TRANSMJ.TTAJ, Ui!TT!lR TO THE UNITED STATES
`DESIGNA'rED/ELECTED OFFICE (DO/EO/US)
`ER 3. U . • C. 371
`I I11ternational Filing Date
`!Priority Date claimed
`International Applicatio11. No.
`I
`.
`I
`Rf:l'.l,IE2ll.L.9.:'.!.§J_,1~.,,,_' ________ .,.l'"'o"'c'"'t"'o"'l;?'"'e"'r'-'J"'.5'"'''--'1"'9'"'9'"'8,_,,,,_/_· -----1'-'0"'c"'t~o"'b""e~r~l~7,_.~1~9~9,_7~v __ _
`Jitle of Invention:
`AMIDE DERIVATIVES OR SALTS THEREO])' v·
`
`410 Rel~gt~Pn1{P.JQocR~2 NAfmr 2000,v
`I 0738.J'L. 0007
`p i Zf(f'96
`1u.s.
`
`Applicant(s) For DO/EO/US:
`Tatsuya MARUYAMA, Takayuki Sll'ZUKI, Kenichi ONDA, Masahiko HAYAKAWA, Hiroyuki MOIUTQMO,
`Tetsuya KIMIZUKA and Tetsuo MATSUI,,.,~
`
`Applica11t herewith submits to the United States Designated/Elected Office (DO/EO/US)
`the following items and other information:
`
`1J.
`2.
`'
`
`3.
`
`41-:1
`
`[X]
`l
`[
`
`( J
`
`(XI
`
`(X]
`
`cX]
`[X]
`
`8.
`
`[ J
`
`9.
`10'
`
`[X]
`l
`[
`
`b.
`c.
`
`This is a FIRST submission of items concerning a filing under 35 u.s.c. 371.
`This is a SECOND or SUBSEQUENT submission of items aonaer11ing a filing under
`35 u.s.c. 371.
`This express request to begin national examination procedures (35 U.S. c. 371 (f))
`at any time rather than delay examination until the expiration of the applicable
`time limit set. in 35 U.S.C. 3'71(b) and PCT Articles 22 and 39(1).
`A proper Demand for rnter11atio11al Prelimi11ary Examination was made by the 19th
`month from the earliest claimed priority date.
`A copy of the International Application a,s filed (35 U.S.C. 37l(c) (2))
`a.
`( ]
`is transmitted herewith (required only i f not transmitted by the
`International Bureau) .
`[X] has been tra11sm:itted by the International Bureau.
`is not required, as the application was filed in the U11ited States
`[ )
`Receiving Office (RO/US) .
`A translation of the International Application into English (35 U.S. C. 37l (c) (2) J •
`Amendments to the claims of the International Application under PCT Article 19
`(35 U.S.C. 3"1(c) (3)).
`[ J are transmitted herewith (required only if not t~·ansmitted by the
`a.
`International Bureau) .
`[ ) have been transmitted by the Inter11ational Bureau.
`[ ] have not been made; however, the time limit for making such
`amendments has NOT expired.
`have 11ot bee11 made and will not be made.
`[XJ
`d.
`A translation of the amendments to the claims under PCT Article 19
`(35 U.S.C. 371(c) (3)).
`(35 a.s.c. 37l(c) (4)).
`An oath or declaration of the inve11tor{s)
`A transl.ation of the annexes to the lnter11ational Preliminary Examination Report
`under PCT Article 36
`(35 u.S.C. 371(c) (5)).
`
`b.
`c.
`
`Items 11. to 16. below co11cern other doownent(s) or i11fo:rmation included:
`
`11.
`12.
`
`l3'
`
`J.4'
`15.
`
`16'
`
`[ l
`[X]
`
`[ l
`[ )
`[ l
`[ ]
`
`[
`
`l
`
`An Informatio11 Disclosure Statement under 37 CFR 1.97 and 1.98.
`An assignment document for recording. A separate cover sheet i11 compliance with
`37 CFR 3.28 and 3.31 is included.
`J!, E'IRST prel J.minary amendment.
`A SECOND or SUBSEQUENT preliminary amendment.
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`A change of power of attor11ey and/or address letter.
`
`Other items or i11formatio11:
`[ J verified Small Entity Statement.
`a.
`[ l Copy of Notification of Missing Requirements.
`b.
`
`PT0_00000002
`
`SAWAI EX. 1015
`Page 1 of 1092
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`

`

`6
`u. s. Al?l?LICATION NO.
`09/52909--
`
`17.
`
`[l\J
`
`I IN'l.'lmNATIONAL Al?l?LICATION NO. I ATTORNlilY DOCKET NUMBER
`Cf~TOS.0007 APR 2000
`IPC:t/JP98/Qjl671
`'
`422 Recd p
`7i CALCULATIONS I
`The following fees are submitted:
`I
`Basic National Fee (37 CFR l.492(a) (1)·(5)):
`I
`Search Report has been prepared by the EPO or JPO ......... $840.00
`lrlter11ational preliminary examination fee paid to
`I
`USP'I'O (37 CFR 1.482) .................................... $670.00
`I
`I
`No international preliminary examination fee paid to
`I
`USPTO (37 Cl?R 1.482) but international search fee
`I
`paid to USPTO (3" CFR 1.445(a)(2)) ...................... $690.00
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`Neither international preliminary examination fee
`I
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`I
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`International preliminary examination fee paid to USl?TO
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`of PCT l'.l.rticle 33(1)-(4) ................................ $ 96.00
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`- - - - · · - - - - - ·
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`surcharge of $1.30.00 for furnishing the oath or declaration later than
`I
`[ l 30 months from the earliest claimed priority date
`' [ l 20
`'~(~3·~1~C~F~R~. ~l~.4~9~2~-~e,.,,_..._,,_ _________________________ ~..._ _____ ,L
`--~C~l~a~i~m~s~----i-1-NYJUber Filed
`I... NtJ,mber Extra
`........ L.--1~lilt~e_.,._ _____ _,.
`I$
`Total Claims
`I
`I
`I X $18. 00
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`8 ·20=
`~xu~d~e~p~e~n~d~e~n~t,_.C~l~a~i~m~s~l-~3~-__,3~=,__ ____ _,_i ___________ ~l~X~S~7~8w·~o~o'-'t~s _ _ _ _____J.
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`.l~.-~E....c..2 .... ~.1.L...........
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`TOTAL NATIONAL FEE
`assignment (37 CFR 1.21(h)). The
`by an appropriate cover sheet
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`TOTAL FEES ENCLOSED
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`-!!"1--~~~~~~~-~--------------~--"c~.""'"'""""1.-1..""-~---L
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`ll.
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`'r'he Commissioner is hereby authorized to charge any additional fees
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`
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`The Commissioner is hereby authorized to charge any other fees due under 37 C.F.R. §1.15
`or §1.17 during the pendency of this application to our De osit Account No. 06-0916.
`
`SEND ALL CORRESPONDENCE TO:
`Finnegan, Henderson, Farabow
`Garrett & Dunner, L.L.P.
`1300 I Street, N.W.
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`
`Reg. No. 2a,220
`
`Submitted: April 7, 2000
`
`ERNEST F. CHAPMAN
`Reg. No. 25,961
`
`PT0_00000003
`
`SAWAI EX. 1015
`Page 2 of 1092
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`

`

`··~Q/529096
`422 Rec'd PCTJPTO O 7 APR 2000.
`
`1
`
`Desc.cLption
`
`AMIDE DERIVATIVES OR SALTS THE:REOF
`
`Technical Field:
`
`The present invention relates to pharmaceuticals and,
`
`more particularly, it relates to novel amide d~rivatives or
`
`salts thereof and also to therapeutic agents for diabetes
`
`mellitus containing them as effective conponents.
`
`Background of the Invention:
`
`Diabetes mellitus is a disease accompanied by continuous
`
`hyperglycemic state and is said to be resulted by action of
`
`many environmental factors and genetic factors.
`
`1~e main
`
`controlling facto.r for blood sugar is insulin, and it has been
`
`known t1:lat hyperglycemia :Ls resulted by deficiency of :Lnsulin
`
`or by excess of factors which inhibit its action (such as
`
`genetic cause, lack of exercise, obesity and stress).
`
`Dicibetes melli tus is i;l»(crnified into two main types. One
`
`is insulin-dependent diabetes mellitus
`
`(IDDM) caused by a
`
`lowering of insulin-secreting f~nction of pancreas due to
`
`autoirrumme diseases, and another is non-insulin-dependent
`
`diabetes mellitus (NIDDMt caused by a lowering of insulin-
`
`secreting function of pancreaso due to pancreatic fatigue
`
`accompanied by continuous high :'.nsulic·1 secretion.
`
`95% or more
`
`PT0_00000004
`
`SAWAI EX. 1015
`Page 3 of 1092
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`

`

`2
`
`of diabetic patients in Japan are said to suffer from NIDDM,
`
`and an increase in the patients due ta a change .in daily .Life
`
`style is becoming a problem .
`
`. As to thr~ therapy of diabetes mellitus, dietetic treatment,
`
`therapeutic exercise and remedy of obesity are mainly conducted
`
`in mild cases while, when the di.sease progresses, oral
`
`antidiabetic drugs (for example, insulin secretion promoters
`
`such as sulfonylurea compounds and
`
`insulin se:-isitivity
`
`potentiators which pott'mtiate the sensitivity of insulin) are
`
`administered.
`
`In seve1~e ca sos, an insulin preparation is
`
`administex·ed. However, there has been a brisk demand for
`
`creation of the drugs whereby higher control for blood sugar
`
`is possible, and development of antidiabetic drugs having a
`
`new mechanism and having high usefulness has been demanded.
`
`U.S. Patents 4,396,627 and 4,478,849 describe phenyl-
`
`ethanolamine derivatives and disclose that those compounds are
`
`useful cis drugs for obesity and for hyperglycemia. Action of
`
`those compounds ls reported to be due to a stimulac:lng action
`to p3-receptors.
`Incidentally, it has been known that p-
`adrenaline receptors are classified :l.nto Pi, f\ 2 and P3 subtypes,
`
`that stimulation of [1 1-receptor causes an increase in heart
`
`rate, that stimulation of flr:::cccoptor: st:i.rn:ila-::.e.s decorr.po1sit:Lon
`
`of glycogen in m•.iscles, whereby synthesis of glycogen is
`
`ir:hibit.ed, causing an action such as :nuscular tremor, and that
`
`stJ.mulatJ on of Pr receptor shows an anti-obesity and an
`
`PT0_00000005
`
`SAWAI EX. 1015
`Page 4 of 1092
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`

`

`,--~
`,_
`
`anti-hyperglycemia action (such as decrease in triglycericle,
`
`decrease in cholesterol and increase in HDL-cholesterol) .
`
`However, those Pragonists also haV<OJ actions caused by
`stimulation of P1- and P2-recoptors such as increase in heart
`
`rate and muscular tremor, and they have a problem in terms of
`
`side effects.
`
`Recently,
`
`:it was ascertained -::hat p-receptors have
`
`differences to species, and it has been reported that even
`
`compounds h,oiving been confirmed to have a Prreceptor
`
`selectivity in rodential animals such as rats show an action
`due to stimulating action to [3 1 - and P2-roceptors in human being.
`In view of the above, investigations for compounds having a
`
`stimulating action wh:ich is selective to ~h-receptor in human
`
`being have been co:-1ducted recently using human cells or cells
`
`where human receptors are expressed. For example, WO 95/29159
`
`describes substituted s•.Jlfonarnide derivuti ves represer:t<C-id by
`
`the formula set forth below and discloses that due to the.i.r
`
`selective stimulating action to th-recep~ors in human being,
`
`thE~Y are useful against obesity, hyperglycemia, etc. However,
`
`this patent does not specifically disclose an insulin secretio;i,
`
`promoting action and an
`
`insul:Ln sensitivity potentia-U.n~:r
`
`action of those compounds.
`
`PTO_OOOOOOOG
`
`SAWAI EX. 1015
`Page 5 of 1092
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`

`

`4
`
`(In tr_e formula, the symbols should be re.ferred to in the
`
`specif1cation of this patent.)
`
`As such, there has been still a demand for creation of
`
`therapeutic agents for diubetes mellitus of a new ;:ype which
`
`have a highly clinical usefulness.
`
`Disclosure of the Invention:
`
`T:C-1e present
`
`inv·entors have conducted <m
`
`int,msive
`
`investigation on compounds having both an insulin secretion
`
`promoting action and an insulin sensitivity potentiating
`
`action and found that novel amide derivatives show both a good
`
`insulin secretion promoting action and a good
`
`insulin
`
`sensitivity potentiating action and furthermore
`
`show a
`
`selectJ.vEJ stimulatir.g action to fh-receptors,
`
`leading to
`
`accompli shr1ent of tte present invention.
`
`Th<:1t is, the p.t:Ernent
`
`invention relates to an amide
`
`der:'.. vative .i:epresented by the general formula (I) set forth
`
`below or a salt thereof that is useful for the therapy of
`
`diabet<is melli tus, having both an insulin secretion promoting
`
`action and an insulin sensitivity potentiating action and
`
`:Eurth,0r having anti-obesity and a.:1U.-hype.r.lipemia actions due
`
`PT0_00000007
`
`SAWAI EX. 1015
`Page 6 of 1092
`
`

`

`<~)'~
`""'
`
`·--
`
`5
`
`to selective st].mulating action to Prreceptors. Ti\e present
`
`invention also relates to a pharmaceutical agent, particularly
`
`to a t:ierapeutic agent for di;:ibetes mellitus containing the
`
`amide de:dvative or
`
`the salt thex:eof 1rn an effective
`
`ingredient.
`
`(I)
`
`(In the formula, each of the symbols means as follows:
`
`ring B: a heteroaryl group which may be substituted and
`
`may be fused with a benzene ring;
`
`X: a bor:d,
`
`lower a lkylene or alkenylene which may be
`
`substituted with hydroxy or· a lower alkyl group, carbonyl, or
`
`a group represented by ~NH- (when X is a lower alkylcne group
`
`which may be substituted with a lower alkyl g.r:oup, the hydrogen
`
`cltoms bonded to the carbon atom constituting the ring B may
`
`form a lower alkylene group togetner with the lower alkyl group
`
`so that a ring i.s formed);
`
`A:
`
`lowe1: a1kylen1'l or a group represented by -lower
`
`al kylen<'!>·-0-;
`
`R1", Hlli: they may be the same or different and each is
`
`a hydrogen <11.:orn or a
`
`lower alkyl group;
`
`PTO_OOOOOOOS
`
`SAWAI EX. 1015
`Page 7 of 1092
`
`

`

`6
`
`H2
`
`: a hydrogen atom or a halogen atom; and
`
`Z: a nitrogen atom or a group represented by =CH-.)
`
`The cornpmmd of the general formula
`
`(I)
`
`is further
`
`illustrated as follows.
`
`In the defin:'..tions used in Urn generi>l formula in c:his
`
`specification, the term "lower" means a linear or branched
`
`hydrocarbon chain having from 1 to 6 carbon atoms unless
`
`otherwise specified.
`
`Specific examples of the "lower alkyl group" are methyl,
`
`ethyl, and linear or branched propyl, butyl, pentyl and hexyl,
`
`prefe::ably an 'alkyJ. having from
`
`l
`
`to 4 carbon atoms, and
`
`particularly preferabty methyl, ethyl, propyl a.nd 2-sopropyl.
`
`Exampl<eJS of the "lower alkylene group" is a divalent group
`
`obtained by removing an arb.it.rary hydrogen atom(s) from the
`
`above "lower a.lX:yl group", pre:'.:erably an a1kylene group hav·ing
`
`from l to 4 carbon atoms, and parti<::ularly preferably methylene,
`
`ethy1ene, propylene and butyh1ne. Examples of the "lower
`
`alkenylene group" are vinylone, propenylene, butenylene,
`
`pentenylene and hexenylene groups.
`
`'The "heteroaryl group which may be fused with a benzene
`
`ring" in the "heteroa.ryl 9roup which may be substituted and
`
`may be fused with a benzene ring" means a ring group where a
`
`benzene ring is fusee with a heterca:r.yl 9ro\1p as mentioned later
`
`or a non-fused heteroaryl group.
`
`PT0_00000009
`
`SAWAI EX. 1015
`Page 8 of 1092
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`

`

`'!
`
`Specific examples of the "·d.ng group where the benzene
`
`ring is fused with a heteroa.ry1 group" a.re fused-ring
`
`heteroarylgroupssuchasquino.lyl, isoquinolyl, quinazo.linyl,
`
`<;pinolidinyl r
`
`quinoxalinyl,
`
`cinnolinyl, benzimidazoly.l,
`
`imidazopyridy.l, benzofurany.l, benzoisoxazolyl, benzoxazolyl,
`
`benzothiazolyl, oxazolopyridyl, isothiazolopyridyl, benzo-
`
`thienyl, etc.; andoxo-addedringssuchascxobenzofurayl, etc.
`
`Examples of
`
`the "heteroaryl 9roup" are monocyc.lic
`
`heteroaryl groups such as fury.l, thienyl, pyrroly.l, imidazolyl,
`
`thiazoly!, pyrazoiyl,
`
`isothiazolyl,
`
`isoxazolyl, pyridyl,
`
`pyrimidyl, pyridazinyl, pyrazinyl, thiadiazolyl, triazo1yl,
`
`tetrazolyl, etc.; and bi cyclic heteroaryl groups such a.s
`
`naphthylidinyl, pyridopyrimidinyl, etc.
`
`The substituent in the "heteroaryl group which may be
`
`substituted and rr.ay be fused w:i.th a benzene ring" may be any
`
`9roup which can be usually substituted in this ring group.
`
`Preferred examples are a halogen atom and lower alkyl, lower
`
`alkenyl,
`
`lower alkynyl, hydroxy, sulfanyl, halo9eno lower
`
`alkyl,
`
`lower alkyl-0-,
`
`lower aikyl-S-,
`
`lower alkyl-0-C0- 1
`
`carboxy, sulfonyl, eulfinyl, lower alky:-so-, lower alkyl-
`
`SOz-,
`
`lower alkyl-CO-, lower alkyl-C:0-0-, carbamoyl,
`
`lower
`
`alkyJ.-NH-·C:O-, di .. ·lower alkyl-N-CO-, nitro, cyano, amino,
`
`guanidino,
`
`lower alkyl-CO-NH-,
`
`lower a lkyl-S0 2 -NE-,
`
`lower
`
`.::ilkyl·-NH-, di-lower alky2.-N-,
`
`-0-lower alkylene-0-, etc.
`
`These substi tu<eo:'ll:s may
`
`furt:h<CJ:r be
`
`subn t.ituted with
`
`a
`
`PT0_00000010
`
`SAWAI EX. 1015
`Page 9 of 1092
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`

`

`B
`
`substituent such as an aryl group, a het~~roaryl group, a halogen
`
`atom, hydroxy, sulfanyl, halogeno lower alky1, lower alkyl-0-,
`
`lower all<yl-S-,
`
`lower alkyl-0-CO-,
`
`carboxy,
`
`sulfonyl,
`
`sulfinyl, lower alkyl-SO-, lower alkyl-802-, lower alkyl-CO-,
`
`lower al kyl-C0-0-, ca:rbamoyl,
`
`lowe:c alkyl·-Nl!-CO-, di-lower
`
`alkyl-N-CO-, nitro, cyano, amino, guanidino,
`
`lower alkyl-
`
`CO-·NH-,
`
`lower alkyl-S0 2-NH-,
`
`low~'r alkyl-NH-, di-lower
`
`alkyl-N-, etc. These substituents such as an aryl group, a
`
`heteroaryl group, etc. may further be substituted with a
`
`halogen atom, etc.
`
`"rhe "lower alkenyl grciup" is a linear. or branched alkenyl
`
`g·.roup herv:.Lng 2 l:o 6 carbon atoms, and its speci:fic examples
`
`are vinyl, propenyl, btitenyl, pentenyl and hexenyl groups.
`
`The "lower alkynyl group" is a linear or branched alkynyl
`
`group having 2 to 6 carbon at.oms, and ils specific examples
`
`are ethynyl, propynyl, butynyl, pentynyl and hexynyl.
`
`The "hc.logen atom" means e:l fluorine atom, a chlorine at.om,
`
`a bromine at.om o.r an iod:i.ne atom, and the "halogeno lowe.r alkyl
`
`group" means a group where an a.rbitrary hydrogen atom or atoms
`
`in the above-mentioned alkyl group is /are subsU. tuted with a
`
`haloge·a atom or at.oms.
`
`The case wbc:l X is a bond means that a ca::bon at.om of the
`
`-CO- gro~p is directly bonded to the ring 3.
`
`The compound (I) o:f the present .Lnventi.on has at least
`
`one ac3yrrm8tr.ic carb0n at.om <md therefore, there are opt..ical
`
`PT0_00000011
`
`SAWAI EX. 1015
`Page 10 of 1092
`
`

`

`, ..
`
`9
`
`i'>mners such as (R)-compou::ids, (S) ··compcmnds, etc., racemates,
`
`diastereomers, etc. The present invention includes all and
`
`each of isolated isomers and mixtures thereof. The present
`
`invention also includes hydrates, solvates (such as those with
`
`ethanol) and polymorphic substances of the compound (I).
`
`The compound (I) of the present invention may form a salt
`
`with an acid. gzamples 01: the salt are ac.id addition salts
`
`with mineral acids such as hydrochloric acid, hydr·obronic acid,
`
`hydroiodic acid, sulfuric acid, :litric acid, phosphoric acid,
`
`etc.; and tt.ose w:'.:th organic acids such as formic acid, acetic
`
`acid, propionic acid, oxalic acid, malonic acid, succinic acid,
`
`fumaric aid, maleic acid, J.actic acid, malic acid, citric acid,
`
`tartaric acid, carbonic acid, picric acid, methanesulfonic
`
`acid, ethanesulfonic acid, glutamic acid, etc.
`
`(Manufacturing Method)
`
`'!'he compound o:: the pres1mt invent.ion or the salt thereof
`
`may be manufactured by application of various synthetic methods
`
`utilizing t'.1.e characteristics of its fundamental skeleton or
`
`type of
`
`the substituent.
`
`R'"presentativc-l manufacturing
`
`methods a.re illustrated as hereundiH·.
`
`First Manufactur.lng Met:hod:
`
`PT0_00000012
`
`SAWAI EX. 1015
`Page 11 of 1092
`
`

`

`10
`
`(l)
`
`{In the form:ilae,
`
`R2
`
`, A, B, X and Z have the same meanings
`
`as defined already; R0 ts a protective 9roup for amino; and
`
`Y1 is a leaving 9roup, and rr.oro specifically hydroxy, lower
`
`alkoxy or halide.)
`
`In thls method, the compound (II) <>nd the compound (III)
`
`arc subjected :.o am:Ldation, and the protective group is then
`
`removed there.from to synthesize the (';Ompound (I) of the present
`
`invention.
`
`'..rhe amidation
`
`in
`
`this manufactur.i:1g method c<m be
`
`conducted by customary manners.
`
`'I'he solvent may vary dependi:i.g upon Y1 of the compound
`
`(III) and mostly, an inert solvi;mt or an alcoholic solvent (such
`
`as isopropanol, etc.) may be applied.
`
`PT0_00000013
`
`SAWAI EX. 1015
`Page 12 of 1092
`
`

`

`~ ..
`
`11
`
`When Y1 is a hydroxy group, a method where the react ion
`
`is conducted in the above-mentioned solvent in the presence
`
`of a condensing agent ma.y be applied.
`
`Examples of the
`
`condensing agent are N, N' -dicyclohexylcarbodiimide
`
`(DCC),
`
`1~ethy:-3- (3···diltletbylaminopropyl) carbodiimide
`
`(EDCI),
`
`1,1'-carbonyldiimidazole
`
`(CPI), diphenylphosphoryl azide
`
`(DPPA), d.1.ethylphosphoryl cyanide (DEPC), etc.
`
`When Y1 is lower alkoxy, a method where the reaction is
`
`conducted under heating or refluxing as it is or in the
`
`above-mentioned inert solvent may be applied.
`
`When Y1 is halide, a method where the reaction is conducteci
`
`in the above-mentioned inert solvent in the presence of a base
`
`may be applied.
`
`Examples of the inert solvent are dimethyJ.formamide (DM?),
`
`dimethylacctamide,
`
`tetrachloroetha.ne,
`
`dichloromethane,
`
`dichloroetbano, chloroform, carbon tetrachlori.de,
`
`tetra-
`
`hydro.Cu.ran, dioxane, dimethoxyethane, ethyl aceta:e, benzene,
`
`toluene, xylene, acetonitrile, dimethyl sulfoxido, etc., and
`
`mixed solvents ther<eJof, and they may be appropriately selected
`
`depending upon each reaction condition. Examp:Les of the baS(2
`
`are inorganic bases such as sodium hydroxide, potassium
`
`hydroxide, sodium ca:cbonate, potassium carbonate, etc.; and
`
`orqanic bases such as N-methylmorpboline,
`
`trietbylamine,
`
`diisopropylethylamine, pyridine, etc.
`
`PT0_00000014
`
`SAWAI EX. 1015
`Page 13 of 1092
`
`

`

`12
`
`1rhe protective group of the amino represented by R" means
`
`a protective group which is conunonly used for amino by those
`
`skilled in the art, and its representative examples are acyl
`
`such
`
`as
`
`formyl,
`
`acetyl,
`
`propionyl, methoxyacetyl,
`
`methoxypropionyl, benzoyl, thienylacetyl, thiazolylacet:yl,
`
`tet:razolylacetyl,
`
`thiazolylglyoxyloyl,
`
`thienylglyoxyloyl,
`
`etc.;
`
`lower
`
`alkoxycar:Oonyl
`
`such
`
`as methoxycarbonyl,
`
`ethoxycarbonyl,
`
`tert-butoxycarbonyl,
`
`etc.;
`
`aralkyloxy-
`
`carbonylsuchasbenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
`
`etc.;
`
`lower
`
`alkanesulfonyl
`
`such
`
`as methanesulfonyl 1
`
`ethanesul fonyl, etc. ; aralkyl such as bEmzyl, p-ni trobenzyl,
`
`benzhydryl, trityl, etc.; tri·· (lower alkyl) silyl such as
`
`trimethylsilyl, etc.; and the like.
`
`Removal of the protective g,roup in th:Ls manufacturing
`
`method may be conducted by customary manners. For example,
`
`the protective group for amino represer.ted by Ra may be easily
`
`removed, for example, by i) a me"thod where in case that the
`
`protective group is benzhydryl, p-methoxybenzyl, trityl,
`
`tert-butoxycarbony1, fcrmyl, etc., t::::eatme:cit with an acid such
`
`as formic acid, trJ,:Elu.o:rnacetic acid, a tr:Lfluo:roacetic acid-
`
`anisolo mixed solution, a hydrobromic acid-acetic acid mixed
`
`solution, a hydrochloric acid-dioxane mixed solution, etc. is
`
`conducted; ii) a rr,ethod where in C<<Se that the p:rot:ectl ve 9roup
`
`is benzyl, p-nitrobenzyl, benzhydryl,
`
`t::::ityl, etc.,
`
`a
`
`catalytic
`
`reduction method using palladium-carbon or
`
`PT0_00000015
`
`SAWAI EX. 1015
`Page 14 of 1092
`
`

`

`-.._,
`
`13
`
`palladium hydroxide-carbon is conducted; and iii) a method
`
`where in case that the protective group is a tri- (lower
`
`alkyl) silyl or the like, treatment with water, fluoride anion
`
`(e.g.,
`
`tetra-n-butylarnmoniurn fluorice,
`
`sodium fluoride,
`
`potassium fluoride, hydrofluoric acid), etc. is conducted.
`
`Second Manufacturing Method:
`
`(I)
`
`(In the formulae, R1
`
`' , R1
`
`h, R2
`
`, A, B, X and Z have the same meanings
`
`as defined already.)
`
`In this manufacturing method, the compound (IV) is reacted
`
`with the compound (V) to give the compound (I) of the present
`
`i,nvention.
`
`PT0_00000016
`
`SAWAI EX. 1015
`Page 15 of 1092
`
`

`

`14
`
`The amine compound (IV) and the compound (17) are reacted
`
`under heating or refluxing for 1 to 24 hours as they are or
`
`in an inert solvent, to give the compound (::) of the present
`
`invent: ion.
`
`Examples of
`
`the
`
`j_nert sol vent are acetoni.trij_e,
`
`tetrahydrofuran, 2-.. butanone, dim~Jthyl sulfoxide and N·(cid:173)
`
`methylpyr.rolidone.
`
`J:n the reaction, a base sue;, as sodium
`
`bicarbonate, potassium carbonate or diisopropylethylami.ne may
`
`be added to the reaction mixture.
`
`Incidentally, in the above manufacturing methods, it is
`
`possible
`
`to purify the resulting substance by removing
`
`undesired by-products by means of
`
`recrystallization,
`
`pulverization, prepar(1.ti.ve thin layer chromatography, silica
`
`gel flash chromatography (as described in W. C. Still, et al.,
`
`J. Or:g. Chem., 43, 2923
`
`(19"78)), · mediun-pressure liquid
`
`chromatography and HPLC. The compound p.roduced through HPLC
`
`can be isolated as a corresponding salt.
`
`The starting material used
`
`in the abovei-ment:Loned
`
`manufacturing methods may be easily manufactu:red by tho methods
`
`wh:Lch are known to those skilled in the art. One of the
`
`representative methods is shown as hereunder.
`
`(Manufacturing Method for the Starting Compound (J:I))
`
`PT0_00000017
`
`SAWAI EX. 1015
`Page 16 of 1092
`
`

`

`(In the formulae,
`
`
`
`R1b, R2 ,R", A and Z have the same meanings
`
`as defined already; R" is a hydrogen atom or an aralky.l-based
`
`protective group for amino; and R" is epoxy, 2-haloacetyl or
`
`1-carboxymethan-1-oL)
`
`This manufacturing method is composed of f:~om step (a)
`
`to ste;p (c) in which the step (a) is a step where the compounc
`
`(VI) is rea.cted with the compound (VII), followed by r.·eduction
`
`react.ion to give the compound (VIIIa) depi:mding upon the type
`
`of ac,; the step (b) is a stop where protection is conducted
`
`whem Rb of the compo-.md (VIIIa) is a hydrogen atom; and the
`
`s-cep (c) is a stop where nitro is reduced to amino to give the
`
`compound (II).
`
`Examples of the aral k.yl-based pr:otect:L ve group for am.ino
`
`used in this manufacturing method are benzyl, p-nitrobenzyl,
`
`benzhydryl, etc.
`
`PT0_00000018
`
`SAWAI EX. 1015
`Page 17 of 1092
`
`

`

`16
`
`Step (a) :
`
`Illustration is made for. the following three cases.
`
`1) When He is epoxy, the compound (VI) may be reacted with
`
`the compound (VII) by the same manne:c as in the above-mentioned
`
`second ma:rnfacturing method. Reaction conditions such as
`
`roactio:i temperature, solvent, etc. are the same as well.
`
`2) When R" is 2·-haloaoetyl, the compound (VI) is reacted
`
`with the compound (VII) in the prese::-ice of a base, followed
`
`by reduction reaction to prepare the compound (VII Ia) . The
`
`base is the same as that mentiom~d in the first manufacturing
`
`method.
`
`The rcducti.on reaction may be conducted in the
`
`above-mentioned inex:t solvent or in a solvent of an alcohol
`
`type with stirring in the presence of a reducing agent.
`
`E:xamples of '.:he reducing ag<rnt are sodium borohyd:rido, scdium
`
`cyanoborohyd:r:ide, lithium aluminum hydride, borane, etc.
`
`3) \\hen H" is 1-caJ'.:boxymethan-:C-ol, the compound (VI) is
`
`reacted with the compound (VII) in the presence of a condensing
`
`agent, fo11owed by r<:;duction reaction in the same manner as
`
`in 2) to prepa::::e the compound (VIIIa). The condonoing agent
`
`is the same as that mentioned in the first mamdacturing method.
`
`Stop (b):
`
`When Hb in the compound (VIIIa) is a hydrogen atom, the
`
`amino group is prot!"cte6 by customary manners using di-(cid:173)
`
`te.1:t·-butyl dicarbon<1t:e 1 et:c., 1;0 prep<we the compound (VIIIa).
`
`PT0_00000019
`
`SAWAI EX. 1015
`Page 18 of 1092
`
`

`

`17
`
`Step (c):
`
`A method for the reduction of ni tro to amino may be
`
`conducted by customary manners such as metallic reducti.on using
`
`iron, zinc, etc. and catalytic reduction using a catalys"L such
`
`as palladium-carbon, palladium hydroxide-carbon, Raney nickel,
`
`etc. Ru becomes a. hydrogen atom depending upon the reduction
`
`conditions, but it may be protected again by customary manners.
`
`(Manufacturing Method for Starting Compound (IV))
`
`X\)
`
`(In tte formulae,
`
`Rb, A, B, X and Y1 have -~he same
`
`meanings as defined already.)
`
`This reaction is a r.eaotion where the cornpoi;.nd (IX) and
`
`tho compound (I II) arc subj ectod to amidation reaction to give
`
`a compound (IV"1) and, when Rb ts a prCJtect.i.vo 9roup :Eor amino,
`
`PT0_00000020
`
`SAWAI EX. 1015
`Page 19 of 1092
`
`

`

`18
`
`the p:rotective group is removed to give a compoi;;nd (IV).
`
`'l'he
`
`amidation reaction can be conducted by the same manner as in
`
`the above-mentioned first manufacturing method, and the
`
`reaction conditions such as reaction temperature, solvent, etc.
`
`are the same as well.
`
`B)
`
`NC .... A~
`~NH
`
`(X)
`
`2
`
`This reaction .Ls a re21ction where the compound (X) and
`
`the corr.pound (III) nn? subjected to Ct::nidation reaction and then
`
`to reduction roa(:tion to give a compou::id (I Vb) .
`
`'rhe amidation
`
`reaction can be conducted by the same manner as in the
`
`above· .. ·mentioned first manufactu:dng method, and the reaction
`
`condi'c:ions such as reaccion temperature, solvent, etc. are the
`
`same as we.11.
`
`In the redection reaction, the <1bove-mentioned
`
`cat a} ytic reduction, or a method where reduction is conducted
`
`usini:;; sodium borohydrlde in the presence of cobalt chloride,
`
`may be applied.
`
`PT0_00000021
`
`SAWAI EX. 1015
`Page 20 of 1092
`
`

`

`19
`
`With regard to other compounds such as the compour.d (III),
`
`the compound (V), the compound (VI), and the compound (VII),
`
`those which are available in the market or are appropriately
`
`synthesized by known methods (such as N-alkylation reaction,
`
`cyclization reaction, hydrolysis reaction, etc.) from the
`
`commercially available compounds may be '.lS~Jd.
`
`The compound
`
`(I) of the present invention which is
`
`manufactured as such i.s isolated a:1d purified as a free compound,
`
`a salt there<Jf obtaj.ned by means of salt formation by customary
`
`with va~ious solvents such as
`
`ethanol, etc., or polymorphic crystals, etc. The isolation
`
`and pur:.Lfica.tion may be conducted by applying common chemic<'ll
`
`operations such as extraction, concentration, evaporation,
`
`crystallization,
`
`filtration,
`
`recrystallization, various
`
`chromatographic methods, EJtc.
`
`Vario·u.s isomers may be is8lated by customary manners
`
`utilizing
`
`the physico-chemical differences between
`
`the
`
`isomers.
`
`For· example,
`
`the racemate can be converted to
`
`stereochemically pure isomers by common racemi.c re,so1ution
`
`(such as a method where the racemate .is changed to dlastereome.r
`
`salts with usual optically active acid (for example, tartaric
`
`acid),
`
`folJowed by optical resolution,
`
`and
`
`the like).
`
`Incidentally, a mixture of diastereom~rs may be separated by
`
`customary method such as fractional crystallizaiton or
`
`oh:comatoqraphy, el:c.
`
`Ir, the <.;ase of an opti.cally act.Lvo
`
`PT0_00000022
`
`SAWAI EX. 1015
`Page 21 of 1092
`
`

`

`20
`
`compound, it may be manufactured starting from an appropriate
`
`optically active material.
`
`Industrial Applicability:
`
`The phenethanol deri vat.i ve of the present invention
`
`represented by the general formula (l) or the salt the:::eof has
`
`both an insulin secretion promoting ac~ion and an insulin
`
`sensitivity potentiating action and also has a selective
`
`p3 -recoptor stimulating action, so that it is useful as a
`
`therapeutic agent for diabetes mellitus.
`
`As
`
`confirmed by
`
`a glucose
`
`tolerance
`
`test and
`
`a
`
`hypoglycemic test in insulin-resisting model animals as
`
`described later, the compound of the present invention has both
`
`a good .insulin secretion promoti.ng action and a good insulin
`
`sensitivity potentiating action, so that its usefulness in
`
`diabetes rnellitus is expected. Althc>ugh the lh-receptor
`
`stimulating action may have a possibility of participating in
`
`expression of the insulin secretio::i. promoting action and the
`
`ir:sulin sensi ti vi ty potentiating action, other mechanism
`
`might also poss.:.bly participate thGrein, and the details
`
`::he;:eof have been still un.'<nown yet.
`
`TJ:e Prreceptor
`
`stimulating action of the compound of the pre.~ent invention
`
`is selective to Pr;hecep-:ors in human being. It has been known
`
`that t·.he stimulation of Prreceptor stimulates decomposition
`
`of fat (decomposit1on of the fat tissue triglyceride .intc
`
`PT0_00000023
`
`SAWAI EX. 1015
`Page 22 of 1092
`
`

`

`'·'
`
`\
`
`21
`
`glycerol and free fatty acid), whereby a disapp<i)arance of fat
`
`mass is promoted. Therefore, the compound of the present
`
`invention has an anti-obesity action and an a.nti-hyperlipemia
`
`action (such as triglyceride lowering action, cholesterol
`
`lowering action and HDI, choleste.rol increasing action) and is
`
`useful as a preventive and therapeutic agent for obesity and
`
`hyperlipemia
`
`(such
`
`hypex--~riglyceride:nia,
`
`hyper-
`
`cholesterolemia
`
`and hypo-HDL-lipoproteinemia) .
`
`diseases have been known as ani;nus factors in diabetes mellitus,.
`
`21rr,e1:Loration of those diseases is useful for px:evention
`
`and therapy of diabetes mell:Ltus as well.
`
`The compound of the present invent:'..on is also useful as
`
`a preventive and therapeutlc agent for other diseases where
`
`the improvement o:E symptom can be achieved by reducing the
`
`syrnptoms of obesity and hyperlipemia such as ischemic coronary
`
`diseases such as arteriosclerosis,