`and forms a fused ring or spiro ring with W2;
`R3 and R4
`are the same or different and each is a hydrogen
`atom, a C1-s alkyl group, a C2-s alkenyl group, a
`C2-e alkynyl group, C(O)Ra, C02Ra, C(O)NRaRb or a C1..;
`4 alkylene-ORa group, wherein Ra and Rb are as
`defined above, or R3 and R4 may form a 3 to 6- ·
`membered ring together with the carbon atom
`
`5
`
`binding thereto; or
`10 R2, R3 or R4
`
`may form, together with W1
`optionally having, in the ring, 1 to 3
`
`, a 5 to 7-membered ring
`
`heteroatoms selected from a nitrogen atom, an
`
`oxygen atom and a sulfur atom;
`
`15 R5 and R6
`
`are the same or different and each is a hydrogen
`atom, a C1-s alkyl group, a C2.- 8 alkenyl group, a
`C2-s alkynyl group, C (0) Ra or C02Ra, wherein Ra is
`as defined above, Rs and R6 may form an N(cid:173)
`containing 5 to 7-membered ring togethe~ with the
`nitrogen atom binding thereto, or, when X is C(R1),
`Rs or R6 may form, together with R1
`, an N-.
`containing 5 to 7-membered ring, wherein N may be
`substituted by Rs or R6
`is a hydrogen atom, a .C1-s alkyl group, a C1- 4
`haloalkyl group, a C2-s alkenyl group, a C2-e
`alkynyl group, C(O)Ra, ORa or NRaRb, wherein .R8 and
`Rb are as defined above, or, when X is C(R1), R7
`may form, together with R1 , a 5 to 7-mernbered
`ring; and
`
`;
`
`20
`
`25 R7
`
`30
`
`is a single bond or a double bond;
`-------
`provided that the following compound is excluded:
`
`7
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`
`wherein Ra is a hydrogen at-om, a nitro group, a chlorine
`
`atom, a methoxy group, a methyl group or a phenyl group.
`
`[3] The anorectic of the above-mentioned [1], wherein the
`
`5
`
`compound having a DGAT inhibitory activity is a compound
`
`represented by the following formula (2):
`
`(2)
`
`Y'-R31
`
`wherein
`lO X' and Y'
`
`15
`
`are the same or different and each is a single
`
`bond, a Ci-4 alkylene group, a C2-4 heteroaJ.kylene
`
`group, -0-, -C02-, -S(O)t-,
`-C(O)-, -NR7
`' - , -C(O)NR7
`' - , -N(Ra')C(O)NR7
`' - ,
`' - , -N(Ra')S02NR7
`-N(R7 ')C02-, -S02NR7
`' - ; -:NR7 'C(O)-,
`-O-C(O)N(R7 ' ) - or -NR7 'S02-,
`wherein R7
`' and Ra' are the same or diff.erent and
`
`each is a hydrogen atom, a C1-a alkyI group, an
`
`aryl group or an aryl Ci-4 alkyl group and k is an
`
`20
`
`integer of 0 or 1-2;
`
`is a hydrogen atom, a halogen atom, a C1-a alkyl
`group, a C2-a alkenyl group, a C2-s alkynyl group,
`a C1-s fluoroalkyl group, a C3-a cycloalkyl group,
`
`a C2-s heteroalkyl group, a C2-a heteroalkenyl
`
`·25
`
`group, a C3-s heterocycloalkyl group, an aryl
`
`group, an aryl Ci-4 alkyl group, a heteroaryl
`
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`
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`group, ORa', SRa', C(O)Ra', C02Ra', C(O)NRa,Rb',
`
`S02Ra', S02NRa'Rb', a nitro group or a cyano group,
`wherein Ra' and Rb' are the same or different and
`
`each is a hydrogen atom, a C1-e alkyl group, a C3-e
`
`5
`
`cycloalkyl gro.up, an aryl group or an aryl Ci-4
`
`alkyl group;
`is a C1-e alkyl group, an aryl Ci-4 alkyl· group,
`ORa', a halogen atom, a nitro group, NRa.,Rb', a·
`cyano group or W1', wherein W1 ' is
`
`R2 '
`
`10
`
`RlO
`
`L_(~ 9·
`
`c.,
`
`S
`
`R
`
`I
`
`15
`
`20
`
`25
`
`wherein R9 and R10 are the same or different and
`each is a hydrogen atom, a C1-e alkyl group, a C2-e
`alkenyl group, a C2-e alkynyl group, a C1-e
`
`fluoroalkyl group, an aryl group or an aryl .Ci-4
`alkyl group, or R9 and R10 may be linked to form a
`5 to 7-mernbered ring optionally having, in the
`
`ring, 1 to 3 heteroatoms selected from a nitrogen
`atom, an oxygen atom ~nd a sulfur atom,.R11 is a
`hydrogen atom, a C1-e alkyl. group, an aryl group
`
`or an aryl Ci-4 alkyl. group, and Ra' and ·Rb' are as
`
`defined above; or
`R1 ' and R2 '
`may be linked to form a 5 to 7-membered ring
`
`optionally having, in the ring, one heteroatom
`
`selected from a nitrogen atom, an oxygen atom and
`
`a sulfur atom·;
`
`R3
`
`'
`
`is a hydrogen atom, a C1-e alkyl. group, an aryl Ci-
`
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`\__i(~R'
`
`\_(?-R'.
`
`I
`
`\
`
`PCT/JP2005/00164J
`4 alkyl group, ORB', a halogen atom, a nitro group,
`NRB'Rb', a cyano group or W2', wherein W2' is
`Ru
`RlO
`RlD
`. N-N
`N-N
`N-N
`\~N~R9 \-'Z;-,R9 \J(s)_R9
`,
`,
`
`Rll
`'
`N-0
`\AN>-R9
`
`Rll
`'
`\-(>-R9
`
`0-N
`\AN)_R9
`
`S-N
`\AN)_R9
`
`N=N
`\~N'N.:_R9
`or
`
`wherein R9
`
`, R10 and R11 are as defined above, and
`
`5
`
`R2
`
`RB' and Rb'are as defined above; or
`' -and R3 '
`may be linked to form a 5 to 7-membered ring
`
`optionally having, in the ring, one het~r9a~om
`
`selected from a nitrogen atom, an oxygen atom and
`
`10
`
`a sulfur atom;
`
`15
`
`20
`
`25
`
`is a· C1-e alkyl group, a C2-e alkenyl group, a C2-e
`
`alkynyl group, a C1-4 fluoroalkyl group, a C2'-e
`heteroalkyl group, a c·2-e heteroalkenyl group, a
`C3-e cycloalkyl group, a C3-e heterocycloalkyl
`
`group, an aryl group, an aryl Ci- 4 alkyl group, a
`heteroaryl group, OR8
`' , SR8
`' , NR8 'Rb', C{O) R8
`
`' ,
`
`C02R8
`
`' , C(O)NR8 'Rb', S02R8
`
`' or S02NR8 'Rb', wherein
`
`R8
`
`' and Rb' are as defined above;
`
`is a hydrogen atom, a .C1-a alkyl group, a C1-e
`fluoroalkyl group, a C3- 8 cycloalkyl group, a C2-e
`heteroalkyl group, a Cz-e heteroalkenyl group, a·
`
`C3-e heterocycloalkyl group, an aryl group, an
`
`aryl Ci-4 alkyl group, a heteroaryl group, a
`' , NRB'R0 ' , a cyano group, C{O)R8
`' , OC02Rc, OC(O).NR8 'R0
`
`halogen atom, OR8
`' , C(O)NR8 'R0
`
`C02R8
`
`' , OC(O)R8
`
`' ,
`
`' ,
`
`NR8 'C(O)Rb', NR8 'C02R0 or NR6 'C(O)NR8 'Rb', wherein
`
`R8
`
`' and Rb' ar·e as defined above and Re is a C1-a
`
`alkyl group, a C3-e cycloalkyl group, an aryl
`
`10
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`R6 '
`
`PCT/JPlOOS/001643
`group or an aryl C1-4 alkyl group; and
`is ORd, NRdRa or S (0) m•Rd,
`
`wherein Rd and Ra are the same or different and
`
`each is a hydrogen atom, a Ci-e alkyl group, a ·C2-e ·
`
`5
`
`alkenyl group,. a C2-e alkynyl group, a C1-e
`
`fluoroalkyl group, C(O)Rr, an aryl group or an
`aryl C1- 4 alkyl group, m' is an integer of 0 or 1-
`2, wherein Rt is a hydrogen atom, a C1-e a.lkyl
`group, an amino group, a C1-o alkylamino group, a
`di (C1-4 alkyl) amino group, an aryl C1-o alkyl· gro:up,
`or a C1-e alkoxy group, or when R6
`R9 may form, together with the nitrogen atom
`binding thereto, an N-containing 4 to 7-membered
`heterocyclic ring wherein the ring may ~urther
`contain 1 or 2 heteroatoms selected from a
`
`' is NRdRa, Rd and
`
`nitrogen atom, an oxygen atom and a sulfur atom.
`(4] The anorectic of the above-mentioned (l], wherein th~
`compound having a DGAT inhibitory activity is a ~ompound
`
`represented by the foilowing formula (3) :
`
`10
`
`15
`
`20
`
`R
`h-co-seoA
`N
`H
`
`(3)
`
`wherein R is a C5-25 alkyl group or a C5-25 alkenyl group, and
`SCoA shows a residue which is a coenzyme A deficient in
`
`the hydrogen atom of a terminal mercapto group.
`
`ZS
`
`[5] The anorectic of the above-mentioned [l], wher:ein the
`
`compound having a DGAT inhibitory activity is a compound
`
`represented by the following formula (4) :
`
`11
`
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`WO 2005/072740
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`PCT/JP2005/001643
`
`N~""°H
`!. :
`
`H
`
`0
`
`(4)
`
`wherein,. when R1
`" is a hydrogen atom, R2 " is a methyl· group.
`or an isopropyl group, and when R1 " is a methyl group, R2 "
`s is a methy). group .
`[6] The anorectic of the above-mentioned [1], wherein the
`
`compound having a DGAT inhibitory activity is a compound
`
`represented by the following formula (5) :
`
`Me Me Me Me Me
`
`Me Me
`
`0
`
`OH
`
`OH
`
`Me
`
`10
`
`OH
`
`(5)
`
`wherein R' is a hydroxyl group or an acetyloxy group.
`
`[ 7] The anorectic of the above-mentioned [ 1] _, wherein the
`
`compound having a DGAT inhibito~y activity is a compound
`
`represented by the following formula (6):
`
`15
`
`Rl"'
`
`Rr·~~ S
`
`N
`H
`
`(6)
`
`wherein R1
`' ' ' is a phenyl group or a halogen-substituted
`phenyl group, R2 ' ' ' is·a hydrogen atom, a c1_ 6 alkyl group,
`a carboxyl group, a C1-& alkoxy-carbonyl group, a cyano
`
`12
`
`13 of 90
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`
`PCT/JP2005/001643
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`gro~p, a C1 _ 6 alky 1-carbamoy 1 group, a N, N-di ( C1-6 alky 1) -
`carbamoyl group or a pyrrolidinocarbonyl group, and R3
`
`' ' '
`
`is a Ci-& alkyl group.
`
`[BJ A method for suppressing appetite, which comprises.
`
`5
`
`administering a pharmaceutically effective am~unt of an
`
`anorectic of any of the above-mentioned [1] to [7J; to a
`
`mammal.
`
`[9] A method for treating or preventing obesity, whi.ch
`
`comprises administering a pharmaceutically effective amount
`
`10 of an anorectic of any of the above-mentioned [1] to [7] .to.
`
`a mammal.
`[10] A method for treating or preventing hyperlipidemia,
`
`which comprises administering a pharmaceutically effective
`
`amount of an anorectic of any of the above-mentioned [1] to
`
`is
`
`[7) to a mammal.
`
`[11) A method for treating or preventing diabetes, which
`
`comprises administering a pharmaceutically effective amount
`
`of an anorectic of any of the above-mentioned [1] to [7] to
`
`a mammal.
`
`2 0
`
`[12] A method for treating or preventing arteriosclerosis,
`
`which comprises administ~ring a pharmaceutically effective
`
`amount of an anorectic of any of the above-mentioned [1] to
`
`[7) to a mammal.
`
`[13] A method for treating or preventing a qoronary disease,
`
`25
`
`which comprises administering a pharmaceutically e·ff ecti ve
`
`amount of an anorectic of any of the above-mentioned [1] to
`
`[7] to a mammal.
`
`[14J A method for treating or preventing hypertension, which
`
`comprises administering a pharmaceutically effective amount
`
`30
`
`of an anorectic of any of the above-mentioned [1] to [/] to
`
`a mammal.
`
`[15] The method of the above-mentioned [9], which further
`
`comprises administering a pharmaceutically effective amount
`
`of other therapeutic agent for obesity to a mammal.
`
`13
`
`14 of 90
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`[16] The method of the above-mentioned [15], wherein said
`
`other therapeutic agent £or obesity is one or more drugs
`
`selected from the group consisting of mazindol, orlistat and···
`
`sibutramine.
`
`5
`
`[17] The method of the above-mentioned [10], which· f.urther
`
`comprises administering a pharmaceutically effective amount
`.
`.
`of other therapeutic agent for hyperlipidemia to a manmal.
`[18] The method of the above-mentioned [17], wherein said
`
`other therapeutic agent for hyperlipidernia is a statin drug.
`
`lO
`
`[19] The method of the above-mentioned [18], wherein the
`
`statin drug is one or more drugs selected from the group
`
`consisting of lovastatin, simvastatin, pravastatin,
`
`fluvastatin, atorvastatin, cerivastatin, pitavastatin,
`
`nisvastatin and rosuvastatin.
`
`15
`
`[20] The method of the above-mentioned [17], wherein said
`
`other therapeutic agent for hyperlipidemia is a fibrate drug.
`
`(21] The method of the above-mentioned [20], wher.ein the
`
`f ibrate drug is one or more drugs selected from the group
`
`consisting of clofibrate, clinofibrate, sinfibrate,
`
`20
`
`fenofibrate, bezafibrate ahd gemfibrozil.
`
`[22] The method of the above-mentioned (17], wherein said
`other therapeutic agent for hyperlipidemia is probucol.
`
`[23] The method of the above-mentioned [17], wherein said:
`
`other therapeutic agent for hyperlipidemia ~s nicotinic acid.
`
`25
`
`[24] The method of the above-mentioned [17], wherein.said
`
`other therapeutic agent for hyperlipidernia is a cholesterol
`
`absorption suppressant.
`
`[25] The method of the above-mentioned (24], wherein the
`
`cholesterol absorption suppressant is one or more drugs
`
`30
`
`selected from the group consisting of ezetimibe, colestimide,
`
`colestyramine and colestipol.
`
`[26] The method of the above-mentioned [17], wherein said
`
`other therapeutic agent.for hyperlipidemia is one or more
`
`drugs selected from the group consisting of an MTP inhibitor,
`
`14
`
`15 of 90
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`an ACAT inhibitor and a CETP inhibitor.
`
`PCT/JP2005/001643
`
`[27] The method of the above-mentioned [11], which further
`comprises administering a pharmaceutically effecti~e amount
`of other therapeutic agent for diabetes to a mammal.
`
`s
`
`[28] The method of the above-mentioned [27], wherein said
`
`other therapeutic agent for diabetes is one or more drilqs
`
`selected from the group consisting of an insulin pr~paration,
`
`a sulfonylurea, an insulin secretagogue, a sulfo11arnide, a _
`
`biguanide, an a glucosidase inhibitor and an insulin
`
`10 sensitizer.
`[29] The method of the above-mentioned [27], wherein said
`
`other therapeutic agent for diabetes is one or more drugs
`
`selected from the group consisting of insulin, glibenclamide,
`tolbu tamide, g lyclopyramide, acetohexamide, g limep'~r ide,
`tolazarnide, gliclazide, nateglinide, glybuzole, metformin
`
`l5
`
`hydrochloride, buformin hydrochloride, voglibose, acarbose
`and pioglitazone hydrochloride.
`
`[30] The method of the above-mentioned [12], which further
`
`comprises administering a pharmaceutically effective amount
`20 of other therapeutic agent for arteriosclerosis to a mammal.
`[31] The method of the above-mentioned [13], which further
`
`comprises administering a pharmaceutically effective amount
`
`of other therapeutic agent for coronary diseases to. a manunal.
`
`[32] The method of the above-mentioned [14],_which further
`2 5 comprises administering a pharmaceutically effective amount
`
`of other therapeutic agent for hypertension to a mammal.
`
`[33] The method of the above-mentioned [32], wherein said
`
`other therapeutic agent for hypertension is one or more
`
`drugs selected from the group consisting of a loop diuretic,
`30 an angiotensin converting enzyme inhibitor, an angiotensin
`
`II receptor antagonist, a Ca antagonist, a ~ blocker, an
`
`a,~ blocker and an a blocker.
`
`[34] The method of the above-mentioned [32], wherein said
`other therapeutic agent for hypertension .. is one or m_ore
`
`15
`
`16 of 90
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`PCT/JP2005/00164J
`drugs selected f rorn the group consisting of a furosernide
`
`sustained-release preparation, captopril, a captopril
`
`sustained-release preparation, enalapril rnaleate,
`
`alacepril, delapril hydrochloride, cilazapril, lisinopril,
`5 banazepril hydrochloride, imidapril hydrochloride,.
`temocapril hydrochloride, quinapril hydrochloride,
`
`trandrapril, perindopril erbumine, losartan potassium~
`
`candesartan cilexetil, nicardipine hydrochloride, a
`
`nicardipine hydrochloride sustained-release preparation,
`10 nilvadipine, nifedipine, a nifedipine sustained-releas~
`
`preparation, benidipine hydrochloride, diltiazem
`hydrochloride, a diltiazem hydrochloride sustained-release
`
`preparation, nisoldipine, nitrendipine, manidipine
`hydrochloride, barnidipine hydrochloride, efonidipine
`
`15 hydrochloride, amlodipine besylate, felodipine,
`cilnidipine, aranidipine, proprapolol hydrochloride, .a
`
`propranolol hydrochloride sustained-release preparation,
`pindolol, a pindolol sustained-release preparation,
`
`indenolol hydrochloride, carteolol hydrochloride, a
`20 carteolol hydrochloride sustained-release preparation,
`bunitrolol hydrochloride, a bunitrolol hydrochloride
`sustained-release preparation, atenolol, acebutolol
`hydrochloride, metoprolol tartrate, a metoprolol,tartrate
`
`sustained-release preparation, nipradilol,.penbutolol
`25 sulfate, tilisolol hydrochloride, carvedilol, bisoprolol
`fumarate, betaxolol hydrochloride, celiprolol
`hydrochloride, bopindolol malonate, bevantolol
`
`hydrochloride, labetalol hydrochloride, arotinolol:
`
`hydrochloride, amosulalol hydrochloride, prazosin
`30 hydrochloride, terazosin hydrochloride, doxazosin. mesylate,
`_bunazosin hydrochloride, a bunazosin hydrochloride
`
`sustained-release preparation, urapidil and phentolamine
`
`mesylate.
`
`As is clear from the following test of the .present
`
`16
`
`17 of 90
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`
`WO 2005/072740
`PCT/JP2005/001643
`invention, a compound having a DGAT inhibitory activity
`
`(e.g., DGATl inhibitory activity), a prodrug thereof and a
`
`pharmaceutically acceptable salt thereof showed a potent
`
`anorectic action. Accordingly, a compound having a DGAT
`
`5
`
`inhibitory activity (e .. g.,. DGATl inhibitory activity) is
`
`useful as an anorectic. Besides as the anorectic, it is
`
`also useful as an agent for treating or preventing
`
`diseases such as obesity, hyperlipidemia, diabetes,
`arteriosclerosis, coronary dise.ase and hypertension.
`
`10
`
`Moreover, a compound having a DGAT inhibitory
`
`activity (e.g., DGATl inhibitory activity) is useful for
`
`combination therapy with other therapeutic agents for
`
`obesity, therapeutic agents for arteriosclerosis,
`
`therapeutic agents for coronary diseases, therapeutic
`
`15 agents for hypertension, therapeutic agents for diabetes
`
`or therapeutic agents for hyperlipidemia.
`Best Mode For Carry~ng OUt The Invention
`The definition of each substituent to be used in the
`
`present specification is as follows.
`
`20
`
`The •oGAT• refers to acyl CoA: diacylglycerol.
`
`acyltransferase or a variant thereof. The diacylglycerol
`
`acyltransferase variants include proteins substantially
`
`homologous to native diacylglycerol acyltransferase. For
`
`example, proteins having one or more. natural!~ or artificially
`25 occurring deletions, insertions or substitutions of .amino
`
`acids, such as diacylglycerol acyltransferase derivatives,
`
`homologs and fragments can be mentioned. The amino acid
`
`sequence of a diacylglycerol acyltransferase variant is
`
`preferably at least about 80% identical, more preferably.at
`
`3 0
`
`least about 90% identical, and most preferably at least about
`
`95% identical, to a native diacylglycerol acyltransferase.
`
`The nhalogen atom" is a chlorine atom, a bromine atom,.
`a fluorine atom or an iodine atom.
`
`The nc1-e alkyl group• is a straight or branched chain
`
`17
`
`18 of 90
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`alkyl group having 1 to 8 (preferably 1 to 6) carbon atoms,
`
`and is exemplified by methyl group, ethyl group, n-propyl
`
`group, isopropyl group, n-butyl group, isobutyl group, .sec(cid:173)
`
`butyl group, tert-butyl group, n-pentyl group, isopentyl
`5 group, neopentyl group, ·tert-pentyl group, n-hexyl •group, ·n(cid:173)
`
`heptyl group, n-octyl group and the like. Of these, "C1-&
`alkyl group" refers to ones having 1 to 6 carbon atoms and
`
`··
`
`"C1-4 alkyl group" refers to ones having 1 to 4 carbon atoms ..
`
`The "Cs-2s alkyl group" is a straight or branched
`10 chain alkyl group having 5-25 (preferably 12-14).carbon
`
`atoms and is exemplified by decyl group, undecyl'gro~p,
`2,2-dimethylundecyl group, 11,11'-dimethyldodecyl group,
`
`dodecyl group, 12-methylt~idecyl group, tridecyl group,
`
`12,12-dimethyltridecyl group, tetradecyl group, ~,6-
`15 dimethyltetradecyl group, pentadecyl group, hexadecyi.
`
`group and the like.
`
`The "C1-s fluoroalkyl group" is a straight or branched
`chain alkyl group having 1-8 (preferably 1-6) carbon atoms,
`which is substituted by 1-17 (preferably 1-5) fluorine
`
`20 atoms and is exemplified by fluoromethyl, difluo~omethyl,
`
`trifluoromethyl, 1- or 2-fluoroethyl, 1,1-difluo+oethyl,
`1,2-difluoroethyl, 1-, 2- or 3-fluoropropyl, 1-, 2-, 3- or
`
`4-fluorobutyl, 1-, 2-, 3-, 4- or 5-fluoropentyl, 1-, 2-,
`3-, 4-, 5- or 6-fluorohexyl, 1-, 2-, 3-, 4~, 5-, 6- o~ .1-
`25 fluoroheptyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-fluorooctyl
`
`and the like.
`
`The "Ci-4 fluoroalkyl group" is a straight or :branched
`chain alkyl group having 1 to 4 carbon atoms,. which is
`
`substituted by 1-9 (preferably 1-5) fluorine atoms and is
`30 exemplified by fluoromethyl, difluoromethyl,
`
`trifluoromethyl, 1- or 2-fluoroethyl, 1,1-difluoroethyl,
`1,2-difluoroethyl, 1-, 2- or 3-fluoropropyl, 1-, .2-, 3- or
`4-fluorobutyl and the like.
`
`The "C2-s heteroalkyl group" is a straight or branched
`
`18
`
`19 of 90
`
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`
`PCT/JPlOOS/001643
`WO 2005/072740
`chain heteroalkyl group comprising 2 to 8 (preferably 2 to
`
`6) carbon atoms and 1 to 3 (preferably 1 or 2) heteroatoms.
`
`As the heteroatom, oxygen atom, nitrogen atom, silicon
`
`atom and sulfur atom can be.mentioned, wherein the nitrogen
`5 and sulfur atoms may be oxidized and the n