ot
`
`Europalsches Patentamt
`
`® 9 ’ £uropeanPatentOffice
`
`Office européen des brevets .
`
`@® Publication number:
`
`:
`
`0 235 796
`
`A2
`
`®)
`
`.
`
`,
`
`EUROPEAN PATENT. APPLICATION
`
`@) Application number: 87102983.1
`@) Dateof filing: 03.03.87
`
`® int. cL“, CO7D 313/12 , CO7D 405/06 ,
`C07D 405/12 , A61K 31/335
`
`
`@) Priority: 03.03.86 JP 45676/86
`®) Applicant: KYOWA HAKKO KOGYO CO., LTD.
`;
`.
`6-1, Ohte-Machi itchome
`:
`@) Date of publication of application:
`. Chiyoda-ku Tokyo(JdP)
`09.09.87 Bulletin 87/37
`
`:
`
`.@) Designated Contracting States:
`BE CH DE ES FR GB IT LI NL
`:
`
`EP0235796A2
`
`@) inventor: Oshima, Etsuo c/o KYOWA HAKKO
`KOGYO CO., LTD|
`Patent Dept. 6-1 Ohteinachi Kchame
`Chiyoda-ku Tokyo(JP)
`Inventor: Kumazawa, Toshiaki c/o KYOWA
`HAKKO KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemach! Itchome
`- Chiyoda-ku Tokya(JP)
`Inventor: Otaki, Shizuo c/o KYOWA HAKKO.
`KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemachi Itchome
`Chiyoda-ku Tokyo(JP)
`Inventor: Obase, Hiroyuki cio KYOWA HAKKO
`KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemachi Itchome
`Chiyoda-ku Takyao(JP)
`Inventor: Ohmori, Kenji cio KYOWA HAKKO
`KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemachi Itchome
`‘Chiyoda-ku Tokyo(JP)
`Inventor: Ishii, Hidee c/o KYOWA HAKKO
`KOGGYO CO., LTD
`Patent Dept 6-1 Ohtemachi Itchome
`Chiyoda-ku Tokyo(JP)
`/
`Inventor: Manabe, Haruhiko cio KYOWA
`HAKKO KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemachi Itchome
`Chiyoda-ku Tokyo(JP)
`inventor: Tamura, Tadafumi c/o KYOWA
`HAKKO KOGYO CO., LTD.
`Patent Dept. 6-1 Ohtemachi itchome
`Chiyoda-ku Tokyo(JP)
`Inventor: Shuto, Katsuichi c/o KYOWA HAKKO
`KOGYO CO., LTD
`Patent Dept. 6-1 Ohtemachi Itchome
`Chiyoda-ku Tokyo(JP)
`
`*
`
`@) Representative: Casalonga, Axel etal
`BUREAU D.A. CASALONGA- JOSSE
`Morassistrasse 8
`D-8000 Munichh &(DE)
`Xerox Copy Centre
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 1
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 1
`
`

`

`
`
`0 235 796
`
`@) Dibenz [b,e] oxepin derivative and antiailergic and antiinflammatory agent.
`
`@) Novel dibenz[b,e}oxepin derivatives are employed in the treatment and controlof allergic conditions such as
`allergic asthma and also employed in the treatmentof inflammation.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 2
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 2
`
`

`

`0 235 796
`
`DIBENZ[b,e]JOXEPIN DERIVATIVE AND ANTIALLERGIC AND ANTIINFLAMMATORY AGENT
`
`Background of the Invention
`Heretofore,
`it has been known that ll-unsubstituted, {I--hydroxy or itoxodibenz{b,eloxepin derivative is
`used for antiinflammatory agents [J. Med. Chem., 24, 633 ~639 (1978)].
`Further,it is known that dibenz{b,eJoxepin derivative wherein substitutents Ra and Rb at t-position have -
`the following definitions, is employed in the treatment and controlofallergic conditions (USP 4,282,365).
`Ra :
`.H, OH, lower alkoxy, lower alkylthio, lower alkylsulfinyl, loweralkylsulfony!, arylthio, NH., NHCHO or
`imidazolyl;
`Rb : H or loweralkyl; -
`or Ra and Rb taken together are = 0, = CH-Re wherein Acis H or aryl.
`Furthermore, it is known thatli-(4-methylpiperazino) dibenz{b,e]oxepin derivative has an antiasthmatic
`activity (USP 4,396,550, USP4,465,835, EP-A-3856).
`‘It is also known that dibenz[b,e]oxepin derivative having the following formula:
`
`-
`
`S—\—-NRgRe
`
`
`
`wherein Rd and Re are loweralkyl and Rf is lower alkyl or halogen, has an antiasthmatic activity (EP-A-
`85870).
`Dibenz[b,eloxepin derivative having an antiallergic activity and having the following structural formula:
`¥
`‘
`
`O- (CH2) rNRgRh
`
`Ri
`
`O
`
`wherein Rg and Rh are alkyl, r is 2 or 3 and Riis alky! or halogen is known (JP-A-227879/84).
`Dibenz[b,ejoxepin derivative having an antiallergic activity and having the following structural formula: |
`
`Rj’
`
`(OL JO)
`
`RK
`
`is -NH-, -S-or -O-, s
`wherein R ;is 4-alkylpiperazino, 3-quinuclidylamino or -Xa-(CH,) sNRrR,, wherein Xs
`is 2 or 3 and Ry and Ry, are alkyl, and R, is CN, 5-tetrazolyl, CONH, or CO.R, wherein R, is H, alkyl or |-
`(ethoxycarbonyloxy)ethy! is known (EP-A-130555).
`Doxepin having an antidepressant activity and having the following structural formula is known(Drugs,
`13,61 (I977)}.
`
`5
`
`10
`
`20
`
`30
`
`35
`
`45
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 3
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 3
`
`

`

`0 235 796
`
`N(Me)>.
`
`[
`
`OL ID)
`
`Dothiepin having an antidepressant activity and having the following structural formula is known {Arz.-
`TAD
`ANY
`Forsch., 2 1039 (1963); ibid., 14 100 (1964)}.
`
`N (Me) 9
`
`ol Je
`
`As the compound having both an antialtergic activity and an antiinflammatory- activity, steroids are
`known.
`It is always desired that a novel compound having an antiallergic activity or an antiinflammatory activity
`be developed.
`
`' Summary of the Invention
`
`The present invention relates to a dibenz{b,e] oxepin derivative represented by the formula (I):
`
`X~ (CH) q~
`
`(I)
`
`wherein A represents a hydroxymethyl, a lower alkoxymethyl, a triphenylmethyloxymethyl, a lower al-
`kanoyloxymethyl, a lower alkanoyl, a carboxy, a lower alkoxy carbonyl, a triphenylmethyioxycarbonyl, -
`CONR,R, (wherein R, and R, are the sameor different and represent hydrogen atom or lower alkyl) 4,4-
`dimethy!-2-oxazoline-2-yl group or -CONHOH; Y represents -(CH.)m°, -CHRs(GH,)m-or -CRe = CRe-(CH,)mn
`whichis substituent at 2-or 3-position of the mother nucleus (wherein R, represents a loweralkyl, Ru and R,
`are the same ordifferent and represent a hydrogen atom or a lower alkyl, m is 0, t, 2, 3 or 4, and the left
`side of the group of Y mentioned above is bound to benzen nucleus); X represents = N-, = CH-or -CH,-;n
`is 0,
`1, 2, 3 or 4; Z represents 4-methyipiperazino, 4-methylhomopiperazino, piperidino, pyrrotidino,
`thiomorpholino, morpholino, or -NRA, (wherein R, and R, are the same or different and represent a
`hydrogen atom or a lower alkyl); and “=== means a single bond or double bond [hereinafter
`referred to as Compound (J) and Compounds with other formula numbers are hereinafter likewise referred
`to], and a pharmaceutically acceptable salt thereof. The present invention further pertains to a pharmaceuti-
`cal composition containing an effective amount of Compound (!) or a pharmaceutically acceptable salt
`thereof as an active ingredient, and a carrier or an excipient.
`The present Compound(|) is useful for treatmentof allergic conditions and inflammation.
`
`10
`
`is
`
`30
`
`38
`
`4§
`
`50
`
`55
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 4
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 4
`
`

`

`0 235 796
`
`
`Detailed Description of the Invention
`
`In the definition of each group of formrula (i), the lower alkyl group includes straight or branched chain
`alkyl groups having | to 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, etc. In the
`definition of the group A, lower alkyl moiety of lower alkoxymethy! group and lower alkoxycarbonyl group
`has the same meaning as previously defined.
`The fower alkoxymethy! group includes methoxymethyl, ethoxymethyi, n-propoxymethyl,
`isopropoxy,
`etc. and the lower alkoxycarbonyl! group includes methoxycarbonyl, ethoxycarbonyl, etc.
`_ In the definition of the group A, the lower alky! moiety of lower aikanoy! group and lower alkanoylox-
`ymethy! group has the same meaning as previously defined.
`’ The lower alkanoy! group includes formyl, acetyl, etc. and the loweralkanoyloxymethyl group includes
`formyloxymethyl, acetyloxymethyl, etc.
`includes pharmaceutically acceptable acid
`The pharmaceutically acceptable salt of Compound (I)
`addition salt, metal salt, ammonium sat, organic amine addition salt, amino acid addition salt, etc.
`The pharmaceutically acceptable acid addition salt of Compound(I) includes inorganic acid salts such
`as hydrochloride, sulfate, phosphate, etc., and organic acid salts such as acetate, maleate, fumarate,
`tartrate, citrate, etc. The pharmaceutically acceptable metal salt includes alkalimetal salts such as sodium
`salt, potassiumsalt, etc., alkaline earch meialsalts such as magnesium salt, calcium salt, etc., and alminium
`salt, zine salt. etc. The pharmaceutically acceptable ‘organic amine addition salt includes addition salt of
`morpholine and piperidine and the pharmaceutically acceptable amino acid addition salt includes addition
`salt of lysine, glysine, phenylalanine, etc.
`Compound (I) is Preparedby.using a compoundrepresented by the-formula’(Hl):
`
`0
`
`( IT)
`
`wherein Y and A have the same meaningsas previously defined of a compound represented by the formula
`«i:
`‘
`
`( IIT)
`
`wherein Y and A havethe same meanings as previously defined as the starting compound. Compound(Il)
`“is disclosed in J. Med. Chem.,19, 941(i976), ibid., 20 , 1499 (1977) and JP-A-21679/83.
`.
`Compound(IH) wherein -Y-A is -COOHis disclosed in JP-A-21679/83 and the other Compounds (Ul) can
`be prepared according to the method described in the publication though they do not occur in the
`publication.
`The process for preparing Compound ()) is: explained, depending on the kind of the group X.
`
`Process A
`
`[Synthesis of Compound(I) wherein X is = CH-(Part 1)]
`
`The carboxy group of Compound (Ila) is protected according to the following reaction scheme.
`
`20
`
`26
`
`- 1
`
`3s
`
`45
`
`55
`
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 5
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 5
`
`

`

`0 235 796
`
`socl,
`G+Y-coog ———____
`
`aoO
`
`0
`
`/. OH
`awe3
`8 cH,
`
`n
`
`10
`
`9
`
`.
`
`socl,
`20a,
`
`;
`
`,
`
`CH,
`
`0
`Ln 2
`Grr, ks
`0
`(Vv)
`In the formulae, Y has the same meaning as previously defined, and Compound (la) is included in
`Compound (i) (compounds with an alphabet suffix following formula number are likewise included in
`compounds with common formula no.).
`Compound(lla) is reacted with | to 5 equivalents of thionyl chloride and | to 5equivalents of 2-amino-2-
`methyl-l-propano! on the basis of Compound (ila)
`in an inert solvent such as methylene chloride,
`if
`necessary in the presence of a base such as triethylamine at a temperature of from 0°C to room
`temperature for | -24 hours to form Compound (iV). Compound (IV) can also be obtained by reacting
`Compound(la) with thionyl chloride in advance and then with 2-amino-2-methyl-l-propanol.
`Compound(IV) is reacted with 1-5 equivalents of thionyl chloride in an inert solvent such as methylene
`chloride, toluene and benzene at a temperature of from 0°C to room temperature for i -24 hours to form
`Compound (V).
`Compounds (la) and (Ib) can be prepared from Compound (¥) according to the following reaction -
`* scheme.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`$0
`
`5S
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 6
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 6
`
`

`

`an
`
`18
`
`20
`
`25
`
`30
`
`55
`
`0 235796
`
`HalMg (CH) 1.12 (VI)
`
`B
`(CH) 2
`2—, Olywt
`
`-H.O
`
`H50
`
`{
`
`oO
`
`{ Ta)
`
`“
`
`Gy ¥-C05R,
`
`( Ib)
`
`“In the formulae, Y, Z, and n have the same menaings as previously defined, Re is hydrogen or a lower
`*alky! group, RF’, is a lower alkyl group and Hal is halogen.
`As used herein, the term lower alkyl has the same meaning as that of lower alkyl in each group of
`formula (I).-Halogen includes chlorine, bromine and iodine.
`Compound (V)
`is
`reacted with |
`-5 equivalents of Compound (VI)
`in an inert solvent such as
`‘tetrahydrofuran and diethyl ether under atmosphere of an inert gas such as nitrogen and argon to form
`' Compound (VII). The reaction is carried out at a temperature of from 0°C to room temperature and is”
`usually completed in | -24 hours.
`- Compound (Vil) is reacted with | -5 equivalents of thiony! chloride or phosphoryl chloride in ‘an inert
`solvent such as methylene chloride in the presence of a base such as pyridine to form Compound(la). The
`reaction is carried out at a temperature of from 0°C to room temperature and is completedin | -24 hours.
`Compound (la) is incubated in an alcohol containing water, such as aqueous methanol solution, in the
`presence of an appropriate acidic catalyst such as p-toluenesulfonic acid at a temperature of from room
`temperature to the boiling point of the solvent to form Compound (Ib) wherein Ry is H. The reaction is
`completed in | -24 hours.
`.
`Compound (Vil) is incubated in an ‘alcohol of R,’OH in the presence of an appropriate acidic catalyst
`such as p-toluenesulfonic acid at a temperature of from roam temperatureto the boiling point of the solvent
`to form Compound(ib) wherein R, is a lower alkyl. The reaction is completedin | -24 hours.
`
`/
`
`Process B
`
`. [Synthesis of Compound (J) wherein X is = CH-(Part 2)]
`
`The carboxy group -of a compound represented by the formula (tla) ‘can be converted to a lower
`alkoxymethy! group or a trityloxymethyl group according to the following reaction scheme.
`.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 7
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 7
`
`

`

`10
`
`“20
`
`3a
`
`35
`
`50
`
`55
`
`0 235 796
`
`
`
`5 G Y-CO5H
`ot| LiAlH,
`
`oH
`
`Gy"cH,08
`
`0
`
`(VIII)
`
`ROH
`
`| One“CHZ0C(PA) Cus1c08,
`
`.
`
`,
`
`“Oxidetion
`
`C(Ph) ,Cl
`
`(Ix)
`
`oxidation
`
`o
`
`
`
`Y-CHIORg!
`
`0
`
`_ (XZ)
`In the formulae, Y has the same meaning as previcusly defined, R, is a lower alkyl group and A,’ is a
`trity! group or a lower alky! group. The term lower alkyl has the same meaning as that of lower alky! in each
`group in formula(I).
`Compound (lia) is reduced with | -5 equivalents of lithium aluminium hydride in tetrahydrofuran at a
`temperature of from 0°C to room temperature for | -24 hours to form Compound (VIII).
`Compound (Vill) is reacted with | -5 equivalents oftrityl chloride in pyridine at a temperature of from
`room temperature to 100°C for | -24 hours to form Compound (1X).
`-
`Campound (IX) is oxidized with | -5 equivalents of an appropriate oxidizing agent such as potassium
`permanganate and pyridinium chlorochromate in an inert solvent such as methylene chloride and acetone to
`form Compound (XI) wherein A, is trityl, The reaction is carried out at a temperature of from 0°C to the
`bailing point of the solvent and is completed in | -24 hours.
`Compound (Vill) is incubated in an alcohol of R,OH in the presence of an appropriate acidic catalyst
`such as sulfuric acid at’ a temperature of from room temperature to the boiling point of the solvent to form
`Compound (X). The reaction is usually completed in 1 -24 hours.
`Compound (X) is oxidized with 1 -5 equivalents of an appropriate oxidizing agent such as Jones reagent
`in an inert solvent such as acetone to form Compound (XI) wherein Ry’ is a lower- alkyl. The reaction is
`carried out at a temperature of from 0°C to the boiling point of the solvent and is usually completed in | -24
`hours.
`The compounds represented by the formulae (Ic) and (Id) and if desired, the compound represented by
`the formula (Je) can be synthesized from Compound (XI} according to the following reaction scheme.
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 8
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 8
`
`

`

`0.235 796
`
`wm
`
`QO
`
`O
`
`(XT)
`
`¥-CH,OR,
`
`[Bates (CH) na? (VI)
`(CH2) n+1?
`
`HO.
`
`(XII)
`(CH
`
`15
`
`20
`
`2s
`
`30
`
`35
`
`45
`
`50
`
`55
`
`~H,O
`OR,'
`9
`
`¥~CH.
`
`0
`
`H
`
`(Id)
`,
`
`;
`
`Oxidation
`
`Ha, CH) 2
`
`
`
`(Te)
`
`In the formulae, Y, Z, Re’, n and Hal have the same meanings as previously defined.
`Compound (XI) is reactedwith Compound (VI) which is Grignard reagent accordingto the same manner
`“as in the reaction step from Compound (V) !o Compound (Vi) in Process A toform Compound (xii).
`.Compound (XI) is subjected to reaction according to the same manner as in the reaction step from
`Compound (Vil) to Compound(la) in Process A to form Compound(Ic).
`Compound (Ic) is incubated in a solvent -ontaining water such as aqueous dioxane in the presence of
`an appropriate acidic catalyst such as p-toluenesulfonic acid at a temperature of from room temperature to
`the boiling point of the solvent to form Compound (Id). The reaction is usually completed in [ -24 hours.
`Compound (id) can also be obtained in one step by incubating Compound (Xil) in a solvent containing
`water such as aqueous dioxane in the presence of an appropriate acidic catalyst such as sulfonic acid at a
`temperature of from room temperature to the boiling point of the solvent. The reaction is usually completed
`in | -24 hours,
`:
`;
`if desired, Compound(Id) is oxidized with | -5 equivalents of an appropriate oxidizing agent such as
`' Jones reagent in an inert solvent such as acetone to form Compound (le). The reaction is carried out ata
`temperature of from 0°C to the boiling point of the solvent and is usually completed in { -24 hours.
`
`,
`
`Process €
`
`[Synthesis of Compound(!) wherein X is =CH-(Part 3)).
`
`9
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 9
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 9
`
`

`

`0 235 796
`
`Y-A' + PhP =CH(CH.) 2
`(XIII)
`
`Ha,
`
`(CH) 92
`
`0
`
`
`CS
`
`°
`(TTb)
`
`cence
`
`SttNRAtha
`
`Qty -a:
`
`0 (
`
`r£)
`
`In the formulae, Y, Z, and n have the same meanings as previously defined. N represents the groups
`falling within the definition of A but lower alkanoy! group.
`in an inert solvent such as
`Compound (Ib) is reacted with |
`-5 equivalents of Compound (XIII)
`tetrahydrofuran under atmosphere of an inert gas such as nitrogen and argon at a temperature of from 0°C
`fo room temperaturefor | -24 hours to form Compound(I; ).
`Compound (XIN) whichis ylide, can be Prepared according to the method described in C.A. 63 16366a -
`
`(1965).
`
`+
`PhP + Hal (CH. dn[Hal ——> Ph.3P (CH, dnpytel - Hal”
`XIV)
`xy)
`
`Dow ot
`
`betel”.
`
`tamer
`
`(XVT)
`
`in the formulae, Hal, n and Z have the same meanings as previously defined and qis tore.
`Compound (XIV) is reacted with an equivalent of triphenylphosphine in toluene at reflux of the solvent
`for | -24 hours to form Compound (XV).
`Compound (XV) is reacted with | -5 equivalents of HZ in ethanol at reflux of the solvent for 1 -24 hours
`and excess HZ is distilled away under reduced pressure. After the addition of 1 -5 equivalents of HHal on
`the basis of Compound (XV), the mixture is incubated ata temperature of from.O°C to the boiling point of
`the solventfor | -24 hours to form Compound (XVI) whichis Wittig reagent.
`Compound (XVIis treated with [| -2 equivalents of an appropriate base such’ as n-butyl lithium in an
`inert solvent such as tetrahydrofuran under atmosphereof an inert gas such as nitrogen and argon to form
`ylide (Xill). The reaction is carried out at -78°C ~ room temperature and is usually completed in | -24 hours.
`
`Process D
`
`[Synthesis of Compound (1) wherein X is =CH-(Part 4)]
`
`10
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 10
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4§
`
`§0
`
`55
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 10
`
`

`

`0 235 796
`
`G
`formaldehyde
`>7— Y-A + or polymerized +
`oN ;
`formaldehyde
`(IIT)
`|
`
`BaNg
`
`
`
`4H2
`
`( Ig)
`In the formulae, Y, Z and A have the same meanings as previously defined.
`The process is known as Prince reaction [New Experimental Chemical Course (Maruzen), Vol. 14,
`Synthesis and Reaction of Organic CompoundIll, page 1375 (1977)}.
`.
`_ Compound (iH),
`| ‘to 5 equivalents of formaldehyde and-|
`to 5 equivalents of HZ are subjected to
`reaction in an inert solvent such as tetrachloroethane in the presence of an acid or reaction in an acid as.
`such serving as a solvent under atmosphere of an inert gas such as nitrogen.and argon to yield Compound
`{Ig).
`
`trioxane, etc. The acid
`The formaldehyde or polymerized formaldehyde includes p-formaldehyde,
`includes acetic acid, trichloroacetic acid,trifluoroacetic acid, etc. The reaction is carried out at a tempera-
`ture of from room temperature to the boiling point of the solvent and is completed in | -24 hours.
`Gompound(II) which is the starting material can be prepared according to the process described in JP-
`A-21679/83, as shown below.
`
`.
`
`
`
`
`
`(IITa)
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`to 5
`to 5 equivalents of methyltriphenylphosphonium bromide ‘and |
`|
`is, Compound (llb),
`That
`equivalents of n-butyl lithium on the basis of Compound(Ib) are subjected to reaction in an inert solvent at
`from -78°C to room temperature for | to'5 hours to yield ylide (XVII) which is reacted with an equivalents of
`Compound (Nb) in an inert solvent at from -78°C to room temperature under atmosphere of an inert gas for
`1 to 24 hours to yield Compould (Illa).
`Theinert gas includes nitrogen, argon, etc. and the inert solvent includes tetrahydrofuran, etc.
`The group A’
`in Compound (lila) can easily. be converted to a lower alkanoyl group as is statedin
`Process | and therefore, Compound(Ill) can easily be prepared.
`
`&5
`
`Process E
`
`[Synthesis of Compound (1) wherein X is = N-]
`
`4
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 11
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 11
`
`

`

`0 235 796
`
`0
`
`°
`(ITb)
`
`GF Era! + HON (CHS) 2
`(XVIIT)
`
`New a
`\ 35) 4
`
`|
`
`( Th)
`
`Compound {Ilb) and [ to 10 equivalents of Compound (XVII) are subjected to reaction in an inert solvent
`such as benzene in the presence of | to 10 equivalents of titanium tetrachloride at from 0°C to the boiling
`point of the solvent under atmosphere of an inert gas such as nitrogen and argon for | to 48 hoursto yield
`Compound (ih).
`
`Process E
`. [Synthesis of Compound(1) wherein X is -CH,-(Part I)]
`
`oO
`Orr]
`i
`
`oO
`(XIX),
`
`‘Halmg (CH,) ntl
`
`
`
`(VI)
`
`«
`
`O
`(Vv)
`
`/
`Reduction
`otk 4
`
`i
`
`Chlorination —
`
`an
`
`cl
`
`|
`
`°
`
`(XX)
`
`—-+
`
`ils) 3
`CH,
`an
`¢°
`Y— |--
`“y i
`
`:
`
`O 9
`- (44)
`
`6
`
`icks),
`cH,
`2
`C)4+Y -CO.R
`oN
`28
`(T3)
`
`.
`
`in the formulae, Y, Z,n, Ry and Hal have the same meanings as previously defined.
`Compound (V) is reduced with | to 5 equivalent oflithium aluminium hydride or sodium borohydride in
`"an inert soivent such as tetrahydrofuran and methanol at from 0°C to room temperature for | to 24 hours to
`yield Compound (xX).
`Compound (XD) and |
`to 5 equivalents of thionyl chloride or phosphoryt chloride are subjectedto
`reaction in an appropriate base such as pyridine at from 0°C to room temperature to yield Compound (XX).
`
`12
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 12
`
`70
`
`1S
`
`20
`
`25
`
`45
`
`50
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 12
`
`

`

`0 235 796
`
`Compound (XX) and | to 5 equivalents of Compound (VI) are subjected to reaction in the same manner
`as in the reaction step from Compound (V) to Campound (Vil) in Process A to yield Compound (i).
`Compound(li) is subjected to reaction in the same manner as in the reaction step from Compound -
`(Vil) to Compound (Ib) or the reaction step fram Compound (la) to Compound (Ib) in Process A to yield
`Compound(lj). -
`
`:
`
`Process G
`
`10
`
`[Synthesis of Compound(I) wherein X is -CH,-(Part 2))
`
`OE
`
`:
`
`OO
`
`cl
`
`(0)
`
`ONS
`(XX)
`
`
`
`,
`
`GQs-2-c,0R,
`
`.. Chlorination
`
`
`:
`
`_
`
`=
`
`G5-y-cH,0R,'
`
`,
`
`o
`(XXII)
`
`_
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Halls (C8,Yna? (VI). OT Cy-¥-cH20R,
`
`CHS- (CH) nz
`
`fo)
`
`.
`
`+
`H
`—_
`
`(CH,)
`2
`
`
`(Tk)
`eas
`Oxidiza-
`tion
`
`2
`
`CH.)
`A 42) 2
`CH,
`
`,
`Cy-x-co,#
`
`;
`
`(Im)
`
`;
`
`- CH
`
`2
`
`(I2)
`
`.
`-
`Gy-Y-CcH,0H
`
`Compound (XXI) is subjected to chlorination in the samme manner as in Process F to yield Compound
`OXXH). Compound (XXH) and Compound (VI) .are subjected to reaction in the same manner as in Process F
`
`to yield Cornpound (Ik). Compound (Ik) is treated in the same manneras in Process B to form Compound .
`
`(It).
`
`Compound (ff) is further treated to form Compound(Im).
`.
`Compound (IX) is included in the definition of the starting material (XX).
`Compound(XI) is reduced with | to 5 equivalentsof lithium alminium hydride or sodium borohydridein
`an inert.solvent such as tetrahydrofuran and methanol at from 0°C to room temperature fortIto 24 hours to
`yield Compound CON).
`:
`
`Process H
`
`[Synthesis of Compound (I) wherein X is -CH,-(Part 3)]
`
`Compound (1) wherein X is -CH.-can also be prepared by subjecting Compounds (la) (Ig) obtained by
`_ the Processes A -D to reduction such as hydrogenation using paradium-carbonas catalyst.
`The intermediates and the desired compounds in each of the processes described above can be
`purified and isolated by a purification method which is usually used in the field of organic chemical.
`synthesis, such asfiltration, extraction with organic solvent such as ethyl acetate and methylene chioride,
`drying, concentration, recrystallization, column chromatography,ete.
`
`.
`
`13
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 13
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 13
`
`

`

`0 235 796
`
`-(lh) obtained in each of the processes described above, with regard to
`Out of Compounds (la)
`stereochemistry at Il-position of dibenz[b,eJoxepin, Compounds(la), (Ib), (Ic), (Id), (fq) and (Ih) are apt to be
`formed as a trans-form and Compound(I) is apt to be formed as a cis-form,with high frequency compared
`with the other form.
`When Compound(I) except Compounds(li) -(im)is produced as a cis-trans mixture, Compound(I) is
`separated and purified by an appropriate method which is usually used in the field of organic chemical
`synthesis, such as column chromatography, recrystallization, etc.
`If desired, cis-form can be converted to transform. For example, cis-form is added to an acetic acid and
`ihe mixture is neated ai refiux in the presence of an appropriate catalyst such as p-toluenesuifonic acid for i
`-24 hours to form trans-form.
`With regard to the denotation of cis-form (or cin-form) and trans form (or anti-form) of Compound(I),
`Compound(I) wherein the substituent bound to the double bond is on the same side as oxygen of oxepin,
`is cis-form (or cin-form) and Cornpound (1) wherein the substituent is on the opposite side is trans-form (or
`anti-form).
`.
`Further, if cis-or trans-form is denoted according to E -Z expression, cis-form (or cin-form) is Z-form
`and trans-form (or anti-form) is E-form.
`For example, the compound represanted by the following formula is cis-form (or cin-form or Z-form).
`
`H
`
`(CH) 72
`
`Table | shows examples of Compound () or pharmaceutically acceptable salts thereof and“Table 2
`
`showsthe structural formuia thereof.
`Table 3 shows characteristic signals in NMR and Table 4 showsretention time in HPLC.
`
`10
`
`15
`
`20
`
`26
`
`30
`
`48
`
`14
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 14
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 14
`
`

`

`10
`
`20
`
`25
`
`-
`
`30
`
`-
`
`38
`
`46
`
`50
`
`55
`
`0 235 796
`
`Table 1
`
`
`Methyl cis-11-(3-dimethylaminopropylidene) -
`
`6,ll-dihydrodibenz [b,e]oxepin-2-carboxylate
`
`
`
`
`
`
`
`
`
`
`trans~ll-(3-dimethylaminopropylidene) -
`Methyl
`6,11-dihydrodibenz [b,e]oxepin-2-carboxylate
`
`
`
`
`
`Ethyl cis-ll-(3-dimethylaminopropylidene) -6,11-
`
`
`dihydrodibenz[(b,e]oxepin-2-carboxylate
`
`
`Ethyl trans-11- (3-dimethylaminopropylidene) -
`6,11-dihydrodibenz [b,e]oxepin-2-carboxylate
`
`
`
`Cis-11- (3-dimethy laminopropylidene) -6,11-
`dihydrodibenz[b,e]oxepin~2-carboxylic acid
`
`
`dihydrodibenz[b,e] oxepin-2-carboxylic acid
`Trans-11-(3-dimethylaminopropylidene) -6,11-
`
`
`6,11-dihydrodibenz [b,e]oxepin-2~carboxylate
`
`
`
`
`
`
`
`
`‘Methyl cis-11- (3-pyrrolidinopropylidene) -6,11-
`dihydrodibenz[b,e]oxepin-2-carboxylate
`
`
`trans~-11- (3-pyrrolidinopropylidene) -
`Methyl
`6,11-dihydrodibenz [b,e] oxepin-2~-carboxylate.
`
`
`
`
`
`Cis-11-(3-pyrrolidinopropylidene)-6,11~
`dihydrodibenz{b,e]oxepin-2-carboxylic acid
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`
`
`
`
`
`Methyl cis-1ll-(3-diethylaminopropylidene) -6,11-
`
`dihydrodibenz[b,e]oxepin~2-carboxylate
`
`Methyl trans-ll~ (3-diethylaminopropylidene) -
`
`
`
`
`
`Cis-1ll-(3-diethylaminopropylidene).-6,11-
`dihydrodibenz (b,e]oxepin-2~carboxylic acid
`
`Trans-Ll- (3-diethylaminopropylidene) -~6,11-
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`
` Trans~1ll- (3-pyrrolidinopropylidene) -6,11-
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 15
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 15
`
`

`

`10
`
`26
`
`25
`
`30
`
`35
`
`45
`
`50
`
`Ss
`
`0 235 796
`
`
`Methyl cis-11-(4-dimethylaminobutylidene) -
`6,l1~dihydrodibenz (b,e]oxepin-2-carboxylate
`
`trans-11l-(4-dimethylaminobutylidene) -
`Methyl
`6,ll-dihydrodibenz [{b,e]oxepin-2-carboxylate
`
`
`
`
`Cis-11- (4-dimethylaminobutylidene) -6,11-
`dihydrodibenz[b,e]oxepin~2-carboxylic acid
`Trans~11l-(4~dimethylaminobutylidene)-6,11-
`dihydrodibenz[b,eloxepin-2-carboxylic acid
`
`
`
`Methyl cis-11~[2-(4-methylpiperazino) ~
`ethylidene]~6,11-dihydrodibenz{b,e]oxepin-2-
`carboxylate
`
`
`
`
`Methyl trans-11-[(2-(4-methylpiperazino) -
`ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`carboxylate
`
`Cis~11-[2-(4-methylpiperazino) ethylidene]-
`6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid
`
`
`
`dihvdrodibenz[b,.e]oxepin-2-carboxvlate
`dihydrodibenz{b,e]oxepin-2-carboxylate
`
`
`
`Trans-ll-[2-(4~methylpiperazino) ethylidene] -
`6,1li-dihydrodibenz[b,e]oxepin-2-carboxylic acid
`
`Methyl cis~-11-(2-morpholinoethylidene) -6,11-
`
`Methyl trans-11-(2-morpholinoethylidene) -6,11-
`
`Methyl cis-11-(2-thiomorpholinoethylidene) -
`
`
`
`Cis-1l-(2-morpholinoethylidene) -6,11-
`
`
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`
`
`
`
`Trans-1ll-(2-morpholinoethylidene)-6,11-
`dihydrodibenz[{b,e]oxepin-2-carboxylic acid
`
`
`6,1l1-dihydrodibenz[b,e]oxepin-2-carhoxylate
`
`Methyl trans-1ll-(2-thiomorpholinoethylidene) -
`6,11-dihydrodibenz(b,e]oxepin-2-carboxylate
`
`
`
`
`Cis-1l- (2-thiomorpholinoethylidene) -6,11-
`dihydrodibenz{b,e]oxepin-2-carboxylic acid
`
`
`
`
` Trans-~1l-(2-thiomorpholinoethylidene) -6,11-
`dihydrodibenz{(b,e]oxepin-2-carboxylic acid
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 16
`
`
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 16
`
`

`

`0 235 796
`
`Methyl trans-1l- (2-pyrrolidinoethylidene) -—
`6,11-dihydrodibenz{b,e]oxepin-2-carboxyvlate
`
`‘Methyl cis-ll-(2-piperidinoethylidene) -6,11-
`dihydrodibenz[b,e]oxepin-2-carboxylate
`
`
` Methyl cis-ll~-(2-pyrrolidinoethylidene) -6,11-
`dihydrodibénz [(b,eJoxepin-2-carboxylate —
`
`
`
`
`
`
`
`
`
`
`Methyl trans-ll-(2- piperidinoethylidene) -6,11-_
`dihydrodibenz[b, ejoxepin-2-carboxylate
` Methyl cis-11-(3--dimethylaminopropylidene) -
`
`
`6,11-~dihydrodibenz [b, eloxepin-2-acetate
`
`
`“Methyl trans-1l-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[{b,eJoxepin-2-acetate
`
`
`Ethyl cis-~11-(3--dimethy laminopropylidene)-6,11-
`dihydrodibenz [b,e] oxepin-2-acetate
`
`
`
`Ethyl
`trans-11-(3-dimethylaminopropylidene) -
`6,11-dihydrodibenz (b,¢)oxepin-2-acetate
`
`
`Cis-11l~(3-dimethylaminopropylidene) -6,11-
`dihydrodibenz[b,eJoxepin-2-acetic acid
`
`
`
`
`
`PY-2G2Rn2
`pul idenel\-
`an
`Trans-ll~(3-dimethylamino
`dihydrodibenz[b,e]oxepin 2-
`cetic acid
`
`
`
`
`
`6,ll-dihydrodibenz[b,e]oxepin-2-acetate
`
`
`
`
`dihydrodibenz (b,e]oxepin-2-acetic acid | Methyl cis-11-(3--pyrrolidinopropylidene) --6, ll-
`dihydrodibenz[{b,e]oxepin-2-acetate
`
`
`Methyl trans-ll-(3-pyrrolidinopropylidene) -
`6,11-dihydrodibenz[b,e]oxepin-2-acetate
`
`
`2a
`
`Methyl cis-11-(4-dimethylaminobutylidene) -6,11-
`dihydrodibenz [b,e]oxepin~2-acetate
`
`Methyl
`
`trans-1l-(4-dimethylaminobutylidene) -
`
`Cis-1l-(4-dimethylaminobutylidene) -6,11-
`dihydrodibenz[b,e]oxepin-2-acetic acid
`
`Trans~-ll-(4-dimethylaminobutylidene) -6,11-
`
`20
`
`25
`
`30
`
`35
`
`45 -
`
`50
`
`55
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 17
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 17
`
`

`

`0 235 796
`
` Cis-11-(3-pyrrolidinopropylidene) ~6,11-
`dihydrodibenz[{b,e]oxepin-2-acetic acid
`
`Trans-l1-(3~pyrrolidinopropylidene) -6,11-
`
`
`
`
`
`
`
`
`
`dihydrodibenz(b,e]oxepin~-2~acetic acid
`
`
`Methyl cis-11-[2-(4-methylpiperazino) ~
`ethy lidene-6,11-dihydrodibenz (b,e] oxepin-2-
`
`
`acetate
`.
`
`
`trans~1l-([2-(4-methylpiperazino) -
`Methyl
`ethylidene-6,11-dihydrodibenz[b,e]oxepin-2-
`acetate
`
`
`
`
`Cis-11-(2-(4-methylpiperazino) -ethylidene-
`6,11-dihydrodibenz[b,eloxepin-2-acetic acid
`
`
`
`Trans-11-(2- (4-methylpiperazino) -ethylidene-
`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid
`
`Methyl cis-3-[1ll-(3-dimethylaminopropylidene) -
`6,11-dihydrodibenz [b,e]oxepin-2-y1] -propionate
`
`propionate
` Methyl trans-3-[11l~(3-dimethylaminopropyli-
`dene) -6,11-dihydrodibenz(b,e]oxepin-2~-yl]-
`
`
`
`
`
`
`
`6,11-dihydrodibenz[b,e]oxepin~-3-acetate
`dihydrodibenz[b,e]oxepin-3-acetic acid
`
`
`dihydrodibenz(b,eJoxepin-3-acetic acid
`
`
`Cis-11-(3-dimethylaminopropylidene) -2-(2-
`hydroxyethy1) ~6,1l1-dihydrodibenz[b,e]oxepin
`
`
` Trans-11-(3-dimethylaminopropylidene) -2- (2-
`
`
`
`
`Cis~3-[11-(3~dimethylaminopropylidene) -6,11-
`Gihydrodibenz[b,ejoxepin-2-yl]-propionic acid
`
`Trans-3~-{(11- (3-dimethylaminopropylidene) -6,11~
`dihydrodibenz[b,eJoxepin-2-yl]-propionic acid
`
`Methyl cis-l1-(3-dimethylaminopropylidene) ~
`6,1ll-dihydrodibenz[b,e] oxepin-3-acetate
`
`Methyl
`
`trans~11l- (3-dimethylaminopropylidene) -
`
`
` Cis-ll-(3-dimethylaminopropylidene) -6,11-
`
`Trans-11l-(3-dimethylaminopropylidene) ~6,11-
`
`hydroxyethyl) -6,11-dihydrodibenz[b,e]oxepin
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 18
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1035, Page 18
`
`

`

`0 235 796 .
`
`Cis-1ll-(3-dimethy laminopropylidene) -2-(2-
`triphenylme thyloxymethy1) -6 ,ll-dihydrodibenz-
`[b,e]oxepin
`Trans~1l-(3--dimethylaminopropylidene) - 2-(2-
`triphenylmethyloxymethy1)-6,11-dihydrodibenz-
`[b,e]oxepin
`
`|
`
`Cis-li-~ (3-dimethylaminopropylidene) -2-(3-
`hydroxypropyl) -6,11-dihydrodibenz{b,e]oxepin
`
`Trans-11-(3-dimethylaminoprop