l||l||||||lllllllllllllillllllllllllIl
`U5005116863A
`
`United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,116,863
`
`[45] Date of Patent:
`Oshima et al.
`May 26, 1992
`
`[54] DIBENZ[B,E]OXEPIN 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 Kogyo Co., Ltd.,
`Tokyo, Japan
`
`[21] App1.No.: 20,900
`
`[22] Filed:
`
`Mar. 2, 1987
`
`Foreign Application Priority Data
`[30]
`Mar. 3. 1986 [JP]
`Japan .................................. 61-45676
`
`Int. Cl.5 ................... A61K 31/335;CO7D 313/12
`[51]
`[52] U.S. C1. .................................... 514/450; 548/215;
`548/525; 549/354; 514/212; 514/2282;
`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; 544/587; 546/196
`[58] Field of Search .................. 540/596, 602; 544/62,
`544/137. 147. 369. 375. 98.7; 546/196: 548/215,
`525; 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 ............................ 549/354 X
`1/1969 Bloom et al. ......... 549/354
`3.420.851
`
`..... 260/333
`3.509,176 4/1970 Winter et a].
`
`8/1981 Rokach ............ 548/252
`4.281365
`8/1983 Takizawa ............................ 549/354
`4,396,550
`
`8/1984 Takizawa ............................ 546/133
`4.465.835
`4/1986 Helsley et a1. .......... 549/354
`4,585.788
`
`6/1986 Takizawa ................ 514/253
`4,596,804
`
`.. 549/354
`4.871.865 10/1989 Lever et a1.
`.......
`......................... 514/450
`4,923,892
`5/1990 Lever et a1.
`
`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) 1039243.
`Benesova, Arz.-—Forsch.. vol. 14 (1964) 100:3.
`Chem. Abs., vol. 63 (1965) l6366a.
`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.
`.1. 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 control of allergic conditions such as
`allergic asthma and also employed in the treatment of
`inflammation.
`
`3 Claims; No Drawings
`
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`
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`
`

`

`1
`
`5,116,863
`
`2
`Doxepin having an antidepressant activity and hav—
`ing the following structural formula is known [Drugs,
`13, 161 (1977)].
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`
`
`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 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
`
`35
`
`The present invention relates to a dibenz[b,e]oxepin
`derivative represented by the formula (I):
`
`X—(CH2)n-Z
`
`(I)
`
`DIBENZ[B,E]OXEPIN DERIVATIVE AND
`PHARMACEUTICAL COMPOSITIONS THEREOF
`
`BACKGROUND OF THE INVENTION
`
`Heretofore, it has been known that ll-unsubstituted,
`ll-hydroxy or
`ll-oxodibenz[b,e]oxepin derivative is
`used for antiinflammatory agents [1. Med. Chem., 21,
`633—639 (1978)].
`g
`Further, it is known that dibenz[b,e]oxepin derivative
`wherein substitutents Ra and Rb at 11-position have the
`following definitions, is employed in the treatment and
`control of allergic conditions (US. Pat. No. 4,282,365).
`Ra: H, OH, lower alkoxy, lower alkylthio, lower alkyl-
`sulfinyl, lower alkylsulfonyl, arylthio, NHz, NHCHO
`or imidazolyl;
`Rb: H or lower alkyl; or Ra and Rb taken together are
`:0, =CH—Rc wherein RC is H or aryl.
`Furthermore,
`it
`is
`known
`that
`ll-(4-methyl-
`piperazino) dibenz[b,e]oxepin derivative has an anti-
`asthmatic activity (US. Pat. No. 4,396,550, US. Pat.
`No. 4,465.835. EP-A-38564).
`It
`is also known that dibenz[b,e]oxepin derivative
`having the following formula:
`
`s/\/ NRdR,
`
`Rf
`
`0
`
`wherein Rd and Re are lower alkyl and Rf is lower
`alkyl or halogen, has an antiasthmatic activity (EP-A-
`85870).
`Dibenz[b,e]oxepin derivative having an antiallergic
`activity and having the following structural formula:
`
`O-‘(CH2)7NRth
`
`@
`
`0
`
`wherein Rg and Rh are alkyl, r is 2 or 3 and Ri is alkyl
`or halogen is known (JP-A‘227879/84).
`Dibenz[b,e]oxepin derivative having an antiallergic
`activity and having the following structural
`
`@
`
`R1
`
`0
`
`40
`
`45
`
`50
`
`55
`
`
`
`Wherein A represents a hydroxymethyl, a 10wer alkox-
`ymethyl,
`a triphenylmethyloxymethyl,
`a lower
`a1-
`kanoyloxymethyl, a lower alkanoyl, a carboxy, a lower
`alkoxy
`carbonyl,
`a
`triphenylmethyloxycarbonyl,
`—CONR1R2 (wherein R1 and R2 are the same or differ-
`ent and represent hydrogen atom or lower alkyl) 4,4-
`dimethyl-Z-oxazoline-2-yl group or -—CONHOH; Y
`represents —(CH2)m——, —-CHR3-—(CH2)m— or
`——CR4=CR5-—(CH2)hd m— which is substituent at 2——
`or 3-position of the mother nucleus (wherein R3 repre-
`sents a lower alkyl, R4 and R5 are the same or different
`and represent a hydrogen atom or a lower alkyl, m is O,
`l, 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-methy1piperazino, 4-methylhomopiperazino, piperi-
`dino, pyrrolidino,
`thiomorpholino, morpholino, or
`—NR6R7 (wherein R5 and R7 are the same or different
`and represent a hydrogen atom or a lower alkyl); and
`3 means a single bond or double bond [hereinafter
`referred to as Compound (I) and Compounds with
`other formula numbers are hereinafter likewise referred
`to], and a pharmaceutically acceptable salt thereof. The
`present invention further pertains to a pharmaceutical
`
`wherein Rj is 4-alkylpiperazino, 3-quinuclidylamino or
`—Xa—(CH2)hd s—NRIRm wherein X,
`is —NH—,
`—S— or —O—, sis 2 or 3 and Rland Rm are alkyl, and
`Rk is CN, 5-tetrazolyl, CONHz or COan wherein R" is
`H, alkyl or l-(ethoxycarbonyloxy)ethyl is known (EP-
`A-l30555).
`
`65
`
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`

`

`5,116,863
`
`4
`disclosed in J. Med. Chem. 19. 941 (1976), ibid.. 20,
`1499 (1977) and JP-A-21679/83.
`Compound (III) wherein -—Y—A is ——COOH is dis-
`closed in JP-A-2l679/83 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 (I) wherein X is =CH— (Part
`1)
`
`The carboxy group of Compound (Ila) is protected
`according to the following reaction scheme.
`
`$002————9H
`">(\0H
`H3C
`CH3
`
`.3
`
`Y coon
`
`OH
`
`500
`CH3 —'>
`CH1
`
`Y—C-N
`'0' H
`
`0
`
`N
`
`Y—<
`
`lCH}
`
`CH3
`
`0
`
`(V)
`
`0 l
`
`l
`
`0
`
`(Ila)
`
`0 l
`
`l
`
`0
`
`(IV)
`
`In the formulae, Y has the same meaning as previ-
`ously defined. and Compound (Ila) is included in Com—
`pound (11) (compounds with an alphabet suffix follow-
`ing formula number are likewise included in compounds
`with common formula No.).
`Compound (Ila) is reacted with 1 to 5 equivalents of
`thionyl chloride and 1 to 5 equivalents of Z-amino-Z-
`methyl-l-propanol on the basis of Compound (Ila) in an
`inert solvent such as methylene chloride, if necessary in
`the presence of a base such as tricthylamine 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 (la) and (lb) can be prepared from Com-
`pound (V) according to the following reaction scheme.
`
`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
`
`5
`
`In the definition of each group of formula (I), the
`lower alkyl group includes straight or branched chain 10
`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
`alkoxymethyl 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.
`the lower alkyl
`In the definition of the group A,
`moiety of lower alkanoyl group and lower alkanoylox-
`ymethyl group has the same meaning as previously
`defined.
`
`15
`
`20
`
`The lower alkanoyl group includes formyl, acetyl, 25
`etc. and the lower alkanoyloxymethyl group includes
`formyloxymethyl, acetyloxymethyl, etc.
`The pharmaceutically acceptable salt of Compound
`(1) includes pharmaceutically acceptable acid addition
`salt. metal salt, ammonium salt, organic amine addition 30
`salt. amino acid addition salt, etc.
`The pharmaceutically acceptable acid addition salt of
`Compound (1)
`includes inorganic acid salts such as
`hydrochloride, sulfate, phosphate, etc., and organic
`acid salts such as acetate, maleate, fumarate, tartrate, 35
`citrate, etc. The pharmaceutically acceptable metal salt
`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- 40
`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 (I) is prepared by using a compound rep- 45
`resented by the formula (II):
`
`(II)
`
`0
`II
`
`O
`
`.
`wherein Y and A have the same meanings as prevnously
`defined or a compound represented by the formula
`(III):
`
`50
`
`55
`
`ll
`
`O
`
`(III) 60
`
`65
`
`wherein Y and A have the same meanings as previously
`defined as the starting compound. Compound (11) is
`
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`

`

`5,116,863
`
`5
`
`O
`
`l HalMgtCHg),,-1Z (v1)
`F4 ____>
`N
`
`H
`
`(CH2an
`
`O
`
`N
`
`_H203
`
`m»
`
`(la)
`
`/‘l20
`
`r—cogag
`
`
`
`(lb)
`
`o n
`
`0
`
`(V)
`
`HO
`
`(cumuz
`.
`
`0
`
`(VII)
`
`Not-1
`
`In the formulae. Y, Z, and n have the same meanings
`as previously defined. R8 is hydrogen or a lower alkyl
`group, R‘s 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
`(1). Halogen includes chlorine, bromine and iodine.
`Compound (V) is reacted with 1—5 equivalents of Com-
`pound (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 1—24
`hours.
`Compound (VII) is reacted with 1—5 equivalents of
`thionyl chloride or phosphoryl chloride in an inert sol-
`vent such as methylene chloride in the presence of a
`base such as pyridine to form Compound (la). 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 methanol solution, in the pres-
`
`35
`
`4O
`
`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 R8 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 (113) wherein R8 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 (IIa) can be converted to a lower alkox-
`ymethyl group or a trityloxymethyl group according to
`the following reaction scheme.
`
`Y—COzl—l
`
`(Ila)
`
`\LLiAlH4
`
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`

`

`5,116,863
`
`~continued
`
`Y—CH30H
`
`OH
`
`0
`
`(VIII)
`
`OH
`
`(IX)
`
`/(Ph)3Cl
`
`Y3};
`
`Y-CH:OC(Ph)3
`
`0R9
`
`O
`
`(X)
`
`\gxidation
`
`/)xidation
`
`Y—CH20R9
`
`(XI)
`
`Y—CH30R9'
`
`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, R9 is a lower alkyl group and R9'
`is a
`Compound (VIII) is incubated in an alcohol of R90H
`trityl group or a lower alkyl group. The term lower
`in the presence of an appropriate acidic catalyst such as
`alkyl has the same meaning as that of lower alkyl 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 (IIa) 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 (VIII).
`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 R9' is a lower alkyl. The reaction is carried out
`temperature to 100° C. for 1—24 hours to form Com-
`at a temperature offrom 0° C. to the boiling point of the
`pound (IX).
`solvent and is usually completed in 1-24 hours.
`Compound (IX) is oxidized with 1-5 equivalents of
`The compounds represented by the formulae (Ic) and
`an appropriate oxidizing agent such as potassium per- 50 (Id) and if desired, the compound represented by the
`manganate and pyridinium chlorochromate in an inert
`formula (Ie) can be synthesized from Compound (XI)
`solvent such as methylene chloride and acetone to form
`according to the following reaction scheme.
`Compound (XI) wherein R9’ is trityl. The reaction is
`
`Y—CH20R9'
`
`0 I
`
`I
`
`0
`
`(X1)
`
`\LHalMg(CHz)n-1Z (VI)
`
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`
`

`

`9
`
`5,116,863
`
`-continued
`
`
`
`(CH2)n-1Z
`
`
`
`10
`
`Y—CH30R9'
`
`H
`
`(CH2an
`
`Y—CH20H
`
`0
`
`(Id)
`
`\LOxidation
`
`(CHl)nz
`
`H_
`
`
`
`Y—C01H
`
`(16)
`
`In the formulae, Y. Z, R9’, n and Hal have the same 40
`meanings as previously defined.
`Compound (X1)
`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 manner as in the reaction step from Com-
`pound (VII) to Compound (la) in Process A to form
`Compound (1c).
`Compound (1c) is incubated in a solvent containing
`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
`point of the solvent. The reaction is usually completed
`in 1-24 hours.
`
`Process C
`
`Synthesis of Compound (I) wherein X is :CH— (Part
`3)
`
`0
`u
`
`0
`(Ilb)
`
`y—A' +
`
`Ph3P=CH(CH2),,Z —)
`(x111)
`
`H
`
`(CI-12),,Z
`
`0
`
`(10
`
`If desired, Compound (Id) is oxidized with l-5 equiv-
`alents of an appropriate oxidizing agent such as Jones
`reagent in an inert solvent such as acetone to form Com-
`pound (Ie). The reaction is carried out at a temperature
`of from 0° C. to the boiling point of the solvent and is
`usually completed in 1—24 hours.
`
`In the formulae, Y, Z, and n have the same meanings
`65 as previously defined. A’ represents the groups falling
`within the definition of A but lower alkanoyl group.
`Compound (11b) is reacted with 1—5 equivalents of
`Compound (XIII) in an inert solvent such as tetrahy-
`
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`

`

`5,116,863
`
`11
`drofuran under atmosphere of an inert gas such as nitro-
`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 CA. 63 16366a
`(1965).
`
`1’th «, Hal(CH2),.-1Hal —9
`(XIV)
`
`+
`Ph3P(CH2),,.;1Ha1.Hal— ;) :fia]
`(VX)
`
`Ph3P(CHz),,+1Z.Hal‘.(HHal)q
`(XVI)
`
`5
`
`10
`
`15
`
`12
`ence of an acid or reaction in an acid as such serving as
`a solvent under atmosphere of an inert gas such as nitro-
`gen and argon to yield Compound (lg).
`The formaldehyde or polymerized formaldehyde
`includes p—formaldehyde’,
`trioxane. etc. The acid in-
`cludes acetic acid, trichloroacetic acid, trifluoroacetic
`acid, etc. The reaction is 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) which is the starting material can be
`prepared according to the process described in JP-A-
`21679/83, as shown below.
`
`Y—A' + Ph3P=CH2 —9
`(xvn)
`
`ll
`
`0
`(”13)
`
`Y—-A
`
`0|
`
`|
`
`0
`
`(11b)
`
`to S equivalents of me-
`1
`That is, Compound (11b),
`thyltriphenylphosphonium bromide and l 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 (11b) in an inert solvent at from —78° C. to
`room temperature under atmosphere of an inert gas for
`1 to 24 hours to yield Compound (111a).
`The inert gas includes nitrogen, argon, etc. and the
`inert solvent includes tetrahydrofuran. etc.
`The group A’ in Compound (IIIa) can easily be con-
`verted to a lower alkanoyl group as is stated in Process
`I and therefore, Compound (111) can easily be prepared.
`Process E
`
`Synthesis of Compound (I) wherein X is:N-
`
`Y—A' + H3N(CH2),,Z ——9
`(XVIII)
`
`N «(CHmZ
`ll
`
`Y—A’
`
`0
`
`(1}!)
`
`0|
`
`|
`
`0
`
`(11b)
`
`to 10 equivalents of Com-
`Compound (11b) and l
`pound (XVIII) are subjected to reaction in an inert
`solvent such as benzene in the presence of 1 to 10 equiv-
`alents of titanium tetrachloride at from 0" C.
`to the
`
`25
`
`20
`
`In the formulae, Hal, n and Z have the same meanings
`as previously defined and q is 1 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 reduced pressure.
`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 30
`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
`Y—A + or polymerized +
`formaldehyde
`
`(III)
`
`HZ Acid 5
`
`
`
`(Is)
`
`In the formulae, Y, Z and A have the same meanings
`as previously defined.
`The process is known as Prince reaction [New Exper-
`imental Chemical Course (Maruzen), Vol. 14, Synthesis
`and Reaction of Organic Compound 111, page 1375
`(1977)].
`Compound (III), 1 to 5 equivalents of formaldehyde
`and 1 to 5 equivalents of HZ are subjected to reaction in
`an inert solvent such as tetrachloroethane in the pres-
`
`65
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1036 p. 007
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1036 p. 007
`
`

`

`5, 1 16, 863
`
`13
`boiling point of the solvent under atmosphere of an inert
`gas such as nitrogen and argon for 1 to 48 hours to yield
`Compound (Ih).
`'
`
`Process F
`
`Synthesis of Compound (I) wherein X is —CH3— (Part
`1)
`
`14
`tion in an appropriate base such as pyridine at from 0°
`C. to room temperature to yield Compound (XX).
`Compound (XX) and l to 5 equivalents of Compound
`(VI) are subjected to reaction in the same manner as in
`the reaction step from Compound (V) to Compound
`(VII) in Process A to yield Compound (Ii).
`Compound (Ii) is subjected to reaction in the same
`
`5
`
`‘
`
`O
`
`Y—< } Reduction ;
`
`N
`
`0
`
`H
`
`0
`
`(V)
`
`OH
`
`O
`(XIX)
`
`Cl
`
`0
`
`O
`
`y—< } Chlorination ;
`
`N
`
`Y
`
`(CH2),,Z
`
`o
`
`(li)
`
`_< } HangtCHz),,slz(vn
`
`\
`
`N
`
`--———-—->
`
`0
`
`\._< l 9
`
`N
`
`(CH2),,Z
`/
`CH3
`
`0
`
`(U)
`
`Y—COgRg
`
`In the formulae, Y. Z. n, R3 and Hal have the same 40 manner as in the reaction step from Compound (VII) to
`meanings as previously defined.
`Compound (lb) or the reaction step from Compound
`Compound (V) is reduced with 1 to 5 equivalent of
`(la) to Compound (lb) 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 I
`to 24 hours to 45
`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)
`
`OH
`
`0
`(XXI)
`
`Cl
`
`0
`(XXII)
`
`Y—CH20R9' Chlorination ;
`
`CH2-(CH2)nZ
`
`HalM (Cl-I2) - 2 VI)
`
`+
`
`Y—CH20R9'_§__LL9mY—CHZORWL9
`
`O
`
`(Ik)
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1036 p. 008
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1036 p. 008
`
`

`

`15
`
`5,116,863
`
`-continued
`
`(CH3),,Z
`
`CH1
`
`16
`
`(CH:);Z
`
`Y—CH30H Oxidation ;
`
`Y_COZH
`
`(1])
`
`0
`
`(1m)
`
`Further, if cis- or trans-form is denoted according to
`5-2 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 formula is cis—form (or cin-form or vaorm).
`
`H
`
`(CH2),,—Z
`
`O
`
`Table 1 shows examples of Compound (I) or pharma-
`ceutically acceptable salts thereof and Table 2 shows
`the structural formula thereof.
`
`15
`
`20
`
`Compound (XXI) is subjected to chlorination in the
`same manner as in Process F to yield Compound
`(XXII). Compound (XXII) and Compound (VI) are
`subjected to reaction in the same manner as in Process
`F to yield Compound (Ik). Compound (IR) is treated in
`the same manner as in Process B to form Compound
`(11).
`Compound (11) is further treated to form Compound
`(Im).
`Compound (IX) is included in the definition of the
`starting material (XXI).
`Compound (X1) 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 l to 24 hours to
`yield Compound (XXI).
`Process H
`
`30
`
`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
`by the Processes A—D to reduction such as hydrogena—
`tion using paradium-carbon as 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 as filtra-
`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 Il-position of dibenz[b,e]oxepin, Compounds
`(Ia), (Ib), (1c), (Id), (lg) 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
`produced as 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 (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 Compound (I) wherein the
`substituent is on the opposite side is trans-form (or anti-
`form).
`
`35
`
`4O
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Table 3 shows characteristic signals in NMR and
`Table 4 shows retention time in HPLC.
`TABLE 1
`Compound
`
`No. Compound (I)
`1
`Methyl cis-ll-(3~dimethylaminopmpylidene)-
`6.1l-dihydrodibenz[b.e]oxepin-2-carboxylaie
`Methyl trans-l l-(3-dimethylaminopropylidene)~
`6.1 l-dihydrodibenz{b.e]oxepin-2-carboxylate
`Ethyl cis-l l-(3-dimelhylaminopropylidene)-6.l1-
`dihydrodibenz[b.e]oxepin~2-carboxylate
`Ethyl trans-1l-(3-dimethylaminopropylidene)—
`6.] l-dihydrodibenz[b.e]oxepin~2-carboxylate
`Cis-l l-(3-dimethylaminopropylidene)-6.l l-
`dihydrodibenzlb.e]oxepin-2-carboxylic acid
`Trans-l l-(3-dimethylaminopropylidene)—6.l 1-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methyl cis-ll-(3-diethylaminopropylidene)-6.l1-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl trans-11~(3-diethylaminopropylidene)-
`6.1l-dihydrodibenz[b.e]oxepin-Z—carboxylate
`Cis-l l-(3-diethylaminopropylidene)-6.1l-
`dihydrodibenz[b.e]oxepin‘2-carboxylic acid
`Trans-l l-(3—diethylaminopropylidene)-6,l 1-
`dihydrodibenz[b,e]oxepin-Zarboxylic acid
`Methyl cis-l l-(3vpyrrolidinopropylidene)—6.l 1-
`dihydrodibenz[b.eloxepin-Z—carboxylate
`Methyl transvl l-(3-pyrrolidinopropylidene)«
`6,1 l-dihydrodibenz[b.e]oxepin-2-carboxylate
`Cis-l l-(3-pyrrolidinopropylidene}6,l )-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Trans-l l—(3-pyrrolidinopropylideneyb.l l-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methyl cis-ll-(4—dimethylaminobutylidene)-
`6.1 l-dih ydrodibenz[b,e]oxepin-2-carboxylate
`Methyl trans-l l-(4—dimethylaminobutylidene)-
`6,] l-dihydrodibenz[b,e]oxepin-2-carboxylate
`Cis-l l-(4—dimethylaminobutylidene)—6.l l-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Trans-l l-(4-dimethylaminobutylidene)-6.l l-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methyl cis-l l-[2-(4—methylpiperazino)-
`ethylidene]-6.l l-dihydrodibenz[b.e]oxepin-2-
`carboxylate
`Methyl trans-l l-[2-(4-methylpiperazino)-
`ethylidene]-6,l l-dihydrodibenz[b,e]oxepin-2-
`carboxylate
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`IO
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1036 p. 009
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1036 p. 009
`
`

`

`17
`
`TABLE l—continued
`
`12
`
`13
`
`14
`
`15
`
`I6
`
`17
`
`18
`
`19
`
`20
`
`Compound
`No.
`
`Compound (I)
`ll
`Cis-l l-[2-(4-methylpiperazino)ethylidene]-
`6.] l-dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Trans-l l-[2-(4-methylpiperazino)ethylidene]-
`6,1l-dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methyl cis-l l-(2-morpholinoethylidene)-6.1 1-
`dihydrodibenzIb.e]oxepin-2-carboxylate
`Methyl trans-ll-(2-morpholinoethylidene)-6,1l-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Cis-l l-(2-morpholinoethylidene)-6,l l-
`dihydrodibenZ[b.e]oxepin-2-carboxylic acid
`Trans-1 1-(2-morpho]inoethylidene)-6.1 1-
`dihydrodibenz[b.e]oxepin-2-carboxy1ic acid
`Methyl cis~1l~(2-thiomorpholinoethylidene)-
`6.1I-dihydrodibenz[b,e]oxepin-Z-carboxylate
`Methyl trans-l l-(2-thiomorpholinoethylidene)-
`6,1l-dihydrodibenz[b,e]oxepin-2-carboxylate
`Cis-ll-(2-thiomorpholinoethylidene)-6.11-
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`Trans-l1-(2-thiomorpholinoethylidene)—6,11—
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`Methyl cis-l l-(2-pyrrolidinoethylidene)-6.l l-
`dihydrodibenz[b,e]oxepin-2-carboxylate
`Methyl trans-11-(2-pyrrolidinoethylidene)—
`6.1l-dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl cis-ll-(2~piperidinoethylidene)-6.1l-
`dihydrodibenzlb.e]oxepin-2-carboxylate
`Methyl trans-l l-(2-piperidinoethylidene)-6,l l-
`dihydrodibenz[b.e]oxepin-Z-carboxylate
`Methyl cis-l1-(3-dimethylaminopropylidene)-
`6.l l-dihydrodibenz[b.e]oxepin-2-acetate
`Methyl trans-11-(3-dimethylaminopropylidene)'
`6.1 1-dihydrodibenz[b.e]oxepin-Z-acetate
`Ethyl cis-l1-(3-dimethylaminopropylidenel-b.1 l-
`dihydrodibenz[b.e]oxepin-2-acetate
`Ethyl trans—1l-(3-dimethylaminopropylidene)-
`6.]1-dihydrodibenz[b.e]oxepin~2-acetate
`Cis-l l-(3-dimethylaminopropylidene)-6.l 1-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-l1-(3-dimethylaminopropylidene)-6.1l-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Methyl cis-l1-(4-dimethylaminobutylidene)-6.1 1-
`dihydrodibenz[b.e]oxepin-2-acetaie
`Methyl trans-1l-(4-dimethylaminobutylidene)-
`6.] l-dihydrodibenz[b,e]oxepin-2-acetate
`Cis-l l-(4-dimethylaminobutylidenel-é,1 1-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-ll~(4-dimethylaminobutylidene)-6.1l-
`dihydrodibenz[b,e]oxepin~2-acetic acid
`Methyl cis-l l-(3-pyrrolidinopropylidene)-6.l l-
`dihydrodibenz[b.e]oxepin-2-acetate
`Methyl trans-1l-(3-pyrrolidinopropylidene)-
`6.1 1-dihydrodibenz[b.e]oxepin-2-acetate
`Cis-l1-(3-pyrrolidinopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-1 l-(3-pyrrolidinopropylidene)-6.1 1-
`dihydrodibenz[b.e]oxepin-2»acetic acid
`Methyl cis-l l-[2-(4-methylpiperazino)-
`ethylidene-6.l l-dihydrodibenz[b,e]oxepin-2-
`acetate
`Methyl trans-1l-[2-(4-methylpiperazino)—
`ethylidene)-6.1 1-dihydrodibenz[b,e]oxepin-2—
`acetate
`Cis-l 1~[2-(4-methylpiperazino)-ethylidene-
`6,1l-dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-1 1-[2-(4—methylpiperazino)-ethy1idene)-
`6,] l-dihydrodibenz[b,e]oxepin-2-acetic acid
`Methyl cis-3-[l l-(3-dimethylaminopropylidene)-
`6,1 l-dihydrodibenz[b,e]oxepin‘Z-yl]-propionate
`Methyl trans-S-[l l-(3-dimethylaminopropyli-
`dene)-6,l l-dihydrodibenzIb,e]oxepin-2-y1]-
`propionate
`Cis-3-[ll-(3-dimethylaminopropylidene)-6,l1-
`dihydrodibenz[b,e]oxepin-2-yl]-propionic acid
`Trans-341 l-(3-dimethylaminopropylidene)-6.1 1-
`dihydrodibenz[b.e]oxepin-Z-yl]-propionic acid
`Methyl cis-l l-(3-dimethylaminopropylidene)-
`6,1 l-dihydrodibenz[b.e]oxepin-3-acetaie
`Methyl trans-l lc(3-dimethylaminopropylidenc)-
`6,1l-dihydrodibenz[b.e]oxepin-3-acetate
`Cis-l1-(3-dimethylaminopropylidene)-6,l l-
`
`26
`
`27
`
`28
`
`29
`
`30
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4o
`
`45
`
`50
`
`55
`
`65
`
`18
`TABLE l-continued
`Compound
`
`Not Compound (I)
`dihydrodibenz[ b.e]oxepin-3-acetic acid
`Trans-ll-(3~dimethylaminopropylidene)-6.1l-
`dihydrodibenz[b.e]oxepin-3-acetic acid
`Cis-l l-(3-dimethylaminopmpylidene)-2-(2-
`hydroxyethyl)-6.11-dihydrodibenz[b.e]oxepin
`Trans-l1-(3-dimethylaminopropylidene)-2-(2-
`hydroxyethyl)-6,l1-dihydrodibenz[b.e]oxepin
`Cis—l1-(3-dimethylaminopropylidene)—2-(2-
`triphenylmethyloxymethyl)-6,1l-dihydrodibenz-
`{b.e]oxepin
`Trans-l l-(3-dimethylaminopropylidene)-2-(2-
`triphenylmethyloxymethyl)-6,l l-dihydrodibenz-
`[b.eloxepin
`Cis-l l-(3-dimethylaminopropylidene)—2-(3-
`hydroxypropyl)-6,l l-dihydrodibenz[b.e]oxepin
`Trans-11~(3-dimethylaminopropylidene)-2-(3-
`hydroxypropyl)-6,1 1-dihydrodibenz[b,e]oxepin
`Methyl cin-l1-(2-diethylaminoethyl)imino-6,1l-
`dihydrodibenz[b,e]oxepin-2-carboxy1ate
`Methyl anti-1l—(2-diethylaminoethyl)imino-
`6,11-dihydrodibenz[b,e]oxepin-Z-carboxylate
`Cin-l l-(2-diethylaminoethyllimino-é.l l-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Anti-1l-(2-diethylaminoethyl)imino-6,ll-
`dihydrodibenz[b.e]oxepin-Z-carboxylic acid
`Methyl cin-l1-(2-dimethylaminoethyl)imino-
`6.1l-dihydrodibenz[b.e]oxepin-Z-acetate
`Methyl anti-l 1-(2-dimethylaminoethyllimino-
`6.1l-dihydrodibenz[b.e]oxepin-2-acetate
`Cin-l1-(2-dimethylaminoethyl)imino-6.1l-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Anti-l l-(2-dimethylaminoethyl)imino-6.l l-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Methyl Cin-l l—(2vdiethylaminoethyl)imino-é,l l-
`dihydrodibenz[b,e]oxepin-2-acetaie
`Methyl anti-1l-(2~diethylaminoethyl)imino-
`6.1 l-dihydrodiben