Européisches Patentarnt
`® 0 European Patent Office
`Office européen des brevets
`
`(19 Publicationnumber:
`
`0 214 779
`A1
`
`(,9
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 863063269
`
`® Date offlling: 15.08.86
`
`101/42,
`121/78,
`31/335, A 61 K 31/19
`
`@ Date of publication of application:
`18.03.87 Bulletin
`87/12
`
`@ Designated Contracting States:
`AT BE CH DE FR GB IT LI NL 3E
`
`®
`
`Inventor: Lever, William 0., Jr.
`338, Grandview Road
`Skillman New Jersey 23558 (US)
`
`Leighton, Harry Jefferson
`1904, White Plains Road
`Chapel HIII North Carolina 27514 (GB)
`
`
`
`
`Applicant: THE WELLCOME FOUNDATION LIMITED
`® Priority: 17.08.85 GB 8520662
`
`63
`183-193 Euston Road
`London NW1 28F (GB)
`
`
`
`
`
`
`Representative: Rollins, Anthony John et al
`Group Patents 8. Agreements The Wellcome Foundation
`Ltd Langley Court
`Beckenham Kent 5113 335 (GB)
`
`® Tricyclic compounds.
`
`@ The present invention provides a compound of formula (I)
`
`8/
`
`9\_.,
`10
`
`
`
`CHtCH ) NR2R3
`2 n
`
`is -CH2-CH2—.
`or a salt. ester or amide thereof: wherein FI‘
`CHz-O- or -O-CH2-: R2 and R3 are the same or different and are
`each hydrogen. C14 alkyl or taken together with the nitrogen
`comprise a nitrogen-containing heterocyclic ring having four to
`six ring members; R4 is a single bond or a C14 bivalent aliphatic
`hydrocarbon group may be joined to the aromatic ring system
`at the 2. 3. 8 or 9 positions; n is 0 to 3. processes for its
`preparation and intermediates therefor. pharmaceutical compo-
`sitions containing it and its use in medicine.
`
`EP0214779A1
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`Bundesdruckerei Berlin
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`Ayla Pharma LLC (IPR2020-00295) Ex. 1033 p. 001
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`

`

`Description
`
`0 214 779
`
`Tricyclic Compounds
`
`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 623259, Neth. Patent Appl. 6407758,
`Neth. Patent Appl. 6411861 and Belg. Patent 641498 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 hereinafter referred to by its
`generic name, doxepin. Doxepin has been accepted as an antidepressant in human clinical chemotherapy and
`an antipruritic for veterinary use. We have now discovered that a group of carboxylic acid derivatives of
`doxepin possess surprisingly potent antihistaminic and antiasthmatic properties. In this invention. compound
`(g)-11‘(3-(dimethylamino)propylidenel—G,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid exhibits extremely
`good antihistaminic activity in vivo.
`Accordingly this invention provides a compound of the formula (l),
`
`
`
`CH(CH2)nNR2R3
`
`(I)
`
`or a salt. ester or amide thereof: wherein R1 is -CH2-CH2-, -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 nitrogen
`comprise a nitrogen—containing heterocyclic ring having four to six ring members:
`R4 is a single bond or a 01-7 bivalent aliphatic hydrocarbon group and may be joined to the aromatic ring
`system at the 2, 3, 8 or 9 positions. n is O to 3.
`Of the compounds of formula (I) those of formula (ll), wherein R1 is as defined herein above. and R5 is a
`single bond or -CH=CH-, are preferred.
`
`RI
`
`RSCOZH
`
`CH(CH2)2N(CH3)2
`
`(II)
`
`The most preferred compounds of formula (II), are those of formula (lla) and formula (llb) wherein R5 is as
`defined for formula (II)
`
`0
`
`o e
`
`ace
`
`CH(CH2)2N(CH3)2
`
`CH(CH2)2N(CH3)2
`
`(IIA)
`
`(IIB)
`
`Examples of compounds of formula (llA) include:
`(1) (9—11-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b.eloxepin-Z-carboxylic acid
`(2) (9-11-(3—(Dimethylamino)propylidene)-6. 11-dihydrodibenz[b.e]oxepin-2—carboxylic acid
`(3) (9-11-(3-(Dimethylaminolpropylidene)-6, 11-dihydrodibenz[b.e]oxepin-3-carboxylic acid
`(4) (Z)-11-(3—(Dimethylamino)propylidene)-6. 11-dihydrodibenz[b,e]oxepin-3-carboxylic acid
`(5) (EH1-(3-(Dimethylamino)propylidene)—6, 11~dihydrodibenz[b.e]oxepin-8-carboxylic acid
`(6) (2)41-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin-8—carboxylic acid
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`(7) (§)-11—(3—(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin09-carboxylic acid
`(8) (Z)-1l-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b.e]oxepins9-carboxylic acid
`(9) (9-11-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b.eloxepin-Z-acrylic acid
`(10) (§)—11-(3-(Dimethylamino)propylidene)-6, 11-dihydrodibenz[b.eloxepin-2-acrylic acid
`Examples of compounds of formula (118) include
`(11)
`(g)-5-(3-(Dimethylamino)propylidene)-10, 11-dihydro-5H-dibenzo[a,d)cyclohepten-S-carboxylic
`acid
`
`(12)
`acid
`
`(§)-5-(3-(Dimethylamino)propylidene)-10, 11~dihydro-5H-dibenzo[a,d]cyclohepten-3-carboxylic
`
`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) and the acid side chain in the case of formula (IIB)),
`If the
`compounds of formula (I) or (II) contain a double bond in the acid bearing side chain, i.e. R4 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 preparation 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 01.5 alkyl esters
`wherein the alkyl group is straight or branched chain and is optionally substituted by halogen. Alkyl esters
`(01.4) 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 01.4 alkanolates.
`Salts of the compounds of formula (I) may be either acid addition salts or salts formed with the carboxylic
`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 pharmaceutically acceptable. but
`non pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or
`pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention. Such
`pharmacologically and pharmaceutically acceptable acid addition salts include, but are not limited to, those
`prepared from the following acids: hydrochloric, sulphuric. nitric, phosphoric, maleic, salicylic, toluene-p—sul-
`phonic, tartaric, citric, methanesulphonic, formic, malonic, isethionic, succinic, naphthalene-Z-sulphonic and
`benzenesulphonic. Also, pharmaceutically acceptable salts can be prepared 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., US. Patents
`3,354,155 and 3,509,175) by reaction of a compound of formula (III).
`
`R!
`
`R4C02H
`
`(III)
`
`The Wittig reagent, Ph3P=CH(CH2)nNR2R3; i.e., formula (IV), is conveniently
`(CsH5)3P=CH(CH2)nNRZR3 (IV)
`prepared by reacting a compound of the formula PhaPCH2(CH2)nNR2RaBr, with a strong base. such as
`sodium hydride or 01-5 alkyl
`lithium in a suitable inert
`solvent.
`such as tetrahydrofuran or
`dimethoxyethane 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 deprotection 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. (R2R3NCH20H2CH2Mg X where X is a halogen atom,
`reacted with a compound of formula (III), followed by dehydration with a strong acid.
`b) A compound of formula (I) wherein Fl‘ is a single bond can be prepared by carboxylation of a
`compound of formula (V)
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`0214 779
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`CH(CH2)nNR2R3
`
`(V)
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`wherein R1. R2. R3 and n are as defined, vide supra and X is a hydrogen or halogen atom (suitably a
`bromine or chloride atom attached directly to the ring system in the 2. 3, 8 or 9 positions. For example. a
`compound of formula (V) can be treated with a metalating agent such as butyI 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 magnesium in an appropriate solvent folIOWed by reaction with carbon dioxide via the Grignard
`procedure (The Merck Index. ninth ed., page ONE-38, Merck and 00., Rahway, N.J. (1976).
`c) A compound of formula (I) wherein R4 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-R5-COR7 (VI)
`wherein R6 is a C1-5 bivalent aliphatic hydrocarbon and R7 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
`facilitated 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
`compound of the formula (VII)
`
`RI
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`0
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`(VII)
`
`wherein Ft1 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, followed
`by a Wittig reaction as described in part a) (i) or (ii), vide supra. The carboxylic acid can be regenerated by
`deprotection if desired.
`A compound of formula (VII) may be prepared by reacting a compound of formula (VIII).
`
`R1
`
`COzH
`
`(VIII)
`
`wherein R1 and X are as defined, vide supra with a dehydrating agent such as (CFgCO)20/BF3-0Et2.
`(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)nNR2Fi3 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 COzH 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
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`0 214 779
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`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 (Ill),
`(9) 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
`compounds 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. 9.9.. by hydrolysis of esters. amides
`and by isomerization about the multiple bonds when such bonds are present or by selective reduction of
`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 bronchoconstriction and
`bronchospasm resulting from acute or chronic bronchitis. The compounds are believed to inhibit the release
`of autacoids (Le. histamine. serotonin and the like) from mast cells and to inhibit directly the antigen-induced
`production of histamine. Thus, they may be classified as mast cell stabilizers with antihistaminic action.
`The 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 conditions including
`nasal allergy. perennial rhinitis. urticaria. angioneurotic oedema, allergic conjunctivitis, food allergy, drug and
`serum reactions, insect bites and stings and desensitizing reactions. The compound 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 endogenously 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, is, 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 compound 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), (§)-11-(3-(dimethylamino)propyli-
`dene)-6,11-dihydrodibenz[b,eioxepin-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 appropriate
`intervals throughout the day as needed. Where three subdoses of compounds of formula (l) are employed,
`each will preferably lie in the range of from 0.014 to 0.08 mg/kg body weight; for example, a typical sub-dose of
`such a compound for a human recipient is between 1 and 20 mg, for example 4 or 8 mg.
`it is
`While it is possible for a compound of formula (I) to be administered alone as the raw chemical,
`preferable to present the compound of formula (l) as a pharmaceutical formulation. Thus, the present invention
`also provides pharmaceutical formulations, both for veterinary and for human medical use, which comprise a
`compound of formula (I)
`together with one or more pharmaceutically acceptable carriers therefor and
`optionally any other therapeutic ingredients. For example, the active compound may be formulated with a
`sympathomimetic agent such as the decongestant pseudoephedrine, an antitussive 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.
`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 compound 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 active
`compound (defined herein as a compound of formula (l)); 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 ingredient(s) may
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`0 214 779
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`(containing 0.1%
`in water
`reverse phase C18 semipreparative column eluted with 200/0 methanol
`triethylamine). Recrystallization of the solid product from water afforded 0.012 g of pure E-2-carboxylic acid,
`m.p. >200°C (decomp). pmr (CDClai 6: 7.85 (d, J=2.0 Hz, 1H, H1), 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 Con21N030050 H20: C, 72.27; H. 6.67: N, 4.21. Found: C. 72.15: H, 6.46: N, 4.22.
`
`Example 2(9/(9—11—(3-(Dimethylamino)propylidene)-6,11-dihydro-dibenz[b.eloxepin-3-carboxylic 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-dimethylformamide 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. 84-855C. pmr
`(CDCIa) 8: 8.0 (m, 1H. He), 6.93-7.69 (m, 7H, aromatic H), 5.47 (s, 2H. ArCH20). 3.89 (s, 3H, CO2CH3).
`Analysis: Calcd. for C15H13 Bros: 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 100/0 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 hydrochloric
`acid. Extracting the acidic solution with ethyl acetate and then concentration 01 the organic layer gave the
`2—(3-bromophenoxy)methyl benzoic acid (35 9) mp. 158-159°C. pmr (CDCLa) 6: 6.10 (m, 1H, H6), 6.84-7.74
`(m, 7H, aromatic H), 6.16 (br s, 1H, C02H), 5.49 (s, 2H, ArCH20).
`Analysis: Calcd. for C14HnBr03: C. 54.74; H, 3.61; Br, 26.02. Found: C. 54.65: H, 3.61; Br, 26.08.
`
`c) 3—Bromo-6. 11-dihydrodibenz[b,e]oxepin-11-one
`in 100 mL of trifluoroacetic
`A suspension of 2—(3-bromophenoxymethyl)benzoate (35 g, 0.11 mole)
`anhydride 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 reduced
`pressure and chromatography of the residue on a silica gel column (Waters Associates. Prep 500) with
`hexane/methylene chloride (70:30) gave the pure product (14 g). m.p. 110-112“C. pmr (CDCLa) 5: 8.10 (d.
`J=9.1 Hz, 1H, H1), 7.90 (dd, J=1.4, 7.6 Hz, 1H, H10) 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, H7), 7.27 (d,J= 1.8 Hz, 1H, H4). 7.24 (dd, J: 1.8. 9.1 Hz. 1H. H2).
`5.18 (s, 2H, ArCH20).
`Analysis: Calcd. for C14HgBrO2: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.13; H, 3.19: Br, 2772.
`
`d)(_E_)/(§)-3—(3-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine
`Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g. 48.0 mmole), 96
`mmole of n-butyl lithium in hexane, and 3-bromo-6, 11-dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole)
`were reacted in 580 mL dry tetrahydrofuran by the procedure of Example 1, step b. This provided an
`(§)/(§)-(1 :3) isomeric mixture of bromoamines (6.0 g). Recrystallization of half of the mixtures (3.0 g) from
`ethyl acetate gave 1.45 g of Z-isomer of 293% stereoisomeric purity (assayed by 'H-NMR) as a white solid.
`pmr (CD03) 6: 7.23-7.31 (m, 4H, aromatic H), 6.92-7.05 (m, 3H, aromatic H), 5.91 (t, 1H, CH= , 70/0 E-isomer),
`5.60 (t, 1H, CH = , 930/0 Z-isomer) 5.15 (very br s, 2H, ArCH20). 3.12 (m. 2H. CH2), 2.99 (m, 2H, NCH2). 2.78 (s.
`6H, NMe2, 930/0 Z-isomer), 2.71 (s, 6H, NMe2, 30/0 E-isomer).
`Analysis: Calcd. for C19H2oBrNO~10 HCl: C, 57.81; H, 5.36; N, 3.55. Found: C. 57.62: H, 5.33: N. 3.54.
`
`e) (§)/(g)-11-(3-(Dimethylamino)propylidenel—G, 11~dihydrodibenz[b,e]oxepin-3-carboxylic acid (Compounds
`3/4)
`
`An isomeric mixture El; (1 :3) of 3-(3-bromo—6, 11-dihydrodibenz[b,e]-11-ylidene]-N,N-dimethylpropylamine
`(3.0 g, 8.5 mmole) in 150 mL dry tetrahydrofuran at —70° C was reacted with 9.4 mmole n-butyl lithium in hexane
`tollowed by gaseous carbon dioxide by the procedure of Example 1, step c, to provide the corresponding
`carboxylic acids as an El; (1:3) stereoisomeric mixture. The mixture was chromatographed on a reverse
`phase PRP-1 semi-preparative column with water/acetonitrile (87:13) to provide 0.08 g of E-isomer (Iyophilized
`powder) and 0.50 g of Z-isomer (Iyophilized powder). pmr (E-isomer) (CDCl3/TFA) 8: 7.85 (dd, J :80. 1.7 Hz,
`1H, H2) 7.50 (d, J = 1.7 Hz, 1H, H4), 7.32-7.43 (m, 4H, aromatic H), 7.16 (m, 1H, H1), 5.99 (t, 1H, CH= ). 5.50 (br s,
`1H, ArCHO), 4.85 (br s. 1H, ArCHO), 3.25 (q, 2H, CH2), 2,86 (s, 3H, NMe), 2.85 (s, 3H, NMe), 2.70 (q, 2H. NCH2).
`pmr (Z—isomer) (CDCLa/TFA) 8: 7.26 (m, 2H. H2 and H4), 7.24-7.36 (m, 4H, aromatic H), 7.16 (m, 1H, H1), 5.71
`(t, 1H, CH = ). 5.20 (very br s, 2H, ArCH20). 3.32 (q, 2H, CH2), 2.91 (s, 3H, NMe), 2.90 (s, 3H, NMe), 2.89 (m, 2H,
`NCHz).
`
`Analysis: Calcd. for C2oH21N03-0.5 HCl-0.2 H20: C, 69.58; H. 6.39; N, 4.06. Found (E-isomer): C, 69.64; H,
`6.25: N, 4.03. Calcd. for C20H21N03-025 H20: C, 73.26; H, 6.61; N, 4.27. Found (Z-isomer): C, 73.20: H, 6.60;
`N, 4.20.
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`Example 3:(E/(Z)-(11-(3-Dimethylamino)propylidene)-6,11—dihydrodibenz[b,e]oxepin-8—carboxylic acid
`
`a)8—Bromo-6.11-dihydrodibenz[b.e]oxepin-11-one
`Phenol (8 g, 85 mmole) and potassium carbonate (11.7 g. 85 mmole) in 150 mL of N,N-dimethylformamide
`was reacted with methyl 4-bromo-a-bromo-2-toluate (20 g, 65 mmole) by the procedure of Example 2, step a
`and followed with alkaline hydrolysis by the procedure of Example 2. step b to give the crude
`4-bromo-2-phenoxybenzoic acid (13 g) which was used without further purification.
`The crude 4-bromo—(2-phenoxymethyl)benzoic acid (13 g. 42 mmole) was cyclized in 50 mL of trifluroacetic
`anhydride containing 1 mL of boron trifluorideether complex by the procedure of Example 2, step c. The solid
`was collected by filtration and washed with water to give 11.9 g of the tricyclic ketone. mp. 125-126°C. pmr
`(CDCLs) 8: 8.17-8.30 (m, 1H, H1). 6.99-7.86 (m, 6H. aromatic H), 5.14 (s, 2H, ArCH2O).
`Analysis: Calcd. for C14HgBrO2: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.15; H. 3.17; Br. 27.73.
`
`b)(_E_)/(§)-3-(8-Bromo-6,11-dihydrodibenz[b.e]oxepin-11-y|idene)-N,N-dimethylpropylamine
`Anhydrous 3—(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96
`mmole of n-butyl lithium in hexane. and 8-bromo-6, 11~dihydrodibenz[b,e]oxepin-11-one (10 g, 34.6 mmole)
`were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an EIZ (1 :35)
`isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z—isomer
`and 1.8 g of an E/Z (1 :4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without
`further purification. pmr (Z-isomer) (CDCIs) 6: 7.38-7.44 (m, 2H, H7 and H9); 7.13-7.18 (m, 3H, aromatic H);
`6.84-6.93 (m, 2H, H2 and H4): 5.70 (t, 1H, CH: ); 5.15 (br s, 2H, ArCH2O); 2.55 (q, 2H, CH2); 2.43 (t, 2H, NCH2);
`2.22 (s. 6H. NMe2).
`Analysis: Calcd. for C19H20BrNO: C, 63.70; H, 5.63; N, 3.91. Found (Z—isomer): C, 63.85; H, 5.65; N, 3.92.
`
`c)(§)/(Z)-11-(3—(Dimethylamino)propylidene)-6,11-dihydrodibenz[b,e]oxepin-8-carboxylic acid (Compounds
`5/6).
`
`An isomeric mixture El; (1:4) of 3-(8—bromo-6, 11-dihydrodibenz[b.e]-11-ylidene)—N,N-dimethylpropylamine
`(1.8 g, 5.0 mmole) in 100 mL dry tetrahydrofuran at -70°C was reacted with 5.5 mmole n-butyl lithium in hexane
`followed by gaseous carbon dioxide by the procedure of Example I, step c, to provide the corresponding
`carboxylic acid as an E/Z (1 :5) stereoisomeric mixture. The mixture was chromatographed on a reverse phase
`PRP~1 semi-preparative column with water/acetonitrile (85:15) to provide 0.05 of E-isomers (lyophilized
`powder) and 0.28 g of Z-isomer (lyophilized powder). pmr (E-isomer) (CDCI3) 8: 7.94 (br s, 1H, H9), 7.70 (br s,
`1H, CO2H). 7.20-7.30 (m, 4H aromatic H), 7.14 (m, 1H, H3), 687 (m, 1H, H2), 6.76 (m, 1H, H4), 5.88 (t, 1H, CH = ),
`5.54 (br s, 1H, ArCHO), 4.85 (br s, 1H, ArCHO), 3.00 (m, 2H. CH2), 2.78 (m, 2H, NCH2), 2.60 (s, 6H. NMez) pmr
`(Z—isomer) (CDCI3) 8: 7.55 (d, J =7.0 Hz, 1H, H9), 7.30 (br s, 1H, CO2H). 7.00-7.25 (m, 4H. aromatic H), 6.84 (m,
`2H. H2 and H4), 5.95 (t, 1H, CH=). 5.70 (br s, 1H, ArCHO), 4.80 (br s, H, ArCHO), 3.35 (br s, 1H CHC=),
`2.50-3.00 (m, 3H. CHC= and NCH2), 2.46 (s, 6H, NMe2)
`Analysis: Calcd. for Con21N03-HCl-04 H20: C, 65.44; H, 6.26; N, 3.82. Found (E-isomer): C, 65.55: H.
`6.51 : N. 3.91. Calcd. for C2oH21N03°22 H20: C, 66.17; H, 7.05; N, 3.86. Found (Z-isomer): C, 66.25; H, 6.93; N.
`3.83.
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`Example 4:(E)/(Z)-11-(3-(Dimethylamino)propylidene)~6,11-dihydrodibenz[b.e]-oxepin-9-carboxylic acid
`
`a)9-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-one
`9-Bromo-6, 11-dihydrodibenz[b.e]oxepin-11-one was prepared as described in US Patent 4,282,365,
`m.p. 104-106“C (Lit. m.p. 1075-1085“ C). pmr (CDClg) 6: 8.02-8.27 (m, 2H. H1 and H10). 6.98-7.73 (m, 5H,
`aromatic), 5.14 (s. 2H, CH2O).
`Analysis: Calcd. for C14HgBr02: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.24; H. 3.18; Br. 27.51.
`
`b) (§)/(§)-3—(9-Bromo—6, 11-dihydrodibenz[b.e]oxepin-11—y|idene)—N,N-dimethyipropylamine.
`Anhydrous 3—(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122
`mmole of n-butyl lithium in hexane. and 9-bromo-6, 11-dihydrodibenz[b.e]oxepin—11—one (12.7 g., 43.8 mmole)
`were reacted in 750 mL dry tetrahydrofuran by the procedure of Example l, Step b. This provided an E/Z (1 :6)
`isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of
`pure Z-isomer as its hydrochloride salt, melting range 91—100“C and 2.16 g. of an E/Z (1:4) isomeric mixture
`which was used in the next step without further purification. pmr (Z—isomer) (CD03) 8: 6.94—7.46 (m, 7H,
`aromatic). 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH2O), 3.07 (m, 4H, NCH2 CH2), 2.75 (s, 6H, NMe2).
`Analysis: Calcd. for C19H2oBrNOOHCl: C. 57.80; H, 5.36; N, 3.54. Found (Z—isomer): C, 57.56: H. 5.41: N,
`3.45.
`
`c(§)-11~3—(Dimethylamino)propylidene—6, 11-dihydrodibenz[b,e]oxepin-9-carboxy|ic acid (Compound 7).
`An isomeric mixture E/Z (1:4) of 3-(9—bromo-6, 11-dihydrodibenz[b,e]-11-ylidene)—N.N-dimethylpropylamine
`(2.0 g., 5.6 mmole) in 100 mL dry tetrahydrofuran at -70" C was reacted with 6.2 mmole n—butyl lithium in hexane
`followed by gaseous carbon dioxide by the procedure of Example I, Step c. to provide the corresponding
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`carboxylic acids as anE/Z (1 :4) stereoisomeric mixture. The mixture was chromatographed on a reverse phase
`PRP-1 semi-preparative column with water/acetonitrile (85:15) to provide 0.06 g of E-isomer of a950/o
`stereoisomeric purity (assayed by HPLC on C15) as pale yellow glass. pmr (DMSO-ds) 8: 7.83 (d, J: 1 Hz, 1H,
`H10). 7.79 (dd, J
`7.2. 1.5 Hz, 1H, H3), 6.69—7.39 (m, 5H. aromatic). 5.85 (t. J =64 Hz. 1H. CH ), 5.2? (s. 2H.
`CH20), 2.81 (m, 4H. NCH2CH2), 2.61 (s. 6H, NMez).
`Analysis: Calcd. for Con21N03028 H20: C, 64.26; H, 7.17; N, 3.75. Found: C. 64.23: H. 6.84: N. 3.76.
`
`d)(_Z_)-11-3-(Dimethylamino)propylidene—6,11-dihydrodibenz[b,e]oxepin-9-carboxy|ic acid(Compound 8)
`Pure (§)-3-(9-bromo-6, 11-dihydrodibenz[b,e]oxepin-11-ylidene)~N,N-dimethylpropylamine (0.78 g., 2.2
`mmole), in cold (-70"C) dry tetrahydrofuran (50 mL), was treated with 2.4 mmole n-butyl lithium in hexane
`followed by gaseous carbon dioxide by the procedure of Example l, Step c. This provided the desired
`carboxylic acid which was recrystallized from water to yield 0.15 9. pure Z-isomer, m.p. >205°C (decomp.)
`with melting at 210°C. pmr (CDCla/Dzo) 8: 7.84 (d, J=1.8 Hz. 1H. H10). 7.81 (dd. J=6.4, 1.8 Hz. 1H, Ha),
`6.94-7.35 (m, 5H, aromatic), 5.78 (t, J =69 Hz, 1H, CH = ). 5.25 (s, 2H. CH20), 3.20 (m, 2H, NCHz), 2.80 (s, 6H,
`NMez), 2.50-2.90 (m, 2H, CH2).
`Analysis: Calcd. for C20H21N03-0.33 H20: C. 73.06; H, 6.62; N, 4.26. Found: C, 72.92; H, 6.59; N, 4.13.
`
`Example(E)/(Z)-11-(3—(Dimethylamino)propylidene)-6,11-dih drodibenz[b,e]oxepin-2-(E)—ac
`
`
`lic acid
`
`
`a)EthyI(§)-6,11-dihydro-11-oxodibenz[b,e]oxepin-acrylate
`A mixture of palladium acetate (0.4 g, 1.73 mmole), triphenylphosphine (0.9 g. 3.46 mmole), 2-bromo-6,
`11-dihydro-11-oxodibenzib,e]oxepin (10 g, 34.6 mmole), ethyl acrylate (13 g, 130 mmole) and tri-n-butylamine
`(7.7 g, 57 mmole) was heated at 130-140°C under a nitrogen atmosphere for six hours. The reaction mixture
`was partitioned between diethyl ether (100 mL) and 0.1N hydrochloric acid (50 mL). Evaporation of the ether
`under reduced pressure gave a yellow solid residue. The crude material was chromatographed on a silica gel
`column (Waters Associates - Prep 500) with hexanes/ethyl acetate (8:2) to give 6.12 g of (E)—acrylate product.
`Recrystallization from ethyl acetate/hexanes gave an analytical sample, m.p. 113-114“C. pmr (CD03) 6: 8.39
`(d, J =24 Hz, 1H, H1). 7.88 (dd, J = 1.5, 7.5 Hz, 1H, H10), 7.70 (d, J = 16.4 Hz,1H,ArCH = ), 7.66 (dd. J = 2.2.8.6
`H2, 1H, H3), 7.46-7.60 (m, 2H, He and H9), 7.38 (dd, J=1.0, 7.3 Hz, 1H. H7), 7.07 (d, J =8.6 H2. 1H, H4). 6.42 (d,
`J=16.0 Hz, 1H, =CHC02), 5.23 (s, 2H, ArCHQO), 4.26 (q, 2H, CH2), 1.34 (t. 3H, CH3).
`Analysis: Calcd. for C19H1504: C, 74.01; H, 5.23. Found: C, 73.90; H, 5.28.
`
`b) (§)/(§)-11-(3—(Dimethy