`Oshima et al.
`
`[54] DIBENZ[B,E]OXEPI!'; DERIVATIVE AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`[75]
`
`Inventors: Etsuo Oshima; Toshiaki Kumazawa;
`Shizuo Otaki; Hiroyuki Obase, all of
`Shizuoka; Kenji Ohmori, Mishirna;
`Hidee Ishii, Shizuoka; Haruhiko
`Manabe, Shizuoka; Tadafumi
`Tamura, Shizuoka; Katsuichi Shoto,
`Shizuoka, all of Japan
`
`[73] Assignee: Kyowa Hakko Kogyo Co., Ltd.,
`Tokyo, Japan
`[21] Appl. No.: 20,900
`[22] Filed:
`Mar. 2, 1987
`
`[30]
`
`Foreign Application Priority Data
`
`Mar. 3. 1986 [JP]
`Japan .................................. 61-45676
`Int. c1.s ................... A61K 31/335; C07D 313/12
`[51]
`[52] U.S. Cl. .................................... 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 .................. 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
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`3,354.155 11/1967 Tretter ............................ 549/354 X
`3,420.851 1/1969 Bloom et al. ........................ 549/354
`3.509,176 4/1970 Winter et al. ....................... 260/333
`4.282,365 8/ 1981 Rokach ............................... 548/252
`4,396,550 8/1983 Takizawa ............................ 549/354
`
`I lllll llllllll Ill lllll lllll lllll lllll lllll 111111111111111111111111111111111
`US005 J J 6863A
`5,116,863
`[JI] Patent Number:
`[45] Date of Patent: May 26, 1992
`
`4.465,835 8/1984 Takizawa ............................ 546/133
`4,585.788 4/1986 Helsley et al. ...................... 549/354
`4,596,804 6/1986 Takizawa ............................ 514/253
`4,871.865 10/1989 Lever et al. ......................... 549/354
`4,923,892 5/1990 Lever et al. ......................... 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
`Wellcorne Foundation Ltd., Chemical Abstracts, vol.
`107 (I 987) 58,673r.
`Metvosova, Arz.-Forsch., vol. 13 (1963) 1039:43.
`Benesova, Arz.-Forsch .. vol. 14 (1964) 100:3.
`Chern. Abs., vol. 63 (1965) J 6366a.
`Drugs, vol. 13 (1977) 161:218.
`J. Med. Chern., vol. 19. No. 7 (1976) 941:6.
`J. Med. Chern., vol. 20, No. 11 (1977) 1499:501.
`J. Med. Chern., vol. 21, No. 7 (1978) 633:9.
`
`Primary Examiner-Richard L. Raymond
`Attorney, Agent, or Firm-Fitzpatrick, Cella, Harper &
`Scinto
`
`ABSTRACT
`[57]
`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,' l'io Drawings
`
`ARGENTUM PHARM. 1028
`
`000001
`
`
`
`1
`
`5,116,863
`
`DIBENZ[B,E]OXEPIN DERIVATIVE AND
`PHARMACEUTICAL COMPOSITIONS THEREOF
`
`2
`Doxepin having an antidepressant activity and hav(cid:173)
`ing the following structural formula is known [Drugs,
`13, 161 (1977)].
`
`5
`
`10
`
`Dothiepin having an antidepressant activity and hav-
`15 ing the following structural formula is known [Arz.(cid:173)
`Forsch., 13 1039 (1963); ibid., 14 100 (1964)].
`
`BACKGROUND OF THE INVENTION
`Heretofore, it has been known that 11-unsubstituted,
`I I-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]oxepin derivative
`wherein substitutents Ra and Rb at 11-position have the
`following definitions, is employed in the treatment and
`control of allergic conditions (U.S. Pat. No. 4,282,365).
`Ra: H, OH, lower alkoxy, lower alkylthio, lower alkyl-
`sulfinyl, lower alkylsulfonyl, arylthio, NH2, NHCHO
`or imidazolyl;
`Rb: H or lower alkyl; or Ra and Rb taken together are
`=O, =CH-Re wherein Re is Hor aryl.
`that 11-(4-methyl- 20
`Furthermore,
`it
`is known
`piperazino) dibenz[b,e]oxepin derivative has an anti(cid:173)
`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 25
`having the following formula:
`
`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
`30 antiallergic activity or an antiinflammatory activity be
`developed.
`
`SUMMARY OF THE INVENTION
`The present invention relates to a dibenz[b,e]oxepin
`35 derivative represented by the formula (I):
`
`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:
`
`40
`
`(I)
`
`Y-A
`
`R;
`
`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
`
`wherein Rj is 4-alkylpiperazino, 3-quinuclidylamino or
`-Xa-(CH2)hd s-NR1Rm wherein Xa is -NH-,
`-S- or -0-, sis 2 or 3 and R1 and Rm are alkyl, and 65
`Rk is CN, 5-tetrazolyl, CONH2 or C02Rn wherein Rn is
`H, alkyl or 1-(ethoxycarbonyloxy)ethyl is known (EP(cid:173)
`A-130555).
`
`45 Wherein A represents a hydroxymethyl, a lower alkox(cid:173)
`ymethyl, a triphenylmethyloxymethyl, a lower al(cid:173)
`kanoyloxymethyl, a lower alkanoyl, a carboxy, a lower
`alkoxy
`carbonyl,
`a
`triphenylmethyloxycarbonyl,
`-CONR1R2 (wherein Rt and Rz are the same or differ-
`50 ent and represent hydrogen atom or lower alkyl) 4,4-
`dimethyl-2-oxazoline-2-yl group or -CONHOH; Y
`represents
`-(CH2)m-,
`-CHR3-(CH2)m-
`or
`-CR4=CRs-(CH2)hd m- which is substituent at 2-
`or 3-position of the mother nucleus (wherein R3 repre-
`55 sents a lower alkyl, ~and Rs are the same or different
`and represent a hydrogen atom or a lower alkyl, m is 0,
`I, 2, 3 or 4, and the left side of the group ofY mentioned
`above is bound to benzen nucleus); X represents =N-,
`=CH- or -CH2-; n is 0, I, 2, 3 or 4; Z represents
`60 4-methylpiperazino, 4-methylhomopiperazino, piperi(cid:173)
`thiomorpholino, morpholino, or
`dino, pyrrolidino,
`-NR6R7 (wherein R6 and R1 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 (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
`
`000002
`
`
`
`5,116,863
`
`3
`composition containing an effective amount of Com(cid:173)
`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.
`
`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(cid:173)
`closed in JP-A-21679/83 and the other Compounds
`5 (III) can be prepared according to the method de(cid:173)
`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.
`
`15
`
`20
`
`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.
`
`rOH
`
`Y-C-1'-tCH, SOCJ, )o
`II H
`CH
`0
`.1
`
`(Ila)
`
`0
`II
`
`(IV)
`
`0
`II
`
`(\!)
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`In the definition of each group of formula (I), the
`lower alkyl group includes straight or branched chain IO
`alkyl groups having I 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(cid:173)
`ymethyl, ethoxymethyl, n-propoxymethyl, isopropoxy,
`etc. and the lower alkoxycarbonyl group includes me-
`thoxycarbonyl, ethoxycarbonyl, etc.
`In the definition of the group A, the lower alkyl
`moiety of lower alkanoyl group and lower alkanoylox(cid:173)
`ymethyl group has the same meaning as previously
`defined.
`The lower alkanoyl group includes formyl, acetyl, 25
`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 30
`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, 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 ofmorpholine and piperi(cid:173)
`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):
`
`0
`II
`
`(II)
`
`Y-A
`
`wherein Y and A have the same meanings as previously
`defined or a compound represented by the formula
`(Ill):
`
`50
`
`(III) 60
`
`Y-A
`
`wherein Y and A have the same meanings as previously
`defined as the starting compound. Compound (II) is
`
`In the formulae, Y has the same meaning as previ(cid:173)
`ously defined. and Compound (Ila) is included in Com(cid:173)
`pound (II) (compounds with an alphabet suffix follow(cid:173)
`ing formula number are likewise included in compounds
`with common formula No.).
`Compound (Ila) is reacted with I to 5 equivalents of
`thionyl chloride and 1 to 5 equivalents of 2-amino-2-
`methyl-1-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 triethylamine at a temper-
`55 ature of from o• 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(cid:173)
`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-
`65 pound (V).
`Compounds (Ia) and (lb) can be prepared from Com(cid:173)
`pound (V) according to the following reaction scheme.
`
`000003
`
`
`
`5
`
`5,116,863
`
`6
`
`0
`II
`
`(V)
`
`0
`
`y---{ ~ HalMg(CH2ln-1Z (\'!)
`
`>
`
`N
`
`0
`
`y---{ ~ -H20>
`
`N
`
`(VII)
`
`~OH
`
`(la)
`
`/120
`
`0
`
`v---{ ~
`
`N
`
`(lb)
`
`In the formulae. Y, Z, and n have the same meanings
`as previously defined. Rs is hydrogen or a lower alkyl 35
`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
`(I). Halogen includes chlorine, bromine and iodine.
`Compound (V) is reacted with 1-5 equivalents of Com- 40
`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 O' C. to
`room temperature and is usually completed in 1-24 45
`hours.
`Compound (VII) is reacted with 1-5 equivalents of
`thionyl chloride or phosphoryl chloride in an inert sol(cid:173)
`vent such as methylene chloride in the presence of a
`base such as pyridine to form Compound (Ia). The reac- 50
`tion is carried out at a temperature of from 0° C. to
`room temperature and is completed in 1-24 hours.
`Compound (Ia) is incubated in an alcohol containing
`water, such as aqueous methanol solution, in the pres-
`
`ence of an appropriate acidic catalyst such asp-toluene(cid:173)
`sulfonic acid at a temperature of from room tempera(cid:173)
`ture to the boiling point of the solvent to form Com(cid:173)
`pound (lb) wherein Rs is H. The reaction is completed
`in 1-24 hours.
`Compound (VII) is incubated in a alcohol of Rs'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 (lb) wherein Rs is a lower alkyl. The reac(cid:173)
`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(cid:173)
`ymethyl group or a trityloxymethyl group according to
`the following reaction scheme.
`
`0
`II
`
`(Ila)
`
`000004
`
`
`
`7
`
`5,116,863
`
`-continued
`
`8
`
`OH
`
`(\'Ill)
`
`/(Ph)JCI ~H
`
`OH
`
`(IX)
`
`~dation
`
`(X)
`
`~xidation
`
`0
`II
`
`(XI)
`
`35
`
`40
`
`In the formulae, Y has the same meaning as previ(cid:173)
`ously defined, R9 is a lower alkyl group and R9' is a
`trityl group or a lower alkyl group. The term lower
`alkyl has the same meaning as that of lower alkyl in
`each group in formula (I).
`Compound (Ila) is reduced with 1-5 equivalents of
`lithium aluminium hydride in tetrahydrofuran at a tem(cid:173)
`perature of from O' C. to room temperature for 1-24
`hours to form Compound (VIII).
`Compound (VIII) is reacted with 1-5 equivalents of 45
`trityl chloride in pyridine at a temperature of from room
`temperature to JOO' C. for 1-24 hours to form Com(cid:173)
`pound (IX).
`Compound (IX) is oxidized with 1-5 equivalents of
`an appropriate oxidizing agent such as potassium per- so
`manganate and pyridinium chlorochromate in an inert
`solvent such as methylene chloride and acetone to form
`Compound (XI) wherein R9' is trityl. The reaction is
`
`carried out at a temperature of from O' C. to the boiling
`point of the solvent and is completed in 1-24 hours.
`Compound (VIII) is incubated in an alcohol of R90H
`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 Rq' is a lower alkyl. The reaction is carried out
`at a temperature of from O' C. to the boiling point of the
`solvent and is usually completed in 1-24 hours.
`The compounds represented by the formulae (le) and
`(Id) and if desired, the compound represented by the
`formula (le) can be synthesized from Compound (XI)
`according to the following reaction scheme.
`
`0
`II
`
`(XI) i HalMg(CH2ln- 1Z (VI) .
`
`000005
`
`
`
`9
`
`5,116,863
`
`10
`
`(XII)
`
`(le)
`
`(Id)
`
`i Oxidation
`
`(le)
`
`45
`
`In the formulae, Y. Z, R9', 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(cid:173)
`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(cid:173)
`pound (VII) to Compound (la) in Process A to form
`Compound (le).
`Compound (le) 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 (Id) is oxidized with 1-5 equiv(cid:173)
`alents of an appropriate oxidizing agent such as Jones
`reagent in an inert solvent such as acetone to form Com- 65
`pound (le). The reaction is carried out at a temperature
`of from o• C. to the boiling point of the solvent and is
`usually completed in 1-24 hours.
`
`55
`
`Process C
`Synthesis of Compound (I) wherein X is =CH- (Part
`3)
`
`0
`II
`
`(lib)
`
`Y-A' +
`
`Ph3P=CH(CH2lnZ -7
`(XIII)
`
`Y-A'
`
`(It)
`
`In the formulae, Y, Z, and n have the same meanings
`as previously defined. A' represents the groups falling
`within the definition of A but lower alkanoyl group.
`Compound (lib) is reacted with 1-5 equivalents of
`Compound (XIII) in an inert solvent such as tetrahy-
`
`000006
`
`
`
`5, 116,863
`
`11
`drofuran under atmosphere of an inert gas such as nitro(cid:173)
`gen and argon at a temperature of from o• C. to room
`temperature for 1-24 hours to form Compound (Ip.
`Compound (XIII) which is ylide, can be prepared
`according to the method described in C.A. 63 16366a 5
`(1965).
`
`Ph3P ~ Ha!(CH2)n-1Hal --7
`(XIV)
`
`l)HZ >
`+
`Ph3P(CH2)n+ 1Hal.Ha1- 2) HHal
`(VX)
`
`T
`
`Ph3P(CH2ln+ 1Z.Ha1- .(HHallq
`
`(XVI)
`
`10
`
`15
`
`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 25
`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 o· 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 35
`(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 40
`4)
`
`formaldehyd~
`Y-A +or polymerized +
`formaldehyde
`
`45
`
`50
`
`HZ Acid >
`
`Y-A 55
`
`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(cid:173)
`gen and argon to yield Compound (lg).
`The formaldehyde or polymerized formaldehyde
`includes p-formaldehyde·, trioxane. etc. The acid in(cid:173)
`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(cid:173)
`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.
`
`0
`II
`
`Y-A' + Ph3P=CH2 --7
`(XVII)
`
`Y-A'
`
`(llla)
`
`That is, Compound (lib), I to 5 equivalents of me(cid:173)
`thyltriphenylphosphonium bromide and 1 to 5 equiva(cid:173)
`lents of n-butyl lithium on the basis of Compound (lib)
`are subjected to reaction in an inert solvent at from
`- 78° C. to room temperature for I to 5 hours to yield
`ylide (XVII) which is reacted with an equivalents of
`Compound (lib) 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 (Illa).
`The inert gas includes nitrogen, argon, etc. and the
`inert solvent includes tetrahydrofuran. etc.
`The group A' in Compound (Illa) can easily be con(cid:173)
`verted to a lower alkanoyl group as is stated in Process
`I and therefore, Compound (III) can easily be prepared.
`
`Process E
`Synthesis of Compound (I) wherein X is=N-
`
`0
`II
`
`Y-A' + H2N(CH2lnZ --7
`(XVIII)
`
`In the formulae, Y, Zand A have the same meanings 60
`as previously defined.
`The process is known as Prince reaction [New Exper(cid:173)
`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 1 to 5 equivalents of HZ are subjected to reaction in
`an inert solvent such as tetrachloroethane in the pres-
`
`65
`
`Y-A'
`
`Compound (lib) and I to 10 equivalents of Com(cid:173)
`pound (XVIII) are subjected to reaction in an inert
`solvent such as benzene in the presence of I to 10 equiv(cid:173)
`alents of titanium tetrachloride at from o· c. to the
`
`000007
`
`
`
`13
`boiling point of the solvent under atmosphere of an inert
`gas such as nitrogen and argon for I to 48 hours to yield
`Compound (lh).
`
`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 I to 5 equivalents of Compound
`(VI) are subjected to reaction in the same manner as in
`5 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
`
`0
`II
`
`Y-{} RoO""'oo )
`
`OH
`
`(XIX)
`
`Cl
`
`0
`
`y--{N }
`
`Chlorination >
`
`(CH2lnZ
`
`/
`CH2
`
`(Ii)
`
`(lj)
`
`In the formulae, Y, Z. n, Rs and Hal have the same 40
`meanings as previously defined.
`Compound (V) is reduced with 1 to 5 equivalent of
`lithium aluminium hydride or sodium borohydride in an
`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-
`
`manner as in the reaction step from Compound (VII) to
`Compound (lb) or the reaction step from Compound
`(la) to Compound (lb) in Process A to yield Compound
`(lj).
`
`Process G
`Synthesis of Compound (I) wherein X is -CH2- (Part
`2)
`
`OH
`
`(XX!)
`
`Cl
`
`CH2-(CH2lnZ
`
`(lk)
`
`000008
`
`
`
`15
`
`5,116,863
`
`-continued
`
`16
`
`--
`(CH,l-Z
`
`/
`CH2
`
`Y-CH 20H Oxidation )
`
`Y-C02H
`
`(II)
`
`Compound (XXI) is subjected to chlorination in the
`same manner as in Process F to yield Compound 15
`(XXII). Compound (XXII) and Compound (VI) are
`subjected to reaction in the same manner as in Process
`F to yield Compound (Ik). Compound (Ik) is treated in
`the same manner as in Process B to form Compound
`(Il).
`Compound (Il) 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 O' C. to room temperature for 1 to 24 hours to
`yield Compound (XXI).
`
`w
`
`30
`
`Process H
`Synthesis of Compound (I) wherein X is -CH2- (Part
`3)
`Compound (I) wherein X is -CH2- can also be
`prepared by subjecting Compounds (Ia)-(lg) obtained 35
`by the Processes A-D to reduction such as hydrogena(cid:173)
`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 40
`in the field of organic chemical synthesis, such as filtra(cid:173)
`tion, extraction with organic solvent such as ethyl ace(cid:173)
`tate and methylene chloride, drying, concentration,
`recrystallization, column chromatography, etc.
`Out of Compounds (Ia)-(Ih) obtained in each of the 45
`processes described above, with regard to stereochem(cid:173)
`istry at I I-position of dibenz[b,e]oxepin, Compounds
`(Ia), (lb), (le), (Id), (lg) and (Ih) are apt to be formed as
`a trans-form and Compound (I.fl is apt to be formed as a
`cis-form, with high frequency compared with the other 50
`form.
`When Compound (I) except Compounds (Ii)-(Im) is
`produced as a cis-trans mixture, Compound (I) is sepa(cid:173)
`rated and purified by an appropriate method which is
`usually used in the field of organic chemical synthesis, 55
`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(cid:173)
`priate catalyst such as p-toluenesulfonic acid for I-24 60
`hours to form trans-form.
`With regard to the denotation of cis-form (or cin(cid:173)
`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 65
`cis-form (or cin-form) and Compound (I) wherein the
`substituent is on the opposite side is trans-form (or anti(cid:173)
`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 represented by the fol(cid:173)
`lowing formula is cis-form (or cin-form or Z-form).
`
`Y-A
`
`Table 1 shows examples of Compound (I) or pharma(cid:173)
`ceutically acceptable salts thereof and Table 2 shows
`the structural formula thereof.
`Table 3 shows characteristic signals in NMR and
`Table 4 shows retention time in HPLC.
`TABLE I
`
`Compound
`l"o.
`
`Compound(!)
`
`2
`
`4
`
`6
`
`9
`
`10
`
`Methyl cis-11-(3-dimethylaminopropylidene)-
`6. l l-dihydrodibenz[b.e ]oxepin-2-carboxylate
`Methyl trans-11-(3-dimethylaminopropylidene)-
`6.11-dihydrodibenz[b,e]oxepin-2-carboxylate
`Ethyl cis-l l-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Ethyl trans-! 1-{3-dimethylaminopropylidene)-
`6.11-dihydrodibenz[b.e ]oxepin-2-carboxy late
`Cis-11-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Trans-l l-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Methyl cis-11-{3-diethylaminopropylidene )-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl trans-l l-(3-diethylaminopropylidene)-
`6.11-dihydrodibenz[b.e]oxepin-2-carboxylate
`Cis-11-(3-diethylaminopropylidene)-6, l 1-
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Trans-11-(3-diethylaminopropylidene)-6, l l(cid:173)
`dihydrodibcnz[b,e]oxepin-2-carboxylic acid
`Methyl cis-11-(3-pyrrolidinopropylidene)-6, l l(cid:173)
`dihydrodibcnz[b,e]oxepin-2-carboxylate
`Methyl trans-11-(3-pyrrolidinopropylidene)-
`6, 11-dihydrodibcnz[b,e]oxepin-2-carboxylate
`Cis-11-(3-pyrrolidinopropylidene)-6,l l(cid:173)
`dihydrodibcnz[b,e]oxepin-2-carboxylic acid
`Trans-11-(3-pyrrolidinopropylidene)-6, l l(cid:173)
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`Methyl cis-11-(4-dimethylaminobutylidene)-
`6,11-dihydrodibcnz[b,e]oxepin-2-carboxylate
`Methyl trans-11-(4-dimethylaminobutylidene)-
`6, 11-dihydrodibcnz[b,e]oxepin-2-carboxylate
`Cis-11-( 4-dimethylaminobutylidene)-6, 11-
`dihydrodibcnz[b,e]oxepin-2-carboxylic acid
`Trans-11-(4-dimethylaminobutylidene)-6,l l(cid:173)
`dihydrodibcnz[b,e]oxepin-2-carboxylic acid
`Methyl cis-11-[2-(4-methylpiperazino)(cid:173)
`ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-
`carboxvlate
`Methyi trans-11-[2-(4-methylpiperazino)(cid:173)
`ethylidene]-6, 11-dihydrodibenz[b.e]oxepin-2-
`carboxylate
`
`000009
`
`
`
`17
`TABLE !-continued
`
`5,116,863
`
`18
`TABLE !-continued
`
`Compound
`No.
`
`Com pound (ll
`
`Compound
`No.
`
`Compound (I)
`
`II
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`22
`
`23
`
`24
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`Cis-11-[2-(4-methylpiperazino)ethylidene)-
`6.l l-dihydrodibenz(b.e)oxepin-2-carboxylic acid
`Trans-11-[2-( 4-methylpiperazino )ethylidene )-
`6, l l-dihydrodibenz[b.e ]oxepin-2-carboxylic acid
`Methyl cis-l l-(2-morpholinoethylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl trans-I 1-(2-morpholinoethylidene)-6, 11-
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Cis-1 l-(2-morpholinoethylidene)-6.11-
`dihydrodibenz[b.e)oxepin-2-carboxylic acid
`Trans-11-(2-morpholinoethylidene )-6.11-
`dihydrodibenz[b.e ]oxepin-2-carboxylic acid
`Methyl cis-11-(2-thiomorpholinoethylidene)-
`6.l l-dihydrodibenz[b,e)oxepin-2-carboxylate
`Methyl trans-11-(2-thiomorpholinoethylidene)-
`6, 11-dihydrodibenz[b,e]oxepin-2-carboxylate
`Cis-l l-(2-thiomorpholinoethylidene)-6.11-
`dihydrodibenz[b,e]oxepin-2-carboxylic acid
`Trans-l l-(2-thiomorpholinoethylidene)-6,11-
`dihydrodibenz[b,e)oxepin-2-carboxylic acid
`Methyl cis-1 l-(2-pyrro!idinoethylidene)-6,11-
`dihydrodibenz[b,e)oxepin-2-carboxylate
`Methyl trans-I l-(2-pyrrolidinoethylidene)-
`6.11-dihydrodibenz[b.e)oxepin-2-carboxylate
`Methyl cis-11-(2-piperidinoethylidene)-6.l l(cid:173)
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl trans-11-(2-piperidinoethylidene)-6,l l(cid:173)
`dihydrodibenz[b.e]oxepin-2-carboxylate
`Methyl cis-11-(3-dimethylaminopropylidene)-
`6.I l-dihydrodibenz[b.e]oxepin-2-acetate
`Methyl trans-l l-(3-dimethylaminopropylidene)-
`6.11-dihydrodibenz[b.e )oxepin-2-acetate
`Ethyl cis-11-(3-dimethylaminopropylidene)-6.l l(cid:173)
`dihydrodibenz[b.e]oxepin-2-acetate
`Ethyl trans-11-(3-dimethylaminopropylidene)-
`6. l 1-dihydrodibenz[b.e]oxepin-2-acetate
`Cis-1 l-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-! 1-(3-dimethylaminopropylidene )-6.11-
`dihydrodibenz[b.e)oxepin-2-acetic acid
`Methyl cis-11-(4-dimethylaminobutylidene)-6.1 l(cid:173)
`dihydrodibenz[b.e]oxepin-2-acetate
`Methvl trans-11-(4-dimethvlaminobutvlidene)-
`6. l 1-dihydrodibenz[b,e]ox~pin-2-acet~te
`Cis-11-(4-dimethylaminobutylidene)-6,l l(cid:173)
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-11-(4-dimethylaminobutylidene)-6.l l(cid:173)
`dihydrodibenz[b,e]oxepin-2-acetic acid
`Methyl cis-11-(3-pyrrolidinopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-2-acetate
`Methyl trans-11-(3-pyrrolidinopropylidene)-
`6.l l-dihydrodibenz[b.e )oxepin-2-acetate
`Cis-11-(3-pyrrolidinopropylidene )-6.11-
`dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-I 1-(3-pyrrolidinopropylidene)-6.11-
`dihydrodibenz[b.e)oxepin-2-acetic acid
`Methyl cis-11-[2-(4-methylpiperazino)(cid:173)
`ethylidene-6, I 1-dihydrodibenz[b,e]oxepin-2-
`acetate
`Methyl trans-11-[2-(4-methylpiperazino)(cid:173)
`ethylidene)-6, l l-dihydrodibenz[b,e)oxepin-2-
`acetate
`Cis-11-[2-(4-methylpiperazino )-ethylidene-
`6, I l-dihydrodibenz[b.e]oxepin-2-acetic acid
`Trans-11-[2-(4-methylpiperazino )-ethylidene)-
`6, I l-dihydrodibenz[b,e]oxepin-2-acetic acid
`Methyl cis-3-(l 1-(3-dimethylaminopropylidene)-
`6,l l-dihydrodibenz[b,e]oxepin-2-yl]-propionate
`Methyl trans-3-[l l-(3-dimethylaminopropyli(cid:173)
`dene)-6,l l-dihydrodibenz[b,e]oxepin-2-yl](cid:173)
`propionate
`Cis-3-[l l-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b,e]oxepin-2-yl]-propionic acid
`Trans-3-[l l-(3-dimethylaminopropylidene)-6,11-
`dihydrodibenz[b.e]oxepin-2-yl]-propionic acid
`Methyl cis-11-(3-dimethylaminopropylidene)-
`6,l l-dihydrodibenz[b.e)oxepin-3-acetate
`Methyl trans-11-(3-dimethylaminopropylidene)-
`6,l l-dihydrodibenz[b,e]oxepin-3-acetate
`Cis-11-(3-dimethylaminopropylidene)-6, l l-
`
`5
`
`31
`
`10 32
`
`15 33
`
`20
`
`34
`
`35
`
`25 36
`
`37
`
`38
`
`30
`
`39
`
`35
`
`40
`
`40
`
`41
`
`45
`
`42
`
`43
`
`50 44
`
`55
`
`45
`
`46
`
`60 47
`
`65
`
`48
`
`49
`
`dihydrodibenz[ b.e)oxepin-3-acetic acid
`Trans-l l-(3-dimethylaminopropylidene)-6.11-
`dihydrodibenz[b.e]oxepin-3-acetic acid
`Cis-11-(3-dimethylaminopropylidene)-2-(2-
`hydroxyethyl)-6.1 l-dihydrodibenz[b.e]oxepin
`T rans-11-(3-dimethylaminopropylidene )-2-(2-
`hydroxyethyl)-6, 11-dihydrodibenz[b,e ]oxepin
`Cis-11-(3-dimethylaminopropylidene)-2-(2-
`triphenylmethyloxymethyl)-6, l l-dihydrodibenz(cid:173)
`[b,e]oxepin
`T rans-11-(3-dimethylaminopropylidene)-2-(2-
`triphenylmethyloxymethyl)-6, l l-dihydrodibenz(cid:173)
`[b.e )oxepin
`Cis- l l-(3-dimethylaminopropylidene)-2-(3-
`hydroxypropyl)-6, l l-dihydrodibenz[b,e ]oxepin
`Trans-11-(3-dimethylaminopropylidene )-2-(3-
`hydroxypropyl)-6, l l-dihydrodibenz[b,e ]oxepin
`Methyl cin-11-(2-diethylaminoethyl)imino-6, l l(cid:173)
`dihydrodibenz[b,e]oxepin-2-carboxylate
`Methyl anti-I 1-(2-diethylaminoethyl)imino-
`6, I 1-dihydrodibenz[b,e ]oxepin-2-carboxylate
`Cin-11-(2-diethylaminoethyl)imino-6, l l(cid:173)
`dihydrodibenz[b.e]oxepin-2-carboxylic acid
`Anti-11-(2-diethylaminoethyl)imino-6, 11-
`dihydrodibenz[b.e)oxepin-2-carboxylic acid
`Methyl cin-11-(2-dimethylaminoethyl)imino-
`6,l l-dihydrodibenz[b.e)oxepin-2-acetate
`Methyl anti-11-(2-dimethylaminoethyllimino-
`6. l l-dihydrodibenz[b.e]oxepin-2-acetate
`Cin-11-(2-dimethylaminoethyl)imino-6. l l(cid:173)
`dihydrodibenz[b,e)oxepin-2-acetic acid
`Anti-11-(2-dimethylaminoethyl)imino-6. l l(c