Patentamt
`European Patent Office
`J E u r o p a i s c h e s
`Office europeen des brevets
`
`(•R) Publication number:
`
`0 2 1 4 7 7 9
`B 1
`
`EUROPEAN PATENT SPECIFICATION
`
`Date of publication of the patent specification :
`11.04.90
`Application number: 86306326.9
`Date of filing: 15.08.86
`
`mt.ci.«: C07D 313/12, C07C 59/86,
`C07C 65/36, C07C 65/38,
`C07C 227/00, C07C 229/28,
`C07C 229/42, A61 K 31 /335,
`A 6 1 K 3 1 / 1 9
`
`Tricyclic compounds.
`
`Priority: 17.08.85 GB 8520662
`
`Date of publication of application :
`18.03.87 Bulletin 87/12
`
`Publication of the grant of the patent:
`11.04.90 Bulletin 90/15
`
`Designated Contracting States:
`AT BE CH DE FR GB IT LI NL SE
`
`References cited:
`EP-A- 0037 254
`EP-A- 0130 555
`GB-A- 1018995
`GB-A- 1412095
`US-A-4307245
`Burger's Medicinal Chemistry, 4th Edn., Vol. 3,
`pages 900-905
`
`0 )
`
`Proprietor: THE WELLCOME FOUNDATION LIMITED,
`183-193 Euston Road, London NW1 2BP(GB)
`
`Inventor: Lever, William O., Jr., 338, Grandvlew Road,
`Sklllman New Jersey 28558(US)
`Inventor: Lefghton, Harry Jefferson, 1904, White Plains
`Road, Chapel Hill North Carolina 27514(GB)
`
`Representative: Rollins, Anthony John et al, Group
`Patents & Agreements The Wellcome Foundation Ltd
`Langley Court, Beckenham Kent BR3 3BS(GB)
`
`M
`O Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to
`the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned
`a statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent
`II convention).
`ACTORUM AG
`
`APOTEX EX1029
`
`Page 1
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`EP 0 214 779 B1
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`Description
`The present invention relates to new chemical compounds which have potent antihistaminic activity, to
`processes for preparing them and to their use in medicine. Belg. Patent 623 259, Neth. Patent Appl. 6
`407 758, Neth. Patent Appl. 6 411 861 and Belg. Patent 641 498 disclose a group of 11-[(dialkylamino)-
`alkylidene]-6,11-dihydrodibenz[b,e]oxepins as psychotherapeutic agents the most outstanding of which
`is the compound named, (11-(3-(dimethylamino)propylidene)-6,11-dihydrodibenz[b,e]oxepin), and herein-
`after referred to by its generic name, doxepin. Doxepin has been accepted as an antidepressant in
`human clinical chemotherapy and an antipruritic for veterinary use.
`Published European Patent Application No 1 30 555 discloses compounds of formula:
`
`r
`
`o Y i
`
`o
`
`i
`
`
`
`wherein Ri represents a cyano group, a 5-tetrazolyl group, a carbamoyl group or -CO2R3 [wherein R3
`represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms or a 1-(ethoxycarbonyloxy)ethyl
`group, and R2 represents a 4-alkylpiperazino group (wherein the alkyl group has 1 to 5 carbon atoms), a
`3-quinuclidinylamino group or -X-(CH2)n-NR4R5 (wherein X represents -NH-, -S- or -O-, R4 and R5
`are same or different and each represents an alkyl group having 1 to 5 carbon atoms and n represents 2
`or 3); and the pharmaceutically acceptable acid addition salts or metal salts thereof, which compounds
`are said to exhibit anti-allergic activity.
`We have now discovered that a group of carboxylic acid derivatives of doxepin possess surprisingly
`potent antihistaminic and antiasthmatic properties. In this invention, compound (Z)-11-(3-(dimethyIamino)-
`propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid exhibits extremely good antihistaminic ac-
`tivity in vivo.
`Accordingly this invention provides a compound of the formula (I),
`
`CH(CH2)nNR2R3
`
`( I )
`
`or a salt, ester or amide thereof; wherein R1 is -CH2-O- or -O- CH2-;
`R2 and R3 are the same or different and are each hydrogen, C1-4 alkyl or taken together with the nitro-
`gen comprise a nitrogen-containing heterocyclic ring having four to six ring members;
`R4 is a single bond or a C1-7 bivalent aliphatic hydrocarbon group and may be joined to the aromatic ring
`system at the 2, 3, 8 or 9 positions, n is 0 to 3.
`Of the compounds of formula (I) those of formula (II), wherein R1 is as defined herein above, and R5 is
`a single bond or -CH=CH-, are preferred.
` R1 > n .
`\ f
`-H
`Jj
`
`^ \
`r
`
`R5CO2H
`
`CH(CH2)2N(CH3)2
`
`( H )
`
`The most preferred compounds of formula (II), are those of formula (Ha) wherein R5 is as defined for
`formula (II)
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`EP 0 214 779 B1
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`n
`CH(CH2)2N(CH3)2
`
`(IIA)
`
`Examples of compounds of formula (IIA) include:
`(1) (Z)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-2-carboxylic acid
`(2) (E)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-2-carboxylic acid
`(3) (E)-1 1 -(3-(Dimethylamino)propylidene)-6, 1 1 -dihydrodibenz[b,e]oxepin-3-carboxylic acid
`(4) (Z)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-3-carboxylic acid
`(5) (E)-1 1 -(3-(Dimethylamino)propylidene)-6, 1 1 -dihydrodibenz[b,e]oxepin-8-carboxylic acid
`(6) (Z)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-8-carboxyIic acid
`(7) (E)-1 1-(3-(DimethyIamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-9-carboxylic acid
`(8) (Z)-1 1 -(3-(DimethyIamino)propylidene)-6, 1 1 -dihydrodibenzib.eloxepin-S-carboxylic acid
`(9) (E)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihydrodibenz[b,e]oxepin-2-acrylic acid
`(1 0) (Z)-1 1 -(3-(Dimethylamino)propylidene)-6, 1 1 -dihydrodibenz[b,e]oxepin-2-acrylic acid
`The compounds of the present invention exist in either the cis (Z) or trans (E) isomers (in relation to
`the bridge oxygen in the case of formula (IIA)). If the compounds of formula (I) or (II) contain a double
`bond in the acid bearing side chain, i.e. Ft4 or R5, there exists a second possibility of Z and E isomeric
`forms. All such geometric isomers and the isomeric mixture of these compounds are included within the
`scope of the present invention. Salts, amides and esters of the compounds of the formula (I) and (II) are
`included within the scope of the invention. While esters and amides of the compounds of the formulae (I)
`and (II) have antihistamine activity in their own right, they may also be useful intermediates in the prepa-
`ration of the carboxy compounds of the formulae (I) and (II). Amides derived from ammonia, primary
`amines or amino acids, such as glycine, are particularly suitable. Suitable esters include conventional
`ester groups known to be useful for protecting carboxylic acid groups such as Ci-6 alkyl esters wherein
`the alkyl group is straight or branched chain and is optionally substituted by halogen. Alkyl esters (Cm)
`are particularly preferred.
`Solvates of the compounds of the formulae (I) and (II) are also included within the scope of the
`present invention. Preferred solvates include hydrates and C1-4 alkanolates.
`Salts of the compounds of formula (I) may be either acid addition salts or salts formed with the carbox-
`ylic acid group. Acid addition salts are preferred but salts formed from the carboxylic acid group may be
`particularly useful in preparing the corresponding carboxy compound. When used in medicine, the salts
`of the compounds of formulae (I) and (II) should be both pharmacologically and pharmaceuticaliy accept-
`able, but non pharmaceuticaliy acceptable salts may conveniently be used to prepare the free active
`compound or pharmaceuticaliy acceptable salts thereof and are not excluded from the scope of this in-
`vention. Such pharmacologically and pharmaceuticaliy acceptable acid addition salts include, but are not
`limited to, those prepared from the following acids: hydrochloric, sulphuric, nitric, phosphoric, maleic,
`salicylic, toluene-p-sulphonic, tartaric, citric, methanesulphonic, formic, malonic, isethionic, succinic,
`naphthalene-2-sulphonic and benzenesulphonic. Also, pharmaceuticaliy acceptable salts can be pre-
`pared as ammonium salts, alkaline metal or alkaline earth salts, such as sodium, potassium or calcium
`salts of the carboxylic acid group.
`The present invention also provides analogous methods for preparing compounds of formula (I), for
`example:
`a) (i) A compound of formula (I) may be prepared via the well known Wittig method (e.g., U.S. Patents
`3,354,155 and 3,509,175) by reaction of a compound of formula (III).
`
`(III)
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`EP 0 214 779 B1
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`The Wittig reagent, Ph3P=CH(CH2)nNR2R3; i.e., formula (IV), is conveniently
`(IV)
`(C6H5)3P=CH(CH2)nNR2R3
`prepared by reacting a compound of the formula Ph3PCH2(CH2)nNR2R3Br, with a strong base, such as
`sodium hydride or Ci-6 alkyl lithium in a suitable inert solvent, such as tetrahydrofuran or dimethoxy-
`ethane at or near room temperature. It will be appreciated by those skilled in the art of organic chemistry
`that protection of the carboxy group may be desirable or required prior to the Wittig reaction and depro-
`tection after the reaction.
`(ii) A compound of formula (I) also may be prepared via the well known Grignard conditions (e.g., Belg.
`623 259) in which a Grignard reagent, i.e. R2R3NCH2CH2CH2Mg X where X is a halogen atom, is react-
`ed with a compound of formula (III), followed by dehydration with a strong acid.
`b) A compound of formula (I) wherein R4 is a single bond can be prepared by carboxylation of a com-
`pound of formula (V)
`
`U
`CH(CH2)nNR2R3
`
`( V )
`
`wherein Ri, R2, R3 and n are as defined, vide supra and X is a hydrogen or halogen atom (suitably a bro-
`mine or chlorine atom attached directly to the ring system in the 2, 3, 8 or 9 positions. For example, a com-
`pound of formula (V) can be treated with a metalating agent such as butyl lithium followed by a reaction
`with carbon dioxide. When X is hydrogen separation of isomers may be required to obtain the desired
`compound of formula (I). When X is a halogen atom, a compound of formula (V) can be reacted with mag-
`nesium in an appropriate solvent followed by reaction with carbon dioxide via the Grignard procedure
`(The Merck Index, ninth ed., page ONR-38, Merck and Co., Rahway, N.J. (1976).
`c) A compound of formula (I) wherein R* is other than a single bond can be synthesized by reacting a
`compound of formula (V) (wherein X is a halogen atom) with a compound of formula (VI),
`CH2=CH-R6-COR7
`(VI)
`wherein R6 is a C1-5 bivalent aliphatic hydrocarbon and W is a removable carboxylic acid protecting
`group such as one derived from a reaction of the carboxylic acid group which has been activated (e.g.
`converted to an acyl chloride) with an alcohol or amine. In some cases this reaction may need to be facili-
`tated by a palladium catalyst (J. Org. Chem. 42, 3903-3907 (1977)). A variation of this method involves a
`reaction of a compound of formula (VII) with a compound of formula VI in a similar manner, vide supra,
`followed by catalytic reduction of the double bond in the carboxylic bearing side chain that followed by
`the Wittig reaction described in Section a) (i) or (ii), vide supra. The carboxylic acid groups may then be
`regenerated by deprotection if required.
`d) When the preparation of a compound of the formula (I) wherein R4 is CH=CH is required, a com-
`pound of the formula (VII)
`
`r ^ V R l V %
`
`< v n )
`wherein R1 is as defined, vide supra and X is halogen can be reacted with acrylic acid or an acrylic acid
`ester, with use of a catalyst if needed, by a method analogous to that described in b), vide supra, fol-
`lowed by a Wittig reaction as described in part a) (i) or (ii), vide supra. The carboxylic acid can be regen-
`erated by deprotection if desired.
`A compound of formula (VII) may be prepared by reacting a compound of formula (VIII).
`
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`EP 0 214 779 B1
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`( v m )
`wherein R1 and X are as defined, vide supra with a dehydrating agent such as (CFaCO^O/BFs'OEta.
`(e) It is possible to convert one compound of the formula (III) to another compound of the formula (III)
`by methods well known to those skilled in the art, for example the reduction of one or more double bonds
`or de-esterification of an ester group or hydrolysis of an amide, followed by a Wittig reaction with
`Ph3P=CH2(CH2)nNR2R3 as described, vide supra.
`(f) A compound of formula (VIII) can be converted to a Grignard reagent or an organolithium reagent
`by methods well known to those skilled in the art (after protecting the CO2H group) then reacted with
`dimethyl formamide to obtain the corresponding aldehyde. Such an aldehyde can be converted to an acid
`by oxidation or reaction with a trialkyl phosphonium acetate or an equivalent. By methods well known in
`the art of organic chemistry, after deprotecting such an acid can be dehydrated as described in d), vide
`supra to give a compound of formula (III).
`(g) A compound of the formula (V) where X is halogen can be reacted with a metal (I) cyanide, such as
`cuprous cyanide to give a corresponding carbonitrile derivative, which can then be converted to com-
`pounds of formula (I), eg the carboxylic acid via hydrolysis.
`Those intermediates that are novel form an important further aspect of the present invention.
`(h) Interconversion of compounds of the formula (I) is possible, e.g., by hydrolysis of esters, amides
`and by isomerization about the multiple bonds when such bonds are present or by selective reduction of
`25 multiple bonds when such bonds are present.
`The compounds of this invention having antiallergic activity may be used for the same indications as
`clinically used antiasthmatic compounds, namely to help to control bronchoconstriction or brochospasm
`characteristic of allergic asthma and exercise induced asthma and the symptoms of bronchoconstrictioa
`and bronchospasm resulting from acute or chronic bronchitis. The compounds are believed to inhibit the
`release of autacoids (i.e. histamine, serotonin and the like) from mast cells and to inhibit directly the anti-
`gen-induced production of histamine. Thus, they may be classified as mast cell stabilizers with antihista-
`Vhe compounds of this invention having antihistamine activity may be used for the same indications as
`clinically used antihistamines, namely to relieve detrimental symptoms (caused by histamine release) of
`nasal stuffiness due to colds and vasomotor rhinitis and for the symptomatic control of allergic condi-
`tions including nasal allergy, perennial rhinitis, urticaria, angioneurotic oedema, allergic conjunctivitis,
`food allergy, drug and serum reactions, insect bites and stings and desensitizing reactions. The com-
`pound may also be used in conditions responsive to its antipruritic activity including allergic dermatoses,
`neurodermatitis, anogenital pruritus, and pruritus of non-specific origin such as eczema, and of specific
`cause such as chickenpox, photosensitivity and sunburn. The present invention therefore provides a
`method for the symptomatic treatment of allergic conditions by the administration of an effective amount
`of a compound of formula (I)- The present invention also provides a method for the antagonism of endog-
`enously released histamine by the administration of an effective amount of a compound of formula (I).
`The compounds of formula (I) are substantially free from sedative effects.
`The amount of active compound, ie, a compound of formula (I) required for use in the above conditions
`will vary with the compound chosen, the route of administration and the condition and mammal undergoing
`treatment, and is ultimately at the discretion of the physician. A suitable oral dose of the active com-
`pound for a mammal is in the range of from 0.003 to 1 .0 mg per kilogram body weight per day; preferably
`from 0.04 to 0.24 mg/kg. For example a typical dose for a human recipient of compound (1), (Z)-11-(3-
`(dimethylamino)propylidene)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid, as the hydrogen chloride
`salt (see Example 7 and Table 1 , vide infra) is between 0.03 and 0.1 mg/kg body weight per day.
`The desired daily dose is preferably presented as from one to six sub- doses administered at appropri-
`ate intervals throughout the day as needed. Where three subdoses of compounds of formula (I) are em-
`ployed each will preferably lie in the range of from 0.014 to 0.08 mg/kg body weight; for example, a typi-
`cal sub-dose of such a compound for a human recipient is between 1 and 20 mg, for example 4 or 8 mg.
`While it is possible for a compound of formula (I) to be administered alone as the raw chemical, it is
`preferable to present the compound of formula (I) as a pharmaceutical formulation. Thus, the present in-
`vention also provides pharmaceutical formulations, both for veterinary and for human medical use,
`60 which comprise a compound of formula (I) together with one or more pharmaceutically acceptable carri-
`ers therefor and optionally any other therapeutic ingredients. For example, the active compound may be
`formulated with a sympathomimetic agent such as the decongestant pseudoephednne, an antrtussive
`such as codeine, an analgesic, an antiinflammatory, an antipyretic, or an expectorant. The carrier(s)
`must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the
`formulation and not deleterious to the recipient thereof.
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`EP 0 214 779 B1
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`The formulations include those suitable for oral, rectal, topical, nasal, ophthalmic or parenteral
`(including subcutaneous, intramuscular and intravenous) administration.
`The formulations may conveniently be presented in unit dosage form and may be prepared by any of
`the methods well known in the art of pharmacy. All methods include the step of bringing the active com-
`pound into association with a carrier which constitutes one or more accessory ingredients. In general,
`the formulations are prepared by uniformly and intimately bringing the active compound into association
`with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product
`into desired formulations.
`Formulations of the present invention suitable for oral administration may be presented as discrete
`units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the ac-
`tive compound (defined herein as a compound of formula (I)); as a powder or granules; or a suspension
`in an aqueous liquid or nonaqueous liquid such as a syrup, and elixir, an emulsion or a draught. A tablet
`may be made by compression or molding, optionally with one or more accessory ingredients. Compressed
`tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-
`flowing form such as a powder or granules which is optionally mixed with a binder, disintegrant, lubricant,
`inert diluent, surface active agent or dispersing agent. Molded tablets comprised of a mixture of the
`powdered active compound with any suitable carrier may be made by molding in a suitable machine.
`A syrup may be made by adding the active compound to a concentrated, aqueous solution of a sugar
`for example sucrose to which may also be added any accessory ingredient(s). Such accessory ingredi-
`ent(s) may include flavourings, an agent to retard crystallization of the sugar or an agent to increase the
`solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol, and suit-
`able preservatives.
`Formulations for rectal administration may be presented as a suppository with a usual carrier such as
`cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.
`Formulations suitable for parenteral administration conveniently comprise a sterile aqueous prepara-
`tion of the active compound which is preferably isotonic with the blood of the recipient.
`Nasal spray formulations comprise purified aqueous solutions of the active compound with preserva-
`tive agents and isotonic agents. Such formulations are adjusted to a pH and isotonic state compatible
`with the nasal mucous membranes.
`Ophthalmic formulations are prepared by a similar method to the nasal spray except that the pH and
`isotonic factors are adjusted to match that of the eye.
`Topical formulations comprise the active compound dissolved or suspended in one or more media such
`as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formula-
`tions. The addition of other accessory ingredients, vide infra, may be desirable.
`In addition to the aforementioned ingredients, the formulations of this invention may further include
`one or more accessory ingredients) selected from diluents, buffers, flavouring agents, binders, disin-
`tegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the
`like.
`The present invention also provides the first use of the compounds of formula (I) in medicine.
`The following Examples are provided by the way of illustration of the present invention and should in
`no way be construed as a limitation thereof. All temperatures indicated are in degrees Celsius
`Example 1 : (EWZH 1-(3-Dimethvlamino^propvlidene)-6, 1 1-dihvdro-dibenzfb.eloxepin-2-carboxvlic acid
`a) 2-Bromo-6,1 1-dihydrodibenz[b,e]oxepin-1 1-one
`2-Bromo-6, 11-dihydrodibenz[b,e]oxepin-1 1-one was prepared as described in US Patent 4,282,365,
`m.p. 132-134°C (Lit. m.p. 136-139°C). pmr (DMSO/d6) 8: 8.13 (d, J=2.6 Hz, 1H, Hi), 7.48-7.83 (m, 5H, aro-
`matic), 7.07 (d, J=8.8 Hz, 1H, H4), 5.31 (s, 2H, CH2O).
`Analysis: Calcd. for C14H9B1O2: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.20; H, 3.18; Br, 27.73.
`b) (E)/(Z)-3-(2-Bromo-6,1 1 -dihydrodibenz[b,e]oxepin-1 1 -ylidene)-N,N-dimethylpropyIamine
`Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (39.4 g., 0.08 mole)
`was suspended in 450 mL of dry tetrahydrofuran and 100 mL of a solution of n-butyl lithium in hexane (1.6
`M) was added dropwise at 0°C under a nitrogen atmosphere during a 30 minute period. After an addition-
`al 10 minutes, 2-bromo-6, 1 1-dihydrodibenz[b,e]oxepin-1 1-one (16.8 g., 0.06 mole) in 150 mL dry tetrahydro-
`furan was added slowly to the deep red solution and the reaction mixture was then refluxed for 18 hours.
`The reaction mixture was poured onto ice-water, and the mixture was extracted with diethyl ether. The
`ether layer was concentrated under reduced pressure and the residue was suspended in water and then
`acidified with 6N hydrochloric acid. The acidic aqueous layer was washed with hexanes and then was
`concentrated to give a gummy residue. The residue was crystallized from ethyl acetate/methanol to pro-
`vide 5.3 g. of pure Z-isomer as its hydrochloride salt, m.p. 201-204°C. The mother liquor was chromato-
`graphed on a silica gel column (Waters Associates -Prep. 500) with ethyl acetate/methanol (8:2) to give
`an additional 2.55 g. of pure Z-isomer as the hydrochloride salt and 2.79 g. of E-isomer as its hydrochlo-
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`ride salt, m.p. 230-233°C. pmr (Z-isomer) (DMSO/d6) 5: 7.25-7.44 (m, 6H, aromatic), 6.81 (degenerate d,
`J=9.1 Hz, 1H, H4), 5.72 (t, J=7.1 Hz, 1H, CH=), 5.22 (s, 2H, CH2O), 3.18 (m, 2H, NCH2), 2.70 (m, 2H,
`CH2), 2.66 (s, 6H, NMe2). pmr (E-isomer) (DMSO/d6) 8: 7.23-7.50 (m, 6H, aromatic), 6.70 (d, J=8.6 Hz,
`1H, H4), 6.10 (t, J=7.2 Hz, 1H, CH=) 5.15 (br s, 2H, CH2O), 3.07 (m, 2H, NCH2), 2.65 (s, 6H, NMe2),
`2.50 (m overlap with DMSO, 2H, CH2).
`c) (Z)-11-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 1)
`A solution of n-butyl lithium in hexane (1 .6 M, 3.5 mL) was added dropwise to a solution of 1 .8 g. pure
`(Z)-3-(2-bromo-6, 11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine in 100 mL of dry
`tetrahydrofuran at -70°C under a nitrogen atmosphere. After the yellowish-orange solution was stirred
`at -70°C for 10 minutes, gaseous carbon dioxide was bubbled through the reaction medium to give a pale
`yellow solution. The solution was allowed to warm gradually to room temperature and was then concentrat-
`ed under reduced pressure. The foamy residue was dissolved in water, and the mixture was neutralized
`15 with 1N hydrochloric acid and then extracted with chloroform. Concentration of the chloroform and re-
`crystallization of the residue from water gave 0.5 g. pure Z-2-carboxylic acid, m.p. 121-123°C. pmr
`(CDCI3) 8: 7.87 (d, J£1 Hz, 1H, Hi), 7.81 (dd, J=7.8, 2.2 Hz, 1H, H3), 7.25-7.28 (m, 4H, aromatic), 6.82
`(degenerate d, J=8.8 Hz, 1H, H4), 6.45 (br s, 1H, CO2H), 5.50 (m, 1H, CH=), 5.20 (br s, 2H, CH2O), 2.92
`(m, 4H, NCH2CH2), 2.66 (s, 6H, NMe2).
`Analysis: Calcd. for C20H2iNO3'0.55 H2O: C, 72.07; H, 6.68; N, 4.20. Found: C, 72.07; H, 6.69; N,
`4.18.
`d) (E)-11-(3-(Dimethylamino)propylidine)-6, 11-dihydrodibenz[b,e]oxepin-2-carboxylicacid (Compound 2).
`Pure (E)-3-(2-bromo-6, 11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine (1.55 g., 4.3
`mmole), was treated under nitrogen in cold (-70°C) tetrahydrofuran (100 mL) with 4.4 mmole of n-butyl
`lithium in hexane followed by gaseous carbon dioxide as described for the Z-isomer (Step C).
`Isolation of the (E)-2-carboxylic acid was achieved by through chromatography of the crude product
`on a reverse phase C18 semipreparative column eluted with 20% methanol in water (containing 0.1% tri-
`ethylamine). Recrystallization of the solid product from water afforded 0.012 g of pure E-2-carboxylic
`acid, m.p. >200°C (decomp.). pmr (CDCI3) 6: 7.85 (d, J=2.0 Hz, 1H, Hi), 7.06-7.78 (m, 5H, aromatic),
`6.47 (d, J=8.5 Hz, 1H, H4), 6.28 (t, J=4.2 Hz, 1H, CH=), 5.85 (m, 1H, ArCH), 4.70 (m, 1H, ArCH), 2.43
`(m, 4H, NCH2CH2), 2.28 (s, 6H, NMe2).
`Analysis: Calcd. for C2oH2iN03'0.50 H20: C, 72.27; H, 6.67; N, 4.21. Found: C, 72.15; H, 6.46; N,
`4.22.
`Example 2: (EWZM 1-(3-(DimethvlaminotoropvlideneV6.1 1-dihvdro-dibenzfb.eloxepin-3-carboxvlic acid
`a) Methyl 2-(3-bromophenoxymethyl)benzoate
`To a mixture of 3-bromophenol (60 g, 0.35 mole) and potassium carbonate (25 g, 0.18 mole) in 250 mL of
`N,N-dimethyIformamide was added methyl a-bromo-2-toluate (65 g, 0.28 mole). The reaction mixture was
`stirred at room temperature for 18 hours, then heated on a steam bath for 3 hours. The mixture was
`poured into ice-water, and the solids were collected by filtration and washed with water to give the crude
`product. Analytical sample was obtained by recrystallization from methylene chloride/hexanes, m.p. 84-
`85°C. pmr (CDCI3) 8: 8.0 (m, 1H, He), 6.93-7.69 (m, 7H, aromatic H), 5.47 (s, 2H, ArCH2O), 3.89 (s, 3H,
`CO2CH3).
`Analysis: Calcd. for C15H13 BrO3: C, 56.09; H, 4.08; Br, 24.88. Found: C, 56.20; H, 4.12; Br, 24.77.
`b) 2-(3-bromophenoxy)methylbenzoic acid
`Methyl 2-(3-bromophenoxy)methylbenzoate (34 g) was refluxed in a mixture of 100 mL of 10% sodium
`hydroxide and 200 mL of methanol for 3 hours. The reaction mixture was concentrated under reduced
`pressure and water was added to the residue. The mixture was then acidified with concentrated hydro-
`chloric acid. Extracting the acidic solution with ethyl acetate and then concentration of the organic layer
`gave the 2-(3-bromophenoxy)methyl benzoic acid (35 g) m.p. 158-159°C. pmr (CDCL3) 8: 8.10 (m, 1H, H6),
`6.84-7.74 (m, 7H, aromatic H), 6.16 (br s, 1H, CO2H), 5.49 (s, 2H, ArCH2O).
`Analysis: Calcd. for Ci4HiiBrO3: C, 54.74; H, 3.61 ; Br, 26.02. Found: C, 54.65; H, 3.61 ; Br, 26.08.
`c) 3-Bromo-6, 1 1 -dihydrodibenz[b,e]oxepin-1 1 -one
`A suspension of 2-(3-bromophenoxymethyl)benzoate (35 g, 0.1 1 mole) in 1 00 mL of trifluoroacetic anhy-
`dride containing 20 drops of boron trifluoride-ether complex was refluxed for 4 hours. The mixture was
`poured into ice-water and then extracted with diethyl ether. Concentration of ether solution under re-
`duced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep
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`500) with hexane/methylene chloride (70:30) gave the pure product (14 g). m.p. 1 10-1 12°C. pmr (CDCU) 8:
`8.10 (d, J=9.1 Hz, 1H, Hi), 7.90 (dd, J=1.4, 7.6 Hz, 1H, Hio) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H H8), 7.48 (dt,
`J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, 1H, H?), 7.27 (d,J=1.8 Hz, 1H, H4), 7.24 (dd, J=1.8, 9.1
`Hz, 1H, H2), 5.18 (s, 2H, ArCH2O).
`Analysis: Calcd. for CuH9Br02: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.13; H, 3.19; Br, 27.72.
`d) (E)/(Z)-3-(3-Bromo-6,1 1 -dihydrodibenz[b,e]oxepin-1 1 -ylidene)-N,N-dimethylpropylamine
`Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48.0 mmo