US005116863A
`United States Patent 15
`5,116,863
`[11] Patent Number:
`May26, 1992
`[45] Date of Patent:
`Oshimaet al.
`
` IOUTA
`
`{54] DIBENZ[B,EJOXEPIN DERIVATIVE AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`[75]
`
`Inventors: Etsuo Oshima; Toshiaki Kumazawa;
`Shizuo Otaki; Hiroyuki Obase, all of
`Shizuoka; Kenji Ohmori, Mishima;
`Hidee Ishii, Shizuoka; Haruhiko
`Manabe, Shizuoka; Tadafumi
`Tamura, Shizuoka; Katsuichi Shuto,
`Shizuoka,all of Japan
`
`[73] Assignee:
`
`Kyowa Hakko KogyoCo., Ltd.,
`Tokyo, Japan
`
`[21] Appl. No.: 20,900
`
`[22] Filed:
`
`Mar, 2, 1987
`
`Foreign Application Priority Data
`[30]
`Mar. 3.1986 [FP]
`Japan csssssssssssssesssesseenens 61-45676
`
`Int. CLS vocecscccseseeee A61K 31/335; CO7D 313/12
`[51]
`[52] U.S. Ch. eessesessssssseesecssssseeenseen 514/450; 548/215:
`548/525; 549/354; 514/212; 514/228.2;
`514/232.8: 514/253; 514/320; 514/374;
`514/422: 540/596; 540/600; 544/62; 544/137;
`544/147; 544/369; 544/375: 544/58.7; 546/196
`[58] Field of Search ........ssss 540/596, 602; 544/62,
`544/137, 147, 369, 375, 98.7; 546/196; 548/215,
`$25; 549/354; 514/212, 222, 233. 234, 236, 237,
`253, 320, 374, 422, 450, 228.2, 232.8
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,354,155 11/1967 Tretter 0c 549/354 X
`3,420,851
`1/1969 Bloom et al. wc
`eee 549/354
`3,509,176 4/1970 Winter et al. 0.
`cee 260/333
`8/1981 Rokach woes 548/252
`4,282,365
`
`8/1983 Takizawa 0... cece 549/354
`4,396,550
`
`
`
`
`
`8/1984 Takizawa oe 546/133
`4,465,835
`4/1986 Helsley et al. oe 549/354
`4.585.788
`
`6/1986 Takizawa oo... 514/253
`4,596,804
`4.873.865 10/1989 Lever et al...
`.. 549/354
`4,923,892
`5/1990 Lever et al. woes 514/450
`FOREIGN PATENT DOCUMENTS
`0069810
`1/1983 European Pat. Off.
`.
`0085870
`8/1983 European Pat. Off.
`.
`0130555
`1/1985 European Pat. Off.
`.
`214779
`3/1987 European Pat. Off.
`.
`0021679
`2/1983 Japan .
`0227879 12/1984 Japan .
`1003950
`9/1965 United Kingdom .
`1018995
`2/1966 United Kingdom .
`
`OTHER PUBLICATIONS
`
`Wellcome Foundation Ltd., Chemical Abstracts, vol.
`107 (1987) 58,673r.
`Metvosova. Arz.-Forsch., vol. 13 (1963) 1039:43.
`Benesova, Arz.~Forsch.. vol. 14 (1964) 100:3.
`Chem. Abs., vol. 63 (1965) 16366a.
`Drugs, vol. 13 (1977) 161:218.
`J. Med. Chem., vol. 19, No. 7 (1976) 941:6.
`J. Med. Chem., vol. 20, No. 11 (1977) 1499:501.
`J. Med. Chem., vol. 21, No. 7 (1978) 633:9.
`
`Primary Examiner—Richard L. Raymond
`Attorney, Agent, or Firm—Fitzpatrick, Cella, Harper &
`Scinto
`
`[57]
`ABSTRACT
`Novel dibenz{b,e]oxepin derivatives are employed in
`the treatment and controlof allergic conditions such as
`allergic asthma and also employed in the treatment of
`inflammation.
`
`3 Claims, No Drawings
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 1
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 1
`
`

`

`1
`
`5,116,863
`
`2
`Doxepin having an antidepressant activity and hav-
`ing the following structural formula is known [Drugs,
`13, 161 (1977).
`
`DIBENZ[B,E]JOXEPIN DERIVATIVE AND
`PHARMACEUTICAL COMPOSITIONS THEREOF
`
`BACKGROUND OF THE INVENTION
`
`5
`
`
`
`Dothiepin having an antidepressant activity and hav-
`ing the following structural formula is known [Arz.-
`Forsch., 13 1039 (1963); ibid., 14 100 (1964)].
`
`N(Me)2
`
`s
`
`As the compound having both an antiallergic activity
`and an antiinflammatoryactivity, steroids are known.
`It is always desired that a novel compound having an
`antiallergic activity or an antiinflammatoryactivity be
`developed.
`SUMMARYOF THE INVENTION
`
`10
`
`—_ Wa
`
`20
`
`25
`
`30
`
`The present invention relates to a dibenz[b,eJoxepin
`derivative represented by the formula (I):
`
`35
`
`(1)
`
`XA(CH)n—Z
`
`1
`
`Heretofore, it has been knownthat 11-unsubstituted,
`li-hydroxy or 11-oxodibenz[b,e]oxepin derivative is
`used for antiinflammatory agents [J. Med. Chem., 21,
`633-639 (1978)].
`Further,it is known that dibenz[b,e]Joxepin derivative
`wherein substitutents Ra and Rb at 11-position have the
`following definitions, is employed in the treatment and
`control ofallergic conditions (U.S. Pat. No. 4,282,365).
`Ra: H, OH,loweralkoxy, lower alkylthio, lower alkyl-
`sulfinyl, lower alkylsulfonyl, arylthio, NH2, NHCHO
`or imidazoly];
`Rb: H or loweralkyl; or Ra and Rb taken together are
`=0, =CH—Rcwherein Re is H or aryl.
`Furthermore,
`it
`is
`known
`that
`11-(4-methyl-
`piperazino) dibenz[b,eJoxepin derivative has an anti-
`asthmatic activity (U.S. Pat. No. 4,396,550, U.S. Pat.
`No. 4,465,835, EP-A-38564).
`It
`is also known that dibenz[b,e]oxepin derivative
`having the following formula:
`
`SNRRe
`
`Ry
`
`Oo
`
`wherein Rd and Reare lower alkyl and Rf is lower
`alky! or halogen, has an antiasthmatic activity (EP-A-
`85870).
`Dibenz[b,eJoxepin derivative having an antiallergic
`activity and having the following structural formula:
`
`O—(CH2)/NRgRp
`
`OL To
`
`oO
`
`wherein Rj is 4-alkylpiperazino, 3-quinuclidylamino or
`—Xa—(CH2)hd s—NRR,, wherein X_ is —NH—,
`—S— or —O—,s is 2 or 3 and Ryand R» are alkyl, and
`Rzis CN,5-tetrazolyl, CONH2 or COoR,, wherein Ry,is
`H,alkyl or 1-(ethoxycarbonyloxy)ethyl is known (EP-
`A-130555).
`
`Wherein A represents a hydroxymethyl, a lower alkox-
`ymethyl,
`a triphenylmethyloxymethyl],
`a
`lower al-
`kanoyloxymethyl, a lower alkanoyl, a carboxy, a lower
`alkoxy
`carbonyl,
`a
`triphenylmethyloxycarbonyl,
`—CONRR2 (wherein R; and R2 are the sameordiffer-
`ent and represent hydrogen atom or loweralkyl) 4,4-
`wherein Rg and Rhare alkyl, r is 2 or 3 and Riis alkyl 50
`dimethyl-2-oxazoline-2-yl group or —CONHOH; Y
`or halogen is known (JP-A-227879/84).
`represents —(CH2),—, —CHR3—(CH2)m—_or
`Dibenz[b,eJoxepin derivative having an antiallergic
`—CR4a=CR5—(CH2)hd m— whichis substituent at 2—
`activity and having the following structural
`or 3-position of the mother nucleus (wherein R3 repre-
`sents a lower alkyl, R4 and Rs are the sameordifferent
`and represent.a hydrogen atom or a loweralkyl, m is 0,
`1, 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 —CH2—; n is 0, 1, 2, 3 or 4; Z represents
`4-methylpiperazino, 4-methylhomopiperazino, piperi-
`dino, pyrrolidino,
`thiomorpholino, morpholino, or
`—NR¢6R7 (wherein R¢ and R7 are the same or different
`and represent a hydrogen atom or a loweralkyl); and
`=== means a single bond or double bond [hereinafter
`referred to as Compound (1) and Compounds with
`other formula numbersare hereinafter likewise referred
`to], and a pharmaceutically acceptable salt thereof. The
`present invention further pertains to a pharmaceutical
`
`45
`
`35
`
`65
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 2
`
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`

`

`5,116,863
`
`3
`composition containing an effective amount of Com-
`pound (I) or a pharmaceutically acceptable salt thereof
`as an active ingredient, and a carrier or an excipient.
`The present Compound(I)is useful for treatment of
`allergic conditions and inflammation.
`,
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`4
`disclosed in J. Med. Chem., 19. 941 (1976), ibid., 20,
`1499 (1977) and JP-A-21679/83.
`Compound(III) wherein —Y—A is —COOHis dis-
`closed in JP-A-21679/83 and the other Compounds
`(III) can be prepared according to the method de-
`scribed in the publication though they do not occur in
`the publication.
`The process for preparing Compound(I) is explained,
`depending on the kind of the group X.
`Process A
`
`Synthesis of Compound (1) wherein X is =CH— (Part
`1)
`The carboxy group of Compound(IIa) is protected
`according to the following reaction scheme.
`
`oO
`li
`
`oO
`
`(IIa)
`
`oO
`II
`
`oO
`
`qv)
`
`OH
`
`meusLent —>
`u H
`CH3
`
`soc}
`
`In the definition of each group of formula (I), the
`lower alkyl group includes straight or branched chain
`alkyl groups having 1 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 lower alkoxymethyl group includes methox-
`ymethyl, ethoxymethyl, n-propoxymethyl, isopropoxy,
`etc. and the lower alkoxycarbonyl! group includes me-
`thoxycarbonyl, ethoxycarbonyl, etc.
`20
`the lower alkyl
`In the definition of the group A,
`Y—COOH q—_—>
`moiety of lower alkanoy! group and loweralkanoylox-
`HiN
`OH
`ymethyl group has the same meaning as previously
`H3C
`CH3
`defined.
`The lower alkanoyl group includes formyl, acetyl,
`etc. and the lower alkanoyloxymethyl group includes
`formyloxymethyl, acetyloxymethyl, etc.
`The pharmaceutically acceptable salt of Compound
`(I) includes pharmaceutically acceptable acid addition
`salt, metal salt, ammonium salt, 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 metalsalt
`includes alkalimetal salts such as sodium salt, potassium
`salt, etc., alkaline earch metal salts such as magnesium
`salt, calcium salt, etc., and alminium salt, zinc salt, etc.
`The pharmaceutically acceptable organic amine addi-
`tion salt includes addition salt of morpholine and piperi-
`dine and the pharmaceutically acceptable amino acid
`addition salt includes addition salt of lysine, glysine,
`phenylalanine, etc.
`Compound(1) is prepared by using a compound rep-
`resented by the formula(II):
`
`30
`
`40
`
`45
`
`oO
`ii
`
`oO
`
`(Vv)
`
`vX Le
`
`0
`
`N
`
`CH;
`
`In the formulae, Y has the same meaning as previ-
`ously defined, and Compound(Ila)is included in Com-
`pound (IJ) (compounds with an alphabet suffix follow-
`ing formula numberarelikewise included in compounds
`with common formula No.).
`Compound(IIa) is reacted with 1 to 5 equivalents of
`thionyl chloride and 1 to 5 equivalents of 2-amino-2-
`methyl-1-propanol on the basis of Compound(IIa)in an
`inert solvent such as methylene chloride, if necessary in
`the presence of a base such astriethylamine at a temper-
`ature of from 0° C. to room temperature for 1-24 hours
`to form Compound (IV). Compound (IV) can also be
`obtained by reacting Compound(Ila) with thionyl chlo-
`ride in advance and then with 2-amino-2-methyl-1-
`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 1-24 hours to form Com-
`pound (V).
`Compounds(Ia) and (Ib) can be prepared from Com-
`pound (V) according to the following reaction scheme.
`
`(1)
`
`50
`
`55
`
`65
`
`wherein Y and A havethe same meaningsas previously
`defined or a compound represented by the formula
`(I):
`
`aid
`
`wherein Y and A have the same meaningsas previously
`defined as the starting compound. Compound(IJ)is
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 3
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 3
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`

`

`5,116,863
`
`HalMe(CH>)y—1Z (VT)
`
`ae ets
`
`H
`
`(CHa)nZ
`
`(Vv)
`
`HO
`
`(CH2)n4.1Z
`
`oO
`
`(VID
`
`oO
`
`mae L
`
`°
`
`(Ia)
`
`J Y
`
`—CO2Rs
`
`°C
`
`sN
`
`Neo
`
`
`
`(Ib)
`
`In the formulae. Y, Z, and n have the same meanings
`as previously defined. Rg is hydrogen or a lower alkyl
`group, R’s is a lower alkyl group and Halis halogen.
`As used herein, the term lower alkyl has the same
`meaningas that of loweralkyl in each group of formula
`(1). Halogen includes chlorine, bromine and iodine.
`Compound(V)is reacted with 1-5 equivalents of Com-
`pound (VJ) in an inert solvent such as tetrahydrofuran
`and diethyl ether under atmosphereofan 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 1-24
`hours.
`Compound (VII) is reacted with 1-5 equivalents of
`thionyl chloride or phosphory] chloride in an inert sol-
`vent such as methylene chloride in the presence of a
`base such as pyridine to form Compound(Ia). The reac-
`tion is carried out at a temperature of from 0° C. to
`room temperature and is completed in 1-24 hours.
`Compound(la)is incubated in an alcohol containing
`water, such as aqueous methanolsolution, in the pres-
`
`35
`
`40
`
`45
`
`50
`
`ence of an appropriate acidic catalyst such as p-toluene-
`sulfonic acid at a temperature of from room tempera-_
`ture to the boiling point of the solvent to form Com-
`pound (Ib) wherein Rg is H. The reaction is completed
`in 1-24 hours.
`Compound(VII)is incubated in a alcohol of Rg’OH
`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 Rg is a lower alkyl. The reac-
`tion is completed in 1-24 hours.
`Process B
`
`Synthesis of Compound(I) wherein X is —=CH— (Part
`2)
`
`The carboxy group of a compound represented by
`the formula (Ila) can be converted to a lower alkox-
`ymethy] group or a trityloxymethy! group according to
`the following reaction scheme.
`
`Y—COjH
`
`oO
`
`(1a)
`
`yes
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 4
`
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`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 4
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`

`

`5,116,863
`
`-continued
`
`Y—CH:20H
`
`OH
`
`oO
`
`(VII)
`
`OH
`
`oO
`
`(IX)
`
`yume
`
`Neo
`
`Y-—-CH20C(Ph)3
`
`OR
`
`oO
`
`(X)
`
`Ngan
`
`fone
`
`Y—CH20R9
`
`oO
`
`(AD
`
`Y—CH20OR)’
`
`35
`
`carried out at a temperature of from 0° C.to the boiling
`In the formulae, Y has the same meaning as previ-
`point of the solvent and is completed in 1-24 hours.
`ously defined, Rg is a lower alkyl group and Ro’ is a
`Compound(VIIDis incubated in an alcohol of RSOH
`trityl] group or a lower alkyl group. The term lower
`in the presence of an appropriate acidic catalyst such as
`alky] has the same meaning as that of lower alky] in
`40 sulfuric acid at a temperature of from room temperature
`each group in formula(I).
`to the boiling point of the solvent to form Compound
`Compound(Ila) is reduced with 1-5 equivalents of
`(X). The reaction is usually completed in 1-24 hours.
`lithium aluminium hydride in tetrahydrofuran at a tem-
`Compound (X)is oxidized with 1-5 equivalents of an
`perature of from 0° C. to room temperature for 1-24
`appropriate oxidizing agent such as Jones reagent in an
`hours to form Compound (VII).
`Compound(VIII) is reacted with 1-5 equivalents of 45 inert solvent such as acetone to form Compound (XI)
`trityl chloride in pyridine at a temperature of from room
`wherein Ro’is a loweralkyl. The reactionis carried out
`temperature to 100° C. for 1-24 hours to form Com-
`at a temperatureof from 0° C.to the boiling point of the
`pound (TX).
`solvent and is usually completed in 1-24 hours.
`Compound(IX) is oxidized with 1-5 equivalents of
`The compoundsrepresented by the formulae (Ic) and
`an appropriate oxidizing agent such as potassium per- so (Id) and if desired, the compound represented by the
`manganate and pyridinium chlorochromate in an inert
`formula (Je) can be synthesized from Compound (XI)
`solvent such as methylene chloride and acetone to form
`according to the following reaction scheme.
`Compound (XI) wherein Rg’is trityl. The reaction is
`
`oO
`li
`
`oO
`
`YD)
`
`Y—CH20R9’
`
`{nsec1Z (VD
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 5
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`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 5
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`

`

`HO.
`
`5,116,863
`
`-continued
`H
`
`(CH2)nZ
`
`(CHa), —1Z Y—CH2ORo’
`
`H
`
`(CHa)nZ
`
`Y—CH20H
`
`yous
`
`(CH2),Z
`
`Y—-CO2H
`
`(Ie)
`
`Process C
`
`Synthesis of Compound(I) wherein X is =CH— (Part
`3)
`
`In the formulae, Y. Z, Ro’, n and Hal have the same 40
`meanings as previously defined.
`Compound (XI) is reacted with Compound (VI)
`which is Grignard reagent according to the same man-
`ner as in the reaction step from Compound (V) to Com-
`pound (VII) in Process A to form Compound (XII).
`Compound (XII) is subjected to reaction according
`to the same manneras in the reaction step from Com-
`pound (VII) to Compound (Ia) in Process A to form
`Compound(Ic).
`Compound (Ic) is incubated in a solvent containing 50
`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 1-24 hours.
`Compound(Id) can also be obtained in one step by
`incubating Compound (XII) 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 60
`point of the solvent. The reaction is usually completed
`in 1-24 hours.
`If desired, Compound(1d)is oxidized with 1-5 equiv-
`In the formulae, Y, Z, and n have the same meanings
`alents of an appropriate oxidizing agent such as Jones
`reagentin an inert solvent such as acetone to form Com- 65 as previously defined. A’ represents the groups falling
`pound (Ie). The reaction is carried out at a temperature
`within the definition of A but lower alkanoyl group.
`of from 0° C. to the boiling point of the solvent and is
`Compound (IIb) is reacted with 1-5 equivalents of
`usually completed in 1~24 hours.
`Compound (XIII) in an inert solvent such as tetrahy-
`
`45
`
`55
`
`0
`I
`
`°
`(lb)
`
`YA’ +
`
`Ph3P=CH(CH)),Z
`°
`(x)
`
`>
`
`H
`
`(CH),Z
`
`:
`
`|
`
`YA’
`
`°
`
`(if)
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 6
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`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 6
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`

`

`5,116,863
`
`11
`drofuran under atmosphereofan inert gas such asnitro-
`gen and argon at a temperature of from 0° C. to room
`temperature for 1-24 hours to form Compound (1).
`Compound (XIII) which is ylide, can be prepared
`according to the method described in C.A. 63 16366a
`(1965).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Ph3P + Hal(CH2),— Hal ——>
`(XIV)
`
`+
`Ph3P(CH3)q= |Hal.Hal— 2 ne
`(VX)
`
`PhaP(CH2),+1Z-Hal~ .(HHal),
`(XVI)
`
`In the formulae, Hal, n and Z have the same meanings
`as previously defined and gq is I or 2.
`Compound (XIV)is reacted with an equivalent of
`triphenylphosphine in toluene at reflux of the solvent
`for 1-24 hours to form Compound (XV).
`Compound (XV)is reacted with 1-5 equivalents of
`HZ in ethanol ar reflux of the solvent for 1-24 hours
`and excess HZ is distilled away under reducedpressure.
`After the addition of 1-5 equivalents of HHal on the
`basis of Compound (XV), the mixture is incubated at a
`temperature of from 0° C. to the boiling point of the
`solvent for 1-24 hours to form Compound (XVI) which
`is Wittig reagent.
`Compound (XVI) is treated with 1-2 equivalents of
`an appropriate base such as n-butyl lithium in an inert
`solvent such as tetrahydrofuran under atmosphere of an
`inert gas such as nitrogen and argon to form ylide
`(XIII). The reaction is carried out at —78° C. to room
`temperature and is usually completed in 1-24 hours.
`Process D
`
`Synthesis of Compound(I) wherein X is =CH— (Part
`4)
`
`formaldehyde
`YA + or polymerized +
`formaldehyde
`
`qi)
`
`HZ Acid >
`
`
`
`(Ig)
`
`In the formulae, Y, Z and A have the same meanings
`as previously defined.
`Theprocess is knownas Prince reaction [New Exper-
`imental Chemical Course (Maruzen), Vol. 14, Synthesis
`and Reaction of Organic Compound III, page 1375
`(1977)].
`Compound(III), 1 to 5 equivalents of formaldehyde
`and | to 5 equivalents of HZ are subjected to reaction in
`an inert solvent such as tetrachloroethane in the pres-
`
`12
`ence of an acid or reaction in an acid as such serving as
`a solvent under atmosphere ofan inert gas such as nitro-
`gen and argon to yield Compound(Ig).
`The formaldehyde or polymerized formaldehyde
`includes p-formaldehyde,
`trioxane, etc. The acid in-
`cludes acetic acid, trichloroacetic acid, trifluoroacetic
`acid, etc. The reactionis carried out at a temperature of
`from room temperature to the boiling point of the sol-
`vent and is completed in 1-24 hours.
`Compound(III) whichis the starting material can be
`prepared according to the process described in JP-A-
`21679/83, as shown below.
`
`Y—A’ + Ph3P=CH) ——>
`(XVID
`
`I
`
`oO
`(IIa)
`
`YA’
`
`°i
`
`l
`
`Oo
`
`(IIb)
`
`to 5 equivalents of me-
`1
`That is, Compound (IIb),
`thyltriphenylphosphonium bromide and | to 5 equiva-
`lents of n-butyl lithium on the basis of Compound(IIb)
`are subjected to reaction in an inert solvent at from
`—78° C. to room temperature for 1 to 5 hours to yield
`ylide (XVII) which is reacted with an equivalents of
`Compound(IIb) in an inert solvent at from —78° C.to
`room temperature under atmosphereofan inert gas for
`1 to 24 hours to yield Compound (IIIa).
`The inert gas includes nitrogen, argon, etc. and the
`inert solvent includes tetrahydrofuran. etc.
`The group A’ in Compound(IIa) can easily be con-
`verted to a lower alkanoyl groupasis stated in Process
`I and therefore, Compound(III) can easily be prepared.
`Process E
`
`Synthesis of Compound(I) wherein X is—=N—
`
`Oo
`ll
`
`oO
`
`(IIb)
`
`Y—A‘ + H2N(CH2),Z ——>
`(XVIID
`
`N~-(CH2)nZ
`il
`
`Y—A’
`
`oO
`
`(Ih)
`
`to 10 equivalents of Com-
`Compound (IIb) and 1
`pound (XVIII) are subjected to reaction in an inert
`solvent such as benzenein the presenceof 1 to 10 equiv-
`alents of titanium tetrachloride at from 0° C.
`to the
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 7
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 7
`
`

`

`13
`boiling point of the solvent under atmosphereofan inert
`gas such as nitrogen and argon for 1 to 48 hoursto yield
`Compound(Ih).
`:
`
`Process F
`
`Synthesis of Compound (I) wherein X is —CH2— (Part
`1)
`
`5,116,863
`
`14
`tion in an appropriate base such as pyridine at from 0°
`C. to room temperature to yield Compound (XX).
`Compound (XX) and 1 to 5 equivalents of Compound
`(VI) are subjected to reaction in the same manner as in
`the reaction step from Compound (V) to Compound
`(VID in Process A to yield Compound(Ii).
`Compound(Ii) is subjected to reaction in the same
`
`5
`
`.
`
`oO
`I
`
`0
`
`(Vv)
`
`oO
`
`vr L Reduction >
`
`N
`
`OH
`
`oO
`(XIX)
`
`Oo
`
`r L Chlorination >
`
`N
`
`cl
`
`oO
`
`x L HalMg(CHa)n+1Z(VD
`
`Y¥—- >
`N
`
`(CH2)nZ
`
`oO
`
`(ii)
`
`oO
`
`v L —>
`
`N
`
`(CH2)nZ
`
`4
`CH?
`
`oO
`
`(lj)
`
`Y—CO2Rs
`
`In the formulae, Y, Z, n, Rg and Hal have the same 49 manneras in the reaction step from Compound (VII) to
`meanings as previously defined.
`Compound(Ib) or the reaction step from Compound
`Compound (V)is reduced with 1 to 5 equivalent of
`(la) to Compound(Ib) in Process A to yield Compound
`lithium aluminium hydride or sodium borohydride in an
`(Ij).
`inert solvent such as tetrahydrofuran and methanol]at
`from 0° C. to room temperature for 1
`to 24 hours to 4s
`yield Compound (XIX).
`Compound (XIX) and 1 to 5 equivalents of thionyl]
`chloride or phosphoryl chloride are subjected to reac-
`
`:
`Process G
`Synthesis of Compound(I) wherein X is —CH2— (Part
`2)
`
`Y—CH20Rs' Chlorination >
`
`OH
`
`O
`(XxD
`
`ci
`
`CH2—(CH2)nZ
`
`HalMg(CHa)n-1Z (VD
`+
`
`Y—CHOR,HOMECHZWD Y—CH20R,’ E>
`
`Oo
`(XXII)
`
`Oo
`
`(Ik)
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 8
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 8
`
`

`

`15
`
`5,116,863
`
`-continued
`
`(CH2)nZ
`
`CH2
`
`\—CH20H Oxidation >
`
`Y—CO2H
`
`(i)
`
`oO
`
`(Im)
`
`Compound (XXIJ)is subjected to chlorination in the
`same manner as in Process F to yield Compound
`(XXID. Compound (XXII) and Compound (VI) are
`subjected to reaction in the same manneras in Process
`F to yield Compound(Ik). Compound(Ik) is treated in
`the same manneras in Process B to form Compound
`(11).
`Compound(I])is further treated to form Compound
`(Im).
`Compound (IX) is included in the definition of the
`starting material (XXI]).
`Compound (XI) is reduced with 1 to 5 equivalents of 25
`lithium alminium hydride or sodium borohydride in an
`inert solvent such as tetrahydrofuran and methanol at
`from 0° C. to room temperature for 1 to 24 hours to
`yield Compound (XXI).
`Process H
`
`20
`
`30
`
`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 represented by the fol-
`lowing formulais cis-form (or cin-form or Z-form).
`
`H
`
`(CHa)y7 Z
`
`oO
`
`Table 1 shows examples of Compound(1) or pharma-
`ceutically acceptable salts thereof and Table 2 shows
`the structural formula thereof.
`Table 3 shows characteristic signals in NMR and
`Table 4 showsretention time in HPLC.
`TABLE1
`
`Synthesis of Compound(I) wherein X is —CH2— (Part
`3)
`Compound (I) wherein X is —CH2— can also be
`prepared by subjecting Compounds(Ia)-(Ig) obtained
`bythe Processes A-D to reduction such as hydrogena-
`tion using paradium-carbonascatalyst.
`The intermediates and the desired compoundsin each
`of the processes described above can be purified and
`isolated by a purification method whichis usually used
`in the field of organic chemical synthesis, such asfiltra-
`tion, extraction with organic solvent such as ethyl ace-
`tate and methylene chloride, drying, concentration,
`recrystallization, column chromatography,etc.
`Out of Compounds (Ia)-(Ih) obtained in each of the
`processes described above, with regard to stereochem-
`istry at I1-position of dibenz[b,eloxepin, Compounds
`(Ia), (Ib), (Ic), (Id), (Ig) 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(Ii)~(Im)is
`producedas a cis-trans mixture, Compound(I) is sepa-
`rated 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 trans-form.
`For example,cis-form is added to an acetic acid and the
`mixture is heated at reflux in the presence of an appro-
`priate catalyst such as p-toluenesulfonic acid for 1-24
`hours to form trans-form.
`With regard to the denotation of cis-form (or cin-
`form) and trans form (or anti-form) of Compound(1),
`Compound (I) wherein the substituent bound to the
`double bondis on the sameside as oxygen of oxepin,is
`cis-form (or cin-form) and Compound (I) wherein the
`substituent is on the opposite side is trans-form (or anti-
`form).
`
`Compound
`No.
`
`35
`
`1
`
`2
`
`3
`
`45
`
`4
`
`50
`
`55
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`65
`
`Compound(I)
`Methy)cis-11-(3-dimethylaminopropylidene)-
`6.11-dihydrodibenz[b.eJoxepin-2-carboxylate
`Methy] trans-11-(3-dimethylaminopropylidene)-
`6,1 1-dihydrodibenz{b,eJoxepin-2-carboxylate
`Ethyl cis-1}-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b.eJoxepin-2-carboxylate
`Ethy!]trans-11-(3-dimethylaminopropylidene)-
`6.1]-dihydrodibenz[b.e]oxepin-2-carboxylate
`Cis-11-(3-dimethylaminopropylidene)-6.1 1-
`dihydrodibenz[b.e]Joxepin-2-carboxylic acid
`Trans-11-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.eJoxepin-2-carboxylic acid
`Methyl cis-11-(3-diethylaminopropylidene}-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl trans-11-(3-diethylaminopropylidene)-
`6.11-dihydrodibenz[b,eJoxepin-2-carboxylate
`Cis-11-(3-diethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]Joxepin-2-carboxylic acid
`Trans-11-(3-diethylaminopropylidene)-6, 1 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Methy!cis-11-(3-pyrrolidinopropylidene)-6,| 1-
`dihydrodibenz[b,eJoxepin-2-carboxylate
`Methy!trans-11-(3-pyrrolidinopropylidene)-
`6,1 1-dihydrodibenz[b,eJoxepin-2-carboxylate
`Cis-11-(3-pyrrolidinopropylidene)-6, 1 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Trans-11-(3-pyrrolidinopropylidene)-6,1 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Methy]cis-11-(4-dimethylaminobutylidene)-
`6,11-dihydrodibenz[b,e]oxepin-2-carboxylate
`Methy] trans-11-(4-dimethylaminobutylidene)-
`6,11-dihydrodibenz[b,eJoxepin-2-carboxylate
`Cis-11-(4-dimethvlaminobutylidene)-6, | 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Trans-!1-(4-dimethylaminobutylidene)-6, 1 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Methy!cis-11-[2-(4-methylpiperazino)-
`ethylidene]-6,11-dihydrodibenz[b,eJoxepin-2-
`carboxylate
`Methy! trans-11-[2-(4-methylpiperazino)-
`ethylidene]-6,1 1-dihydrodibenz[b.eJoxepin-2-
`carboxylate
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 9
`
`
`IPR2018-01020 and IPR2018-01021, Exhibit 1036, Page 9
`
`

`

`17
`TABLE1-continued
`
`Compound (1)
`Cis-11-[2-(4-methylpiperazino)ethylidene}-
`6,11-dihydrodibenz[b.eJoxepin-2-carboxylic acid
`Trans-! 1-[2-(4-methylpiperazino}ethylidene]-
`6,11-dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methy!cis-11-(2-morpholinoethylidene)-6.11-
`dihydrodibenz[b,e]oxepin-2-carboxylate
`Methy!trans-11-(2-morpholinoethylidene)-6, 1 1-
`dihydrodibenz[b.eloxepin-2-carboxylate
`Cis-] 1-(2-morpholinoethylidene)-6, 1}-
`dihydrodibenz[b.eJoxepin-2-carboxylic acid
`Trans-11-(2-morpholinoethylidene)-6,1 1-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methylcis-11-(2-thiomorpholinoethylidene)-
`6.1 1-dihydrodibenz[b,eJoxepin-2-carboxylate
`Methy! trans-11-(2-thiomorpholinoethylidene)-
`6,11-dihydrodibenz[b,eJoxepin-2-carboxylate
`Cis-11-(2-thiomorpholinoethylidene)-6,11-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Trans-11-(2-thiomorpholinoethylidene)-6,| 1-
`dihydrodibenz[b,eJoxepin-2-carboxylic acid
`Methyl cis-11-(2-pyrrolidinoethylidene)-6,11]-
`dihydrodibenz[b,e]oxepin-2-carboxylate
`Methy] trans-11-(2-pyrrolidinoethylidene)-
`6.11-dihydrodibenz[b.e]oxepin-2-carboxylate
`Methylcis-11-(2-piperidinoethylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methy! trans-11-(2-piperidinoethylidene)-6,11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methy!cis-11-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b.e]oxepin-2-acetate
`Methy! trans-11-(3-dimethylaminopropylidene)-
`6.1 1-dihydrodibenz[b,eJoxepin-2-acetate
`Ethyl cis-1]-(3-dimethylaminopropylidene)-6.1 1-
`dihydrodibenz[b.e]oxepin-2-acetate
`Ethy! trans-11-(3-dimethvlaminopropylidene)-
`6.11-dihydrodibenz[b.eloxepin-2-acetate
`Cis-11-(3-dimethylaminopropylidene)-6.]1-
`dihydrodibenz[b.eJoxepin-2-acetic acid
`Trans-]1-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Methyl cis-11-(4-dimethylaminobutylidene)-6.} 1-
`dihydrodibenz[b.e]oxepin-2-acetate
`Methy!trans-11-(4-dimethylaminobutylidene)-
`6.11-dihydrodibenz[b,e]Joxepin-2-acetate
`Cis-11-(4-dimethylaminobutylidene)-6,1 1-
`dihydrodibenz[b.eJoxepin-2-acetic acid
`Trans-11-(4-dimethylaminobutylidene)-6. 1 1-
`dihydrodibenz[b,eJoxepin-2-acetic acid
`Methy!cis-11-(3-pyrrolidinopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-acetate
`Methyl trans-11-(3-pyrrolidinopropylidene)-
`6.11-dihydrodibenz[b,eJoxepin-2-acetate
`Cis-11-(3-pyrrolidinopropylidene)-6. 11-
`dihydrodibenz[b.eJoxepin-2-acetic acid
`Trans-11-(3-pyrrolidinopropylidene)-6, 11-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Methylcis-11-[2-(4-methylpiperazino)-
`ethylidene-6,] 1-dihydrodibenz[b,eJoxepin-2-
`acetate
`Methyl trans-11-[2-(4-methylpiperazino)-
`ethylidene)-6,1 1-dihydrodibenz[b,e]oxepin-2-
`acetate
`Cis-11-{2-(4-methylpiperazino)-ethylidene-
`6,11-dihydrodibenz[b,e]oxepin-2-acetic acid
`Trans-11-[2-(4-methylpiperazino)-ethylidene)-
`6,11-dihydrodibenz[b,eJoxepin-2-acetic acid
`Methy]cis-3-[1 1-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b,eJoxepin-2-yl]-propionate
`Methyl trans-3-[11-(3-dimethylaminopropyli-
`dene)-6,1 1-dihydrodibenz[b,eJoxepin-2-yl]-
`propionate
`Cis-3-[1 1-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-yl]-propionic acid
`Trans-3-[11-(3-dimethylaminopropylidene)-6, | 1-
`dihydrodibenz[b,e]oxepin-2-yl]-propionic acid
`Methy!cis-11-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b.e]oxepin-3-acetate
`Methy}trans-1i1-(3-dimethylaminopropylidene)-
`6,11-dihydrodibenz[b,e]oxepin-3-acetate
`Cis-11-(3-dimethylaminopropylidene)-6, 1 1-
`
`Compound
`No.
`ih
`
`12
`
`16
`
`17
`
`18
`
`19
`
`26
`
`27
`
`28
`
`29
`
`30
`
`5,116,863
`
`18
`TABLE1-continued
`Compound
`No.
`
`Compound (1)
`dihydrodibenz{ b.eJoxepin-3-acetic acid
`Trans-1}1-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b.e]oxepin-3-acetic acid
`Cis-11-(3-dimethylaminopropylidene)-2-(2-
`hydroxyethyl)-6.11-dihydrodibenz[b.eJoxepin
`Trans-11-(3-dimethylaminopropylidene)-2-(2-
`hydroxyethy])-6, 1 1-dihydrodibenz[b,eJoxepin
`Cis-11-(3-dimethylaminopropylidene)-2-(2-
`triphenylmethyloxymethy])-6,1 1-dihydrodibenz-
`[b,eloxepin
`Trans-11-(3-dimethylaminopropylidene)-2-(2-
`triphenylmethyloxymethy])-6,1 1-dihydrodibenz-
`[b.eJoxepin
`Cis-11-(3-dimethylaminopropylidene)-2-(3-
`hydroxypropyl)-6, 1 1-dihydrodibenz[b,e]oxepin
`Trans-11-(3-dimethylaminopropylidene)-2-(3-
`hydroxypropyl)-6,1 1-dihydrodibenz[b,eJoxepin
`Methyl cin-11-(2-diethylaminoethy]l)imino-6,11-
`dihydrodibenz[b,eJoxepin-2-carboxylate
`Methyl anti-11-(2-diethylaminoethy]l)imino-
`6,11-dihydrodibenz[b,eJoxepin-2-carboxylate
`Cin-11-(2-diethylaminoethy}imino-6,1 1-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Anti-11-(2-diethylaminoethy])imino-6,11-
`dihydrodibenz[b.eJoxepin-2-carboxylic acid
`Methyl cin-]1-(2-dimethylaminoethy])imino-
`6,11-dihydrodibenz[b,eJoxepin-2-acetate
`Methy!anti-]1-(2-dimethylaminoethy])imino-
`6,11-dihydrodibenz[b.eJoxepin-2-acetate
`Cin-11-(2-dimethylaminoethy)imino-6.1 1-
`dihydrodibenz[b,eJoxepin-2-acetic acid
`Anti-11-(2-dimethylaminoethyl)imino-6, | 1-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Methy! cin-11-(2-diethylaminoethyl)imino-6,1 1-
`dihydrodibenz[b,e]oxepin-2-acetate
`Methy!anti-11-(2-diethylaminoethyl)imino-
`6.11-dihydrodibenz[b.eJoxepin-2-acetate
`Cin-11-(2-diethylaminoethyl )imino-6,1 1-
`dihydrodibenz[b,eJoxepin-2-acetic acid
`Anti-11-(2-diethylaminoethy])imino-6.11-
`dihydrodibenz[b,e]oxepin-2-acetic acid
`Methyl cin-11-(3-dimethylaminopropyl)imino-
`6,1 1-dihydrodibenz[b.e]oxepin-2-acetate
`Methy! anti-11-(3-dimethylaminopropyl)imino-
`6,11-dihydrodibenz[b,eJoxepin-2-acetate
`Cin-11-(3-dimethylaminopropyl)imino-6, 1 1-
`dihydrodibenz[b,e]oxepin-2-acetic acid
`Anti-11-(3-dimethylaminopropylimino-6,11-
`