`
`[19]
`
`Lever, Jr. et al.
`
`[11] Patent Number:
`
`4,871,865
`
`[45] Date of Patent:
`
`Oct. 3, 1989
`
`[54] TRICYCLIC AROMATIC COMPOUNDS
`
`[75]
`
`Inventors:
`
`0. William Lever, Jr., Skillman, N.J.;
`Harry J. Leighton, Chapel Hill, NC.
`
`[73] Assignee: Burroughs Wellcome Co., Research
`Triangle Park, NC.
`
`[21] Appl. No.: 894,306
`
`[22] Filed:
`
`Aug. 7, 1986
`
`Foreign Application Priority Data
`[30]
`Aug. 17, 1985 [GB] United Kingdom ................. 8520662
`
`Int. Cl.4 ................... C07D 313/12; C07C 87/459
`[51]
`[52] US. Cl. ..................................... 549/354; 562/442
`[58] Field of Search ......................................... 549/354
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`......................... 260/243
`9/1959 Jacob et a1.
`2,905,668
`9/1968 Kollonitsch et a1.
`.
`3,401,192
`1/1969 Bloom et a1. ........................ 549/354
`3,420,851
`4/1970 Tretter ............. 260/333
`3,509,175
`
`9/1980 Hu et a1. ......... 435/188
`4,223,013
`
`8/1981 Rokach et a1.
`.
`..... 548/252
`4,282,365
`............................. 562/442
`4,307,245 12/1981 Hu et a1.
`
`FOREIGN PATENT DOCUMENTS
`
`37254 10/ 1981 European Pat. Off.
`92114 10/1983 European Pat. Off.
`130555
`1/1985 European Pat. Off.
`1018995
`2/1966 United Kingdom .
`1412095 10/ 1975 United Kingdom .
`
`.
`.
`.
`
`OTHER PUBLICATIONS
`
`M. Leitold et a1., Arzneim.-—Forsch./Di‘ug. Res. 34(1),
`No. 4, (1984), pp. 468—473.
`C. A. Stone et a1., J. Med. Chem, vol. 8 (1965), pp.
`829—835.
`
`Wilson et a1., Textbook of Organic Medicinal and Phar-
`maceutical Chemistry, 3rd ed. (1956), J. B. Lippincott
`Co., pp. 374—376.
`Stedman’s Medical Dictionary, 23rd ed. (1976), p. 648.
`Remington’s Pharmaceutical Sciences, 14th ed. (1970),
`Mack Publ. Co., pp. 1142—1144, 1152—1153.
`
`Primary Examiner—Richard L. Raymond
`Assistant Examiner—Ba Trinh
`Attorney, Agent, or Firm—Donald Brown
`
`[57]
`
`ABSTRACT
`
`The present invention relates to compounds of formula
`I
`
`8
`
`9
`
`R1
`
`4
`
`3
`
`2
`
`R4c02H
`
`(I)
`
`10
`
`1
`H
`CH(CH2),.NR2R3
`
`or a salt, ester or amide thereof; wherein R1 is —CH-
`2—CH2—, CHz—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 nitro-
`gen-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; 11 is 0 to 3, and
`their use as anithistamine and antiasthma agents.
`
`B. A. Patel et a1., J. Org. Chem, vol. 42(24) (1977), pp.
`3903—3907.
`
`3 Claims, No Drawings
`
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`4,871,865
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`TRICYCLIC AROMATIC COMPOUNDS
`
`2
`-continued
`
`(IIB)
`
`0 R5C02H
`
`||
`CH(CH2)2N(CH3)2
`
`dihy-
`
`5
`
`15
`
`20
`
`ex-
`
`(1)
`
`3O
`
`8
`
`9
`
`7
`
`10
`
`R1
`
`4
`
`3
`
`2
`
`R4c02H
`
`1
`II
`CH(CH2),.NR2R3
`
`The present invention relates to new chemical com-
`pounds which have potent antihistaminic activity, to
`processes for preparing them and to their use in medi-
`cine. Belg. Patent 623259, Neth. Patent Appl. 6407758,
`Neth, Patent Appl. 6411861 and Belg. Patent 641498
`Examples of compounds of formula (IIA) include:
`disclose a group of 1l-[(dialkylamino)alky1idene]-6,1l- 10
`(1)
`(2)-11-(3-(Dimethylamino)propylidene)-6,l l-dihy-
`dihydrodibenz[b,e]oxepins as psychotherapeutic agents
`drodibenz[b,e]oxepin-2-carboxylic acid,
`the most outstanding of which is the compound named,
`(2)
`(E)-1 l-(3-(Dimethylamino)propylidene)—6,l l-dihy-
`(1 l-(3-(dimethylamino)propylidene)-6, 1 l-dihy-
`drodibenz[b,e]oxepin-2-carboxylic acid,
`drodibenz[b,e]oxepin), and hereinafter referred to by its
`(3)
`(E)-1 1-(3-(Dimethylamino)propylidene)-6,1 l-dihy-
`generic name, doxepin. Doxepin has been accepted as
`drodibenz[b,e]oxepin-3-carboxy1ic acid,
`an antidepressant in human clinical chemotherapy and
`(4)
`(2)-11-(3-(Dimethylamino)propylidene)-6,l l-dihy-
`an antipruritic for veterinary use. We have now discov-
`drodibenz[b,e]oxepin-3-carboxylic acid,
`ered that a group of carboxylic acid derivatives of doxe-
`(5)
`(E)-1 1-(3-(Dimethy1amino)propylidene)-6,l l-dihy-
`pin possess surprisingly potent antihistaminic and anti-
`drodibenz[b,e]oxepin-8-carboxy1ic acid,
`asthmatic properties. In this invention, compound (Z)-
`(6)
`(2)-1 l-(3-(Dimethylamino)propylidene)-6, l l-dihy-
`l l-(3-(dimethylamino)propylidene)-6, 1 l-dihy-
`drodibenz[b,e]oxepin-8-carboxylic acid,
`(E)-l 1-(3-(Dimethylamino)propylidene)-6,1 1-
`drodibenz[b,e]oxepin-2-carboxylic
`acid exhibits
`drodibenz[b,e]oxepin-9-carboxylic acid,
`tremely good antihistaminic activity in vivo.
`Accordingly this ivention provides a compound of 25 (8)(2)-l1-(3-—(Dimethylamino)propylidene)-6,1l-dihy-
`drodibenz[b,e]oxepin-9-carboxylic acid,
`the formula (I),
`(9)
`(E)-l 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihy-
`drodibenz[b,e]oxepin—Z-acrylic acid,
`(10) (Z)-1 1-(3-(Dirnethylamino)propylidene)-6,1 1-dihy-
`drodibenz[b,e]oxepin—2-acrylic acid.
`Examples of compounds of formula (11B) include;
`(1 1) (E)-5—(3-(Dimethylamino)propylidene)— 10, l l-dihy-
`dro-SH—dibenzo[a,d]cyclohepten-3-carboxylic acid,
`(12) (2)-5-(3-(Dimethylamino)propylidene)-10,1 1-dihy-
`dro-SH-dibenzo[a,d]cyclohepten-3-carboxylic acid.
`The compounds of the present invention exist in ei‘
`ther 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 (11B)). If the com-
`pounds of formula (I) or (11) 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 com-
`pounds 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 com-
`pounds 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 pro-
`tecting carboxylic acid groups such as C1.5 alkyl esters
`wherein the alkyl group is straight or branched chain
`and is optionally substituted by halogen. Alkyl esters
`(Cl—4) are particularly preferred.
`Solvates of the compounds of the formulae (1) and
`(II) are also included within the scope of the present
`invention. Preferred solvates include hydrates and CM
`alkanolates.
`
`or a salt, ester or amide thereof; wherein
`R1 is —CH2—CH2——-, ——CH2—O— or —0— 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 hav-
`ing four to six ring members;
`R4 is a single bond or a CM bivalent aliphatic hydro-
`carbon group and may be joined to the aromatic ring
`system at the 2, 3, 8 or 9 positions. 11 is O to 3.
`Of the compounds of formula (I) those of formula
`(11), wherein R1 is as defined herein above, and R5 is a
`single bond or —CH=CH——, are preferred.
`
`35
`
`45
`
`50
`
`(II)
`
`CH(CH2)2N(CH3)2
`
`55
`
`The most preferred compounds of formula (II), are
`those of formula (11a) and formula (IIb) wherein R5 is as
`defined for formula (II)
`
`o
`
`(IIA)
`
`O O RSCOZH
`
`ll
`CH(CH2)2N(CH3)2
`
`65
`
`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 particu-
`larly useful
`in preparing the corresponding carboxy
`compound. When used in medicine, the salts of the
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`
`3
`compounds of formulae (I) and (II) should be both
`pharmacologically and pharmaceutically acceptable,
`but non pharmaceutically acceptable salts may conve-
`niently be used to prepare the free active compound or
`pharmaceutically acceptable salts thereof and are not
`excluded from the scope of this invention. Such phar-
`macologically and pharmaceutically acceptable acid
`addition salts include, but are not limited to, those pre-
`pared from the following acids: hydrochloric, sul-
`phuric, nitric, phosphoric, maleic, salicylic, toluene-p- 1o
`sulphonic,
`tartaric, citric, methanesulphonic, formic,
`malonic,
`isethionic,
`succinic, naphthalene—Z—sul-
`phonic and benzenesulphonic. Also, pharmaceutically
`acceptable salts can be prepared as ammonium salts,
`alkaline metal or alkaline earth salts, such as sodium, 15
`potassium or calcium salts of the carboxylic acid group.
`The present invention also provides analogous meth-
`ods for preparing compounds of formula (I), for exam-
`ple:
`(a) (i) A compound of formula (I) may be prepared 20
`via the well known Wittig method (e.g., US. Pat. Nos.
`3,354,155 and 3,509,175) by reaction of a compound of
`formula (III).
`
`R1
`
`“R4COZH
`
`ll0
`
`(III) 25
`
`30
`
`The Wittig reagent, Ph3P=CI-I(CH2),,NR2R3; i.e., for-
`mula (IV), is conveniently
`
`(IV) 35
`(Celt!s)3P=CI-I(CHz)nI\TRzR3
`prepared by reacting a compound of the formula
`Ph3PCH2(CH2),,NR2R3Br, with a strong base, such as
`sodium hydride or C14; alkyl lithium in a suitable inert
`solvent, such as tetrahydrofuran or dimethoxyethane at
`or near room temperature. It will be appreciated by 40
`those skilled in the art of organic chemistry that protec-
`tion 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 45
`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,
`reacted 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 compound
`of formula (V)
`
`50
`
`R1
`
`“x
`
`II
`CH(CH2),.NR2R3
`
`(V) 55
`
`60
`
`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 for— 65
`mula CV) can be treated with a metalating agent such as
`butyl lithium followed by a reaction with carbon diox-
`ide. When X is hydrogen separation of isomers may be
`
`4,871,865
`
`4
`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 sol-
`vent followed by reaction with carbon dioxide via the
`Grignard procedure (The Merck Index, ninth ed., page
`ONR-38, Merck and Co., Rahway, NJ. (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 varia-
`tion of this method involves a reaction of a compound
`of formula (VII) with a compound of formula IV in a
`similar manner, vide supra, followed by catalytic reduc-
`tion 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.
`((1) When the preparation of a compound of the for-
`mula (I) wherein R4 is CH=CH is required, a com-
`pound of the formula (VII)
`
`R
`
`(VII)
`
`“x
`
`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, 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
`
`(VIII)
`
`Q OxC02H
`
`wherein R1 and X are as defined, 'vide supra with a
`dehydrating agent such as (CF3CO)2O/BF3.OEt2.
`(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 know to those skilled in the art (after
`protecting the C02H group) then reacted with dimethyl
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`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 or-
`ganic chemistry, after deprotecting such an acid can be 5
`dehydrated as described in (d), vide supra to give a
`compound of formula (III).
`(g) A compound of the formula (V) where X is halo-
`gen can be reacted with a metal (I) cyanide, such as
`cuprous cyanide to give a corresponding carbonitrile 10
`derivative, which can then be converted to compounds
`of formula (1), 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) 15
`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 multiple
`bonds when such bonds are present.
`The compounds of this invention having antiallergic 20
`activity may be used for the same indications as clini-
`cally used antiasthmatic compounds, namely to help to
`control bronchoconstriction or brochospasm character-
`istic of allergic asthma and exercise induced asthma and
`the symptoms of bronchoconstriction and broncho- 25
`spasm resulting from acute or chronic bronchitis. The
`compounds are believed to inhibit the release of auta—
`coids (i.e. histamine, serotonin and the like) from mast
`cells and to inhibit directly the antigen-induced produc-
`tion of histamine. Thus, they may be classified as mast 30
`cell stabilizers with antihistaminic action.
`The compounds of this invention having antihista-
`mine activity may be used for the same indications as
`clinically used antihistamines, namely to relieve detri-
`mental symptoms (caused by histamine release) of nasal 35
`stuffiness due to colds and vasomotor rhinitis and for
`the symptomatic control of allergic conditions includ-
`ing nasal allergy, perennial rhinitis, urticaria, angioneu-
`rotic oedema, allergic conjunctivitis, food allergy, drug
`and serum reactions, insect bites and stings and desensi- 40
`tizing reactions. The compound may also be used in
`conditions response to its antipruritic activity including
`allergic dermatoses, neurodermatitis, anogenital pruri-
`tus, and pruritus of non-specific origin such as eczema,
`and of specific cause such as chickenpox, photosensitiv- 45
`ity and sunburn. The present invention therefore pro-
`vides a method for the symptomatic treatment of aller-
`gic 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 50
`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, ie, a compound of 55
`formula (I) required for use in the above conditions will
`vary with the compound chosen, the route of adminis-
`tration and the condition and mammal undergoing
`treatment, and is ultimately at the discretion of the phy-
`sician. A suitable oral dose of the active compound for 60
`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—(dime-
`thylamino)propylidene)—6,1 1—dihydrodibenz[b,e]ox-
`epin—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.
`
`65
`
`4,871,865
`
`6
`The desired daily dose is preferably presented as from
`one to six sub-doses administered at appropriate inter-
`vals throughout the day as needed. Where three sub-
`doses of compounds of formula (I) 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.
`While it is possible for a compound of formula (I) to
`be administered alone as the raw chemical, it is prefera-
`ble to present the compound of formula (I) as a pharma-
`ceutical formulation. Thus, the present invention also
`provides pharmaceutical formulations, both for veteri-
`nary and for human medical use, which comprise a
`compound of formula (I) together with one or more
`pharmaceutically acceptable carriers therefor and op-
`tionally any other therapeutic ingredients. For example,
`the active compound may be formulated with a sympa-
`thomimetic agent such as the decongestant pseudoe-
`phedrine, 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, rec~
`tal, topical, nasal, ophthalmic or parenteral (including
`subcutaneous, intramuscular and intravenous) adminis-
`tration.
`
`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 meth-
`ods include the step of bringing the active compound
`into association with a carrier which constitutes one or
`more accessory ingredients. In general, the formula-
`tions are prepared by unifome and intimately bringing
`the active compound into association with a liquid car-
`rier or a finely divided solid carrier or both and then, if
`necessary, shaping the product into desired formula-
`tions.
`
`Formulations of the present invention suitable for
`oral administration may be presented as discrete units
`such as capsules, cachets, tablets or lozenges, each con-
`taining a predetermined amount of the active compound
`(defined herein as a compound of formula (1)); 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 com-
`pression or molding, optionally with one or more acces-
`sory 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 pow-
`der or granules which is optionally mixed with 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 com-
`pound to a concentrated, aqueous solution of a sugar for
`example sucrose to which may also be added any acces-
`sory ingredient(s). Such accessory ingredient(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 ex-
`ample glycerol or sorbitol, and suitable preservatives.
`Formulations for rectal administration may be pres-
`ented as a suppository with a usual carrier such as cocoa
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`7
`butter, or hydrogenated fats or hydrogenated fatty car-
`boxylic acids.
`Formulations suitable for parenteral administration
`conveniently comprise a sterile aqueous preparation 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 preservative
`agents and isotonic agents. Such formulations are ad-
`justed 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 iso-
`tonic 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 formulations. 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 ingredient(s) selected from diluents,
`buffers, flavouring agents, binders, disintegrants, sur-
`face 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 tempera-
`tures indicated are in degrees Celsius.
`EXAMPLE 1
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`8
`column (Waters Associates-Prep. 500) with ethyl aceta-
`te/methanol (8:2) to give an additional 2.55 g. of pure
`Z-isomer as the hydrochloride salt and 2.79 g. of E-iso-
`mer as its hydrochloride salt, m.p. 230°—233° C. pmr
`(Z-isomer) (DMSO/ds) 6: 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, CH2), 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) 6: 7.23-7.50 (m, 6H, aromatic),
`6.70 (d, J=8.6 Hz, 1H, H4)» 6.10 (t, J=7.2 Hz, 1H,
`CH2) 5.15 (br s, 2H, CH20), 3.07 (m, 2H, NCH2), 2.65
`(s, 6H, NMe2), 2.50 (m overlap with DMSO, 2H, CH2).
`
`(C)
`(Z)-1 l-(3-(Dirnethylamino)propylidene)-6,1 l-dihy-
`drodibenz[b,e]oxepin-2-carboxylic acid (Compound 1)
`
`A solution of n-butyl lithium in hexane (1.6M, 3.5
`mL) was added dropwise to a solution of 1.8 g. pure
`(Z)-3-(2-bromo-6, l 1-dihydrodibenz[b,e]oxepin-1 1-
`ylidene)-N,N-dimethylpropylamine in 100 mL of dry
`tetrahydrofuran at —70° C. under a nitrogen atmo-
`sphere. 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 concen-
`trated under reduced pressure. The foamy residue was
`dissolved in water, and the mixture was neutralized
`with 1N hydrochloric acid and then extracted with
`chloroform. Concentration of the chloroform and
`
`recyrstallization of the residue from water gave 0.5 g.
`pure Z-2—carboxylic acid, m.p.
`121°—123° C. pmr
`(CDC13) 8: 7.87 (d, Jél Hz, 1H, H1), 7.81 (dd, J=7.8,
`2.2 Hz, 1H, H3), 7.25-7.28 (m, 4H, aromatic), 6.82 (de-
`generate d, J =8.8 Hz, 1H, H4), 6.45 (br s, 1H, COzH),
`5.50 (m, 1H, CH2), 5.20 (br s, 2H, CH20), 2.92 (m, 4H,
`NCH2CH2), 2.66 (s, 6H, NMe2).
`Analysis: Calcd. for C20H21N03.0.55 H2O: C, 72.07;
`H, 6.68; N, 4.20. Found: C, 72.07; H, 6.69; N, 4.18.
`
`(E)/(Z)-1 1-(3-(Dimethylamino)propylidene)-6, 1 1-dihy-
`drodibenz[b,e]oxepin—2-carboxylic acid
`
`35
`
`(a) 2-Bromo-6,1 l-dihydrodibenz[b,e]oxepin-1 l-one
`2-Bromo-6,1 1-dihydrodibenz[b,e]oxepin-1 l-one was
`prepared as described in U.S. Pat. No. 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, H1), 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 C14H9Br02: 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-dimethylpropylamine
`
`Anhydrous 3-(dirnethylamino)propyltriphenylphos-
`phonium 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 (1.6M)
`was added dropwise at 0° C. under a nitrogen atmo-
`sphere during a 30 minute period. After an additional 10
`minutes,
`2—bromo-6, l 1-dihydrodibenz[b,e]oxepin-
`11-one (16.8 g., 0.06 mole) in 150 mL dry tetrahydrofu-
`ran 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 provide 5.3 g. of pure Z-iso-
`mer as its hydrochloride salt, m.p. 201°-204° C. The
`mother liquor was chromatographed on a silica gel
`
`45
`
`50
`
`55
`
`60
`
`65
`
`(d)
`(E)-l 1-(3-(Dimethylamino)propylidine)-6, 1 l-dihy-
`drodibenz[b,e]oxepin-2-carboxylic acid (Compound 2)
`
`Pure (E)-3-(2-bromo-6,1 1-dihydrodibenz[b,e]oxepin—
`11-ylidene)-N,N-dimethylpropylamine
`(1.55
`g.,
`.43
`mole), was treated under nitrogen in cold (——70° C.)
`tetrahydrofuran (100 mL) with 4.4 mole 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 chroma-
`tography of the crude product on a reverse phase C18
`semipreparative column eluted with 20% methanol in
`water (containing 0.1% triethylamine). Recrystalliza-
`tion of the solid product from water afforded 0.012 g of
`pure E-2-carboxylic acid, m.p. >200“ C. (decomp.).
`pmr (CDC13) 6: 7.85 (d, J =2.0 Hz, 1H, H1), 7.06-7.78
`(m, 5H, aromatic), 6.47 (d, J :85 Hz, 1H, H4), 6.28 (t,
`J =4.2 Hz, 1H, CH2), 5.85 (m, 1H, ArCH), 4.70 (m,
`1H, ArCH), 2.43 (m, 4H, NCH2CH2), 2.28 (s, 6H,
`NMez).
`Analysis:'Ca1cd. for C20H21NO3.0.50 H2O: C, 72.27;
`H, 6.67; N, 4.21. Found: C, 72.15; H, 6.46; N, 4.22.
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1034 p. 005
`
`Ayla Pharma LLC (IPR2020-00295) Ex. 1034 p. 005
`
`
`
`9
`
`EXAMPLE 2
`
`4,871,865
`
`(E)/(Z)- l 1-(3-(Dimethy1amino)propylidene)-6, l l-dihy-
`drodibenz[b,e]oxepin-3-carboxylic acid
`
`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-Z-
`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. Analyti-
`cal sample was obtained by recrystallization from meth-
`ylene chloride/hexanes, m.p. 84°-85° c. pmr (CDC13) 8:
`8.0 (m, 1H, H6), 6.93—7.69 (m, 7H, aromatic H), 5.47 (s,
`2H, ArCH20), 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 concentrate under reduced pres-
`sure 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 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, H5),
`6.84—7.74 (m, 7H, aromatic H), 6.16 (br s, 1H, COzH),
`5.49 (s, 2H, ArCH20).
`Analysis: Calcd. for C14H11Br03: C, 54.74; H, 3.61;
`Br, 26.02. Found: C, 54.65; H, 3.61; Br, 26.08.
`
`(c) 3-Bromo-6,1 l-dihydrodibenz[b,e]oxepin-1 l-one
`A suspension of 2-(3-bromophenoxymethyl)benzoate
`(35 g, 0.11 mole) in 100 mL of trifluoroacetic 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. Con-
`centration 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 (CDCL3) 6: 8.10 (d, J=9.1 Hz, 1H,
`H1), 7.90 (dd, J =1.4, 7.6 Hz, 1H, Hm) 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=l.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, ArCH2O).
`Analysis: Calcd. for C14H9Br02: 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, l 1-dihydrodibenz[b,e]oxepin-1 1-
`ylidene)-N,N—dimethylpropylamine
`
`Anhydrous 3-(dimethy1amino)propyltriphenylphos-
`phonium bromide hydrobrornide (24.5 g, 48.0 mmole),
`96 mole 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 I, step b. This provided an
`(E)/(Z)-(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 £93% stereoi-
`someric purity (assayed by ’H-NMR) as a white solid.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`10
`(m, 4H, aromatic H),
`7.23—7.31
`(CDC13) 6:
`pmr
`6.92—7.05 (m, 3H, aromatic H), 5.91 (t, 1H, CH2, 7%
`E-isomer), 5.60 (t, 1H, CH2, 93% Z-isomer) 5.15 (very
`br s, 2H, ArCH20), 3.12 (m, 2H, CH2), 2.99 (m, 2H,
`NCH2), 2.78 (s, 6H, NMez, 93% Z-isomer), 2.71 (s, 6H,
`NMe2, 3% E-isomer).
`Analysis: Calcd. for C19H20BrNO.l.O HCl: C, 57.81;
`H, 5.36; N, 3.55. Found: C, 57.62; H, 5.33; N, 3.54.
`
`(e)
`(E)/(Z)-1 1-(3-(Dimethylamino)propy1idene)—6, 1 l-dihy-
`drodibenz[b,e]oxepin-3-carboxylic acid (Compounds
`3/4)
`
`An isomeric mixture E/Z (1:3) of 3-(3-bromo-6,11-
`dihydrodibenz[b,e]-l l-ylidene]-N,N-dimethylpropyla-
`mine (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 followed by gaseous carbon dioxide by the
`procedure of Example 1, step c, to provide the corre-
`sponding carboxylic acids as an E/Z (1:3) stereoiso-
`meric mixture. The mixture was chromatographed on a
`reverse phase PRP-l semi-preparative column with
`water/acetonitrile (87:13) to provide 0.08 g of E-isomer
`(lyophilized powder) and 0.50 g of Z-isomer (lyophi-
`lized powder). pmr (E-isomer) (CDCl3/TFA) 8: 7.85
`(dd, J =8.0, 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, CH2), 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)
`(CDCL3/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,
`CH2), 5.20 (very br s, 2H, ArCH2O), 3.32 (q, 2H,
`CH2), 2.91 (s, 3H, NMe), 2.90 (s, 3H, NMe), 2.89 (m,
`2H, NCH2).
`Analysis: Calcd. for C20H21NO3.O.5 HC1.0.2 H20: C,
`69.58; H, 6.39; N, 4.06. Found (E-isomer): C, 69.64; H,
`6.25; N, 4.03. Calcd. for C20H21N03.0.25 H20: C, 73.26;
`H, 6.61; N, 4.27. Found (Z-isomer): C, 73.20; H, 6.60; N,
`4.20.
`
`EXAMPLE 3
`
`(E)/(Z)-(1 1-(3-Dimethylamino)propy1idene)-6, l 1-dihy-
`drodibenz[b,e]oxepin-8-carboxylic acid
`
`(a) 8-Bromo-6, 1 1-dihydrodibenz[b,e]oxepin-1 1-one
`
`Phenol (8 g, 85 mole) and potassium carbonate (11.7
`g, 85 mole) in 150 mL of N,N—dimethylformamide
`was reacted with methyl Lbromo-a-bromo-Z-toluate
`(20 g, 65 mole) by the procedure of Example 2, step a
`and folloed with alkaline hydrolysis by the procedure of
`Example 2, step b to give the crude 4-bromo-2-phenox—
`ybenzoic acid (13 g) which was used without further
`purification.
`The crude 4-bromo-(2-phenoxymethyl)benzoic acid
`(13 g, 42 mole) was cyclized in 50 mL of trifluoroace-
`tic 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, m.p. 125°—126° C.
`pmr (CDCL3) 8: 8.17;14 8.30 (m, 1H, H1), 6.99—7.86 (m,
`6H, aromatic H), 5.14 (s, 2H, ArCH20).
`Analysis: Calcd. for C14H9Br02: C, 58.16; H, 3.14;
`Br, 27.64. Found: C, 58.15; H, 3.17; Br, 27.73.
`
`Ayla Pharma LLC (IPR