United States Patent
`
`[19]
`
`[11] Patent Number:
`
`5,037,845
`
`Oxford
`
`[45] Date of Patent:
`
`Aug. 6, 1991
`
`[54]
`
`INDOLE DERIVATIVE
`
`OTHER PUBLICATIONS
`
`[75]
`
`Inventor: Alexander W. Oxford, Royston,
`England
`
`M. Dorole et a1., Chem. Abst., vol. 100, No. 103l75y
`(1983).
`
`[73] Assignee: Glaxo Group Limited, England
`
`[21] App1.No.: 317,682
`
`[22] Filed:
`
`Mar. 1, 1989
`
`Primary Exam1'ner—-Mary E. Ceperley
`Attorney, Agent, or Firm-—Bacon & Thomas
`
`[57]
`
`ABSTRACI“
`
`A compound of formula (I)
`
`H3C
`
`\
`
`NSO2CH;_
`
`CH3
`
`CH3CH2N
`
`NH
`
`and its physiologically acceptable salts and solvates are
`described as useful in treating and/or preventing pain
`resulting from dilatation of the cranial vasculature in
`particular migraine.
`The compound (I) may be prepared, for example, by
`cyclizing a compound of formula (II)
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 82,666, Aug. 7, 1987, aban-
`doned, which is a continuation of Ser. No. 761,392,
`Aug. 1, 1985, abandoned.
`
`Foreign Application Priority Data
`[30]
`Aug. 1, 1984 [GB] United Kingdom ............... .. 8419575
`
`[51]
`Int. Cl.5 ................... .. A61K 31/40; CO7D 209/16
`
`[52] U.S. Cl. ......................... .. 514/415; 548/504
`[58] Field of Search ....................... .. 548/504; 514/415
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`................ .. 548/500
`5/1967 Sletzinger et al.
`3,322,787
`. 548/500
`3,624,103 ll/1971 De Martiis et a1.
`,. 548/500
`4,283.4l0
`8/1981 Schut et al.
`...... ..
`
`4,816,470
`3/1989 Dowle et al.
`....................... 514/415
`
`FOREIGN PATENT DOCUMENTS
`
`H3C
`
`\
`
`NSO2Cl-I2
`
`H
`
`-
`
`145459
`8115513
`8115514
`8115515
`8309429
`8418618
`
`.
`
`6/1985 European Pat. Off.
`2/1982 France .
`2/1982 France .
`2/1982 France .
`1/1984 France .
`6/1985 France .
`
`(11)
`
`.
`
`NHN=CH(CH2)3N
`
`CH3
`
`/
`
`CH3
`
`12 Claims, No Drawings
`
`   
`


`
`Lannett Holdings, Inc. LAN 1029
`
`

`
`1
`
`INDOLE DERIVATIVE
`
`5,037,845
`
`2
`therein, which compound has special advantages. Thus,
`we have discovered that by a selection of two specific
`substituents, namely the methylaminosulphonylmethyl
`group at the 5-position of the indole nucleus and the
`N,N-dimethylaminoethyl substituent at the 3-position, a
`compound having a combination of highly advanta-
`geous properties for the treatment of migraine is ob-
`tained.
`invention provides 3-[2-(dime-
`Thus the present
`thylamino)ethy1]-N-methyl-lg-indole-5-methanesuL
`phonamide, of formula (1)
`
`}{3C
`
`NSOZCH2
`
`CH3
`
`(1)
`
`/
`
`CH2Cl-l2N
`
`CH3
`
`NH
`
`This application is a continuation, of application Ser.
`No. 082,666, filed Aug. 7, 1987 now abandoned, which
`is a continuation of Ser. No. 761,392, filed Aug. 1, 1985,
`which is now abandoned.
`'
`This invention relates to an indole derivative of use in
`the treatment of migraine, to processes for its prepara-
`tion, to pharmaceutical compositions containing it and
`to its medical use.
`
`The pain of migraine is associated with excessive
`dilatation of the cranial vasculature and known treat-
`ments for migraine include the administration of com-
`pounds having vasoconstrictor properties such as ergot-
`amine. However, ergotamine is a non—selective vaso-
`constrictor which constricts blood vessels throughout
`the body and has undesirable and potentially dangerous
`side effects. Migraine may also be treated by administer-
`ing an analgesic, usually in combination with an antic-
`metic, but such treatments are of limited value.
`There is thus a need for a safe and effective drug for
`the treatment of migraine, which can be used either
`prophylactically or to alleviate an established headache,
`and a compound having a selective vasoconstrictor
`activity would fulfil such a role.
`Furthermore, in conditions such as migraine, where
`the drug will usually be administered by the patient, it is
`highly desirable that the drug can be taken orally. It
`should therefore possess good bioavailability and be
`effectively absorbed from the gastro-intestinal tract so
`that prompt relief of symptoms can occur. The drug
`should also be safe (i.e. free from toxic effects) when
`administered by the oral route.
`A wide variety of indole derivatives have been de-
`scribed as being of use in the treatment of migraine. In
`our published UK Patent Application No. 2l2421OA we
`describe indoles of the general formula
`
`R1RgN503CHR3
`
`AlkNK;R5
`
`NH
`
`wherein R1 represents a hydrogen atom or a C1_5 alkyl
`or C3.(, alkenyl group; R2 represents a hydrogen atom or
`a C1-3 alkyl, C3_5 alkenyl, aryl, ar(C14)alkyl or C5_7
`cycloalkyl group; R3 represents a hydrogen atom or a
`C1_3 alkyl group; R4 and R5, which may be the same or
`different, each represents a hydrogen atom or a C1_3
`alkyl or propenyl group or R4 and R5 together form an
`aralkylidene group; and Alk represents an alkylene
`chain containing two or three carbon atoms which may
`be unsubstituted or substituted by not more than two
`C1_3 alkyl groups, and physiologically acceptable salts
`and solvates thereof.
`As
`indicated in UK Patent Application No.
`2l242lOA, compounds of the above formula selectively
`constrict the carotid arterial bed of the anaesthetised
`dog and are thus potentially useful for the treatment of
`migraine.
`We have now found a particular compound which
`falls within the scope of the group of compounds de-
`scribed and claimed in UK Patent Application No.
`2l242l0A but which is not
`specifically disclosed
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`and its physiologically acceptable salts and solvates
`(e. g. hydrates).
`The compounds according to the invention are useful
`in treating and/or preventing pain resulting from dilata-
`tion of the cranial vasculature, in particular migraine
`and related disorders such as cluster headache.
`The compound of formula (I) potently and selec-
`tively constricts the carotid arterial bed following intra-
`venous administration as shown by tests in anaesthetised
`dogs. This potent and selective vasoconstrictor action
`has also been demonstrated in vitro. Further tests in
`anaesthetised dogs have shown that the compound of
`formula (I) is effectively and consistently well absorbed
`from the gastro-intestinal tract following intra-duodenal
`administration, quickly producing a sustained vasocon-
`striction in the carotid arterial bed.
`At doses at which the compound of formula (I)
`would be efficacious in the treatment of migraine it has
`no significant effect on blood pressure and heart rate
`and no significant bronchoconstrictor effect on the
`lung.
`The compound of formula (I) may safely be adminis-
`tered orally as well as intravenously.
`The combination of these properties possessed by the
`compound of formula (I) is highly desirable in the treat-
`. merit of migraine and the compound (I) has significant
`advantages, as demonstrated by the aforementioned
`experimental tests, over compounds which have previ-
`ously been described as being of use in the treatment of
`migraine, such as those disclosed in published UK Pa-
`tent Application No. 2l242lOA. It is particularly advan-
`tageous that the compound of formula (I) is effectively
`absorbed from the gastro-intestinal tract in a consistent
`manner.
`
`Furthermore, tests in guinea pigs have shown that the
`compound of formula (I) promotes gastric emptying
`following oral administration, and hence relieves gas-
`tric stasis. Gastric stasis is a symptom commonly associ-
`ated with migraine. He_nce the ability of the compound
`of formula (I) to relieve gastric stasis is a further benefi-
`cial property of this compound in the treatment of mi-
`graine.
`Suitable physiologically acceptable salts of the com-
`pound of formula (I) include acid addition salts formed
`with organic or inorganic acids for example hydrochlo-
`rides, hydrobromides, sulphates, nitrates, phosphates,
`formates, mesylates, citrates, benzoates, fumarates, ma-
`
`65
`
`

`
`3
`leates and succinates. Other salts may be useful in the
`preparation of the compound of formula (I) e.g. creati-
`nine sulphate adducts, and salts with e.g. toluene-p-sul-
`phonic acid.
`Where a salt of the compound (1) according to the
`invention is formed with a dicarboxylic acid, such as
`succinic acid, the salt may be formed with either one or
`both of the carboxylic acid groups, i.e.
`the salt may
`contain either one or two moles of the compound (I) per
`mole of acid. A preferred salt according to the inven-
`tion is the succinate, most preferably the 1:1 succinate.
`According to a further aspect, the invention provides
`a method of treatment of a human subject suffering
`from or susceptible to pain resulting from dilatation of
`the cranial vasculature, such as migraine or cluster
`headache, by administration of a compound of formula
`(I) or a physiologically acceptable salt or solvate
`thereof. The method of treatment preferably comprises
`oral administration of a compound of the invention.
`Accordingly, the invention also provides a pharma-
`ceutical composition adapted for use in medicine which
`comprises the compound of formula (1) and/or a physi-
`ologically acceptable salt or solvate (e.g. hydrate)
`thereof, formulated for administration by any conve-
`nient route. Such compositions may be formulated in
`conventional manner using one or more pharmaceuti-
`cally acceptable carriers or excipients. The compounds
`according to the invention may be formulated for oral,
`sub-lingual, parenteral, rectal or intra-nasal administra-
`tion, or in a form suitable for administration by inhala-
`tion or insufflation. Formulations of the compounds for
`oral administration are preferred.
`The pharmaceutical compositions for oral administra-
`tion may take the form of, for example, tablets or cap-
`sules prepared by conventional means with pharmaceu-
`tically acceptable excipients such as binding agents (e.g.
`pregelatinised maize starch, polyvinylpyrrolidone or
`hydroxypropyl methylcellulose);
`fillers (e.g.
`lactose,
`sucrose, mannitol, maize starch, microcrystalline cellu-
`lose or calcium hydrogen phosphate); lubricants (e.g.
`stearic acid, polyethylene glycol, magnesium stearate,
`talc or silica); disintegrants (e.g.) potato starch, sodium
`starch glycollate or croscarmellose sodium); or wetting
`agents (e.g. sodium lauryl sulphate). The tablets may be
`coated by methods well known in the art. Liquid prepa-
`rations for oral administration may take the form of, for
`example, aqueous or oily solutions, syrups, elixirs, emul-
`sions or suspensions, or they may be presented as a dry
`product for constitution with water or other suitable
`vehicle before use. Such liquid preparations may be
`prepared by conventional means with pharmaceutically
`acceptable additives such as suspending agents (e.g.
`sorbitol
`syrup, cellulose derivatives, glucose/sugar
`syrup, gelatin, aluminum stearate gel, or hydrogenated
`edible fats); emulsifying agents (e.g. lecithin, acacia or
`sorbitan mono-oleate); non-aqueous vehicles (e.g. al-
`mond oil, oily esters, ethyl alcohol or fractionated vege-
`table oils); and preservatives (e.g. methyl or propyl
`p-hydroxybenzoates or sorbic acid). The liquid prepara-
`tions may also contain conventional buffers, flavouring,
`colouring and sweetening agents as appropriate.
`A proposed dose of the compounds of the invention
`for oral administration to man (about 70 kg body-
`weight) for the treatment of migraine is 0.1 mg to 100
`mg, for example 0.5 mg to 50 mg; preferably 2 mg to 40
`mg, of the active ingredient per'dose which could be
`administered up to 8 times per day, more usually 1 to 4
`times per day. It will be appreciated that it may be
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`5,037,845
`
`4
`necessary to make routine variations to the dosage de-
`pending on the age and weight of the patient, as well as
`the severity of the condition to be treated. It should be
`understood that unless otherwise indicated, the dosages
`are referred to in terms of the weight of compound (I)
`as the free base.
`The compounds of the invention may be formulated
`for parenteral administration by injection, preferably
`intravenous or subcutaneous injection eg. by bolus
`injection or continuous intravenous infusion. Formula-
`tions for injection may be presented in unit dosage form
`eg in ampoules or in multi-dose containers, with an
`added preservative. The compositions may take such
`forms as suspensions, solutions or emulsions in oily or
`aqueous vehicles, and may contain formulatory agents
`such as suspending, stabilising and/or dispersing agents
`and/or agents to adjust the tonicity of the solution.
`Alternatively, the active ingredient may be in powder
`form for constitution with a suitable vehicle, e.g. sterile
`pyrogen-free water, before use.
`The overall daily dose administered by injection may
`be in the range 50 pg to 50 mg, e.g. 0.5 to 20 mg, which
`may for example be divided into 2,3 or 4 doses.
`The compounds of the invention may also be formu-
`lated in rectal compositions such as suppositories or
`retention enemas, e.g. containing conventional supposi-
`tory bases such as cocoa butter or other glycerides.
`Tablets for sub-lingual administration may be formu-
`lated in a similar manner to those for oral administra-
`tion.
`For intra-nasal administration the compounds of the
`invention may be used as a liquid spray or in the form of
`drops.
`Dosages of the compounds of the invention for rectal,
`sublingual or intranasal administration to man (of aver-
`age body weight e.g. about 70 kg) for the treatment of
`migraine may be similar to those described previously
`for oral administration.
`For administration by inhalation the compounds ac-
`cording to the invention are conveniently delivered in
`the form of an aerosol spray presentation from pressu-
`rised packs, with the use of a suitable propellant, e.g.
`dichlorodifluoromethane,
`trichlorofluoromethane, di-
`chlorotetratluoroethane, carbon dioxide or other suit-
`able gas, or from a nebuliser. In the case of a pressurised
`aerosol the dosage unit may be determined by providing
`a valve to deliver a metered amount. Capsules and car-
`tridges of e.g. gelatin for use in an inhaler or insuftlator
`may be formulated containing a powder mix of a com-
`pound of the invention and a suitable powder base such
`as lactose or starch.
`Aerosol formulations are preferably arranged so that
`each metered dose or “puff” delivered from a pressur-
`ized aerosol contains 0.2 mg to 2 mg of a compound of
`the invention, and each dose administered via capsules
`and cartridges in an insufilator or an inhaler contains 0.2
`mg to 20 mg of a compound of the invention. Adminis-
`tration may be several times daily, for example from 2 to
`8 times, giving for example 1, 2 or 3 doses each time.
`The overall daily dose by inhalation will be similar to
`that for oral administration.
`The compounds of the invention may, if desired, be
`administered in combination with one or more other
`therapeutic agents, such as analgesics, anti-inflamma-
`tory agents and anti-nauseants.
`The compound of formula (I) and its physiologically
`acceptable salts and solvates (e.g. hydrates) may be
`prepared by the general methods outlined hereinafter.
`
`

`
`5,037,845
`
`5
`According to one general process (A), the compound
`of formula (I) may be prepared by cyclisation of the
`compound of formula (11)
`
`H3C
`
`\
`
`H
`
`NS02CH2
`
`(11)
`
`CH3
`
`/
`
`10
`
`CH3
`
`NHN=CH(CHz)3N
`
`The reaction may conveniently be effected in aque-
`ous or non-aqueous reaction media and at temperatures
`of from 10° to 200° C., preferably 50° to 125° C.
`Particularly convenient embodiments of process (A)
`are described below.
`The cyclisation is desirably carried out in the pres-
`ence of polyphosphate ester in a reaction medium
`which may comprise one or more organic solvents,
`preferably halogenated hydrocarbons such as chloro-
`form, dichloromethane, dichloroethane, dichlorodifluo-
`romethane, or mixtures thereof. Polyphosphate ester is
`a mixture of esters which may be prepared from phos-
`phorus pentoxide, diethylether and chloroform accord-
`ing to the method described in ‘Reagents for Organic
`Synthesis’, (Fieser and Fieser, John Wiley and Sons
`1967).
`Alternatively the cyclisation may be carried out in
`aqueous or non-aqueous media, in the presence of an
`acid catalyst. When an aqueous medium is employed
`this may be an aqueous organic solvent such as an aque-
`ous alcohol (e.g. methanol, ethanol or isopropanol) or
`an aqueous ether (e.g. dioxan or tetrahydrofuran) as
`well as mixtures of such solvents and the acid catalyst
`may be for example an inorganic acid such as concen-
`trated hydrochloric or sulphuric acid or an organic
`acid, such as acetic acid. (In some cases the acid catalyst
`may also act as the reaction solvent). In an anhydrous
`reaction medium, which may comprise one or more
`alcohols or ethers (e.g. as previously described) or es-
`ters (e. g. ethyl acetate), the acid catalyst will generally
`be a Lewis acid such as boron trifluoride, zinc chloride
`or magnesium chloride.
`According to a particular embodiment of this cyclisa-
`tion process, the compound of formula (I) may be pre-
`pared directly by the reaction of the compound of for-
`mula (III)
`
`H3C
`
`\
`/H
`
`NSO3CH2
`
`(III)
`
`NHNH2
`
`or a salt (e.g. the hydrochloride salt) thereof, with the
`compound of formula (IV)
`
`OHC(CH3)3N
`
`CH3
`
`/
`
`CH3
`
`(IV)
`
`or a salt or protected derivative thereof (such as an
`acetal,
`for example, a dialkyl or cyclic acetal e.g.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
`6
`formed with an appropriate alkyl orthoformate or diol,
`or protected as a bisulphite addition complex), using the
`appropriate conditions as previously described for the
`cyclisation of the compound of formula (II).
`(The
`Fischer-Indole Synthesis, B. Robinson p488—Wiley
`1982). It will be appreciated that in this embodiment of
`the cyclisation process (A) a compound of formula (II)
`is formed as an intermediate and reacted in situ to form
`the desired compound of formula (I).
`The compound of formula (II) may, if desired, be
`. isolated as an intermediate by reacting the compound of
`formula (III), or a salt or protected derivative thereof
`with the compound of formula (IV) or a salt or pro-
`tected derivative thereof, in water or in a suitable sol-
`vent, such as an aqueous alcohol (e.g. methanol) or an
`aqueous ether (e.g. dioxan) and at a temperature of, for
`example, from 10° to 30° C. If an acetal of the com-
`pound of formula (IV) is used it may be necessary to
`carry out the reaction in the presence of an organic or
`inorganic acid (for example, acetic or hydrochloric
`acid).
`The compound of formula (III) may be prepared for
`example as described in UK Patent Application No.
`2l2421OA.
`As illustrated in the following general processes (B)
`and (C), the dimethylamino substituent may be intro-
`duced at
`the 3-position by conventional
`techniques
`involving modification of a substituent at the 3-position
`or direct introduction of the aminoalkyl substituent into
`the 3-position.
`Thus a further general process (B) for preparing the
`compound of formula (1) involves reacting a compound
`of general formula (V)
`
`NSO2CH2
`
`CHZCHZY
`
`(V)
`
`H_zC
`
`\
`
`H
`
`NH
`
`(wherein Y is a readily displaceable atom or group) or a
`protected derivative thereof, with dimethylamine.
`Suitable displaceable atoms or groups Y include a
`halogen atom (e. g. chlorine, bromine or iodine); a group
`OR5 where OR5 is, for example, an acyloxy group,
`which may be derived from a carboxylic or sulphonic .
`acid,
`such
`as
`an
`acetoxy,
`chloroacetoxy,
`di-
`chloroacetoxy,
`triiluoroacetoxy,
`p-nitrobenzoyloxy
`p-toluenesulphonyloxy or methanesulphonyloxy group;
`or a group @NR7RgR9E9, where R7, R3 and R9 each
`represents a C1_3 alkyl group, and E‘ represents an
`' anion such as a halide ion, e.g. a chloride, bromide or
`iodide ion.
`
`The displacement reaction may conveniently be ef-
`fected in an inert organic solvent (optionally in the
`presence of water), examples of which include alcohols,
`e.g. ethanol; cyclic ethers e.g. dioxan or tetrahydrofu-
`ran; acyclic ethers, e.g. diethylether; esters e.g. ethyl
`acetate; amides e.g. N,N-dimethylformamide; and ke-
`tones e.g. acetone, methylethylketone or methylisobu-
`tylketone. The process may be carried out at a tempera-
`ture of, for example, —l0° to + 150° C., preferably 20”
`to 100° C.
`‘
`
`

`
`5,037,845
`
`7
`The compounds of formula (V) wherein Y is a halo-
`gen atom may be prepared by reacting the hydrazine of
`formula (III) with an aldehyde (or a protected deriva-
`tive thereof) of formula (VI)
`
`OHC(CH3)3Y
`
`(VI)
`
`(wherein Y is as previously defined) in an aqueous alco-
`hol (e.g. methanol) or an aqueous ether (e.g. dioxan)
`containing an acid (e. g. acetic or hydrochloric acid) or 1
`by reacting the compound of formula (VII)
`
`0
`
`(VII)
`
`5
`
`1
`
`O
`
`2
`
`H3C
`
`\
`
`H/
`
`NSOZCH2
`
`CH2CH2OH
`
`N H
`
`with the appropriate halogenating agent such as a phos-
`phorus trihalide, thionyl chloride or N-bromosuccini-
`mide and triphenylphosphine, in a suitable solvent, for
`example pyridine or tetrahydrofuran. The compound of 2
`formula (VII) may also be used to prepare compounds
`of formula (V), wherein Y is a group OR6 by acylation
`with the appropriate activated species derived from a
`carboxylic or sulphonic acid (e.g. an anhydride or sul-
`phonyl chloride) using conventional techniques. The
`alcohol (VII) may be prepared for example by cyclisa-
`tion of the appropriate hydrazone as described in UK
`Published Patent Application No. 2l50932A.
`Compounds of formula (V) where Y represents the
`group 63NR7RgR9E9 may be prepared from the corre-
`sponding primary amine by reaction with an appropri-
`ate alkylating agent, for example as described in general
`process (E) hereinafter.
`The compound of formula (I) may also be prepared
`by another general process (C) involving reduction of a
`compound of general formula (VIII)
`
`3
`
`3
`
`5
`
`O
`
`5
`
`(VIII)
`
`4
`
`5
`
`50
`
`NH
`
`H3C
`
`\
`/1-1
`
`NSOQCH3
`
`(wherein W is a group capable of being reduced to give
`the required dimethylaminoethyl group) or a salt or
`protected derivative thereof.
`The required —(CH2)—2 and dimethylamino moi-
`eties may be formed by reduction steps which take 5
`place separately or together in any appropriate manner.
`Groups which may be reduced to the —(CH2)—2
`moiety include the corresponding unsaturated group
`and corresponding groups containing one or more car-
`bonyl functions and/or a hydroxyl group.
`The group W may be a group which is itself reduced
`to the dimethylaminoethyl moiety. Examples of such
`groups include -(CI-I2)2N(CH3)COR1o (where R10
`represents a hydrogen atom, or an alkoxy or aralkoxy
`group)? ~COCON(CH3)2; —-CHzCON(CH3)2; ——CH-
`(OH)CH2N(CH3)2; and —-COCH2N(CH3)2.
`Alternatively W may represent a group which gives
`the dimethylaminoethyl moiety upon reduction in the
`
`6
`
`5
`
`5
`
`8
`presence of dimethylamine, for example —-—CH2CN and
`—CH2CHO.
`-
`A particularly suitable method for preparing the
`compound of formula (I) is reductive methylation of the
`corresponding amino or methylamino derivative with
`formaldehyde in the presence of a suitable reducing
`agent. It will be appreciated that. at least two equiva-
`lents of formaldehyde should be used when the starting
`material is the primary amine. If desired, the formalde-
`hyde may first be condensed with the amine and the
`intermediate thus formed may subsequently be reduced.
`Reduction of the compound of formula (VIII) may be
`effected by conventional methods, for example by cata-
`lytic hydrogenation or using a reducing agent such as an
`alkali metal or alkaline earth metal borohydride or cya-
`noborohydride. The reduction may conveniently be
`effected in an organic reaction medium which may
`comprise one or more organic solvents. Suitable sol-
`vents include alcohols, e. g. ethanol or propanol; cyclic
`ethers, e.g. dioxan or tetrahydrofuran; acyclic ethers
`e.g. diethyl ether; amides, e.g. dimethylformamide; es-
`ters, e.g. ethyl acetate, and nitriles e.g. acetonitrile.
`It will be appreciated that the choice of reducing
`agent and reaction conditions will be dependent on the
`nature of the group W.
`Suitable reducing agents which may be used in the
`above process for the reduction of compounds of for-
`mula (VIII) wherein W represents, for example,
`the
`group —CH(OH)CH2N(CH3)z include hydrogen in the
`presence of a metal catalyst, for example Raney Nickel
`or a noble metal catalyst such as platinum, platinum
`oxide, palladium or rhodium, which may be supported,
`for example, on charcoal, kieselguhr or alumina. In the
`case of Raney Nickel, hydrazine may also be used as the
`source of hydrogen. This process may conveniently be
`carried out in a solvent such as an alcohol e.g. ethanol,
`an ether, e.g. dioxan or tetrahydrofuran, an amide, e.g.
`dimethylformamide or an ester e.g. ethyl acetate, and at
`a temperature of from — 10° to -+-50° C., preferably ——5°
`to +30° C.
`The reduction process may also be effected on com-
`pounds of formula (VIII) wherein W represents, for
`example,
`the
`group —CH(OH)CH2N(CI-I3);
`or
`—COCH3N(CH3)2 using an alkali metal or alkaline
`earth metal borohydride or cyanoborohydride e.g. so-
`dium or calcium borohydride or cyanoborohydride
`which process may conveniently be carried out in an
`alcohol such as propanol, ethanol or methanol, and at a
`temperature of from 10° to 100° C., preferably 50° to
`100° C. In some instances, the reduction using a borohy-
`dride may be carried out in the presence of cobaltous
`chloride.
`Reductive methylation of the aminoethyl or me-
`thylaminoethyl compound corresponding to formula (I)
`with formaldehyde may be also effected using an alkali
`metal or alkaline earth metal borohydride or cyanobor-
`ohydride. The reaction may be effected in an aqueous
`or non-aqueous reaction medium, conveniently in an
`alcohol as just described, or an ether, e.g. dioxan or
`tetrahydrofuran, optionally in the presence of water. In
`this embodiment, the reaction may be effected in the
`presence of an acid e. g. acetic acid, and at a temperature
`in the range 0" to 100° C., preferably 5° to 50° C.
`Reduction of compounds of formula (VIII) wherein
`W represents,
`for
`example,
`the
`groups
`-—(CH2)2N(CH3)CHO, —CH;CON(CH3)2, —CH-
`(OH)CH2N(CH3)2,
`—COCON(CI-I3);
`and
`
`i
`
`

`
`5,037,845
`
`9
`—COCHzN(CH3)2 may also be carried out using a
`metal hydride such as lithium aluminium hydride. This
`process may be carried out in a solvent, for example, an
`ether such as tetrahydrofuran, and conveniently at a
`temperature of from -10‘ to +100” C., preferably 50'’
`to 100° C.
`
`10
`example by reduction of a compound of general for-
`mula (X)
`
`5
`
`XSO2CH2
`
`X
`
`(
`
`)
`
`NH
`
`(wherein X is as previously defined and W is the group
`CH2CN or CH2CI-IO) or a salt or protected derivative
`thereof,
`in the presence of dimethylamine, using the
`general methods described above for general process
`(C).
`A compound of formula (IX) wherein X represents a
`halogen atom may be prepared for example by reacting
`the corresponding sulphonic acid derivative or a salt
`thereof with a halogenating agent such as a phosphorus
`halide or oxyhalide in an inert organic solvent e.g. phos-
`phorus pentachloride in dichloromethane. A sulphonic
`acid of formula (IX) where X is OH, may be prepared
`for example by acid or base catalysed hydrolysis of an
`ester of formula (IX), (i.e. a compound wherein X rep-
`resents the group OR11).
`Compounds of formula (X) and sulphonic acid deriv-
`atives of formula (IX) (wherein X is a hydroxy group)
`may be prepared by analogous methods to those de-
`scribed in European Published Patent Application No.
`145459 and ‘A Chemistry of Heterocyclic Compound-
`s—Indoles Part II’ Chapter VI edited by W. J. Hamil-
`ton (l972) Wiley Interscience, New York.
`According to a further general process (E) the com-
`pound of formula (I) may be prepared by reacting the
`compound of formula (XI)
`
`R12
`
`\
`
`H
`
`NSO2CI-I;
`
`CHgCH3N
`
`/
`
`\
`
`Rail)
`
`R14
`
`NH
`
`(wherein R12, R13 and R14 each represents hydrogen or
`a methyl group, at least one of R12, R13 and R14 being
`hydrogen) with a methylating agent. Methylating
`agents which may be used in this process include methyl
`halides (e.g. methyl iodide), methyl tosylate, or dimeth-
`ylsulphate. It will be appreciated the methylating agent
`should be used in sufficient quantity to introduce the
`required number of methyl groups. Thus for example
`when two of R12, R13 and R14 represent hydrogen at
`least two equivalents of the methylating agent should be
`employed. The reaction is conveniently carried out in
`an inert organic solvent such as an amide (e. g. dimethyl-
`formamide), an ether (e.g. tetrahydrofuran) or an aro-
`matic hydrocarbon (e.g. toluene) preferably in the pres-
`ence of a base. Suitable bases include, for example, alkali
`metal hydrides, such as sodium or potassium hydride;
`alkali metal amides, such as sodium amide; alkali metal
`carbonates, such as sodium carbonate; or alkali metal
`alkoxides such as sodium or, potassium methoxide,
`ethoxide or t-butoxide; .or tetrabutylammonium fluo-
`ride. When a methyl halide is employed as the methylat-
`ing agent, the reaction may also be carried out in the
`
`IO
`
`A particular embodiment of general process (C) in-
`volves the reduction of a compound of formula (VIII)
`wherein W is the group ——CHzCN, for example, by
`catalytic reduction with hydrogen in the presence of a
`catalyst such as palladium on charcoal or rhodium on
`alumina in the presence of dimethylamine. The reduc-
`tion may be effected in a suitable solvent such as an
`alcohol, e.g. methanol or ethanol.
`The starting materials or intermediate compounds of 15
`general formula WIII) may be prepared by analogous
`methods to those described in UK Published Patent
`Application No. 2124210, or by modification of the
`5-position substituent as in process (D) below.
`According to another general process (D), the com-
`pound of formula (I) may be prepared by reacting a
`compound of formula (IX)
`
`20
`
`XSO3CI-I3
`
`CI-I3CH3N
`
`(IX? 25
`
`/
`
`\
`
`CH3
`
`CH3
`
`N
`H
`
`(where X represents a leaving atom or group) or a salt
`thereof, with methylamine.
`Examples of suitable leaving atoms or groups X in the
`compounds of general formula (IX) include a halogen
`atom (e.g. a fluorine, chlorine or bromine atom) or a
`group OR11 where R11 represents a hydrocarbyl group
`such as an aryl group, e. g. phenyl. The aryl group may
`be unsubstituted or substituted by one or more substitu-
`ents such as halogen atoms; or nitro; cyano; amino; alkyl
`e.g. methyl; alkoxy e.g. methoxy; acyl, e.g. acetyl and
`alkoxycarbonyl e.g. ethoxycarbonyl groups. The leav-
`ing atom or group represented by X is preferably a
`phenoxy group.
`.
`The reaction is conveniently carried out in the pres-
`ence of a solvent and may be effected in an aqueous or
`non-aqueous reaction medium.
`The reaction medium may thus comprise one or more
`organic solvents, such as ethers, e. g. dioxan or tetrahy-
`drofuran; amides e.g. N,N-dimethylforrnamide or N-
`methylpyrrolidone; alcohols e.g. methanol or ethanol;
`esters e. g. ethyl acetate; nitriles e. g. acetonitrile; haloge-
`nated hydrocarbons e.g. dichloromethane; and tertiary
`amines e.g. triethylamine or pyridine, optionally in the
`presence of water. In some cases methylamine may
`itself serve as the solvent.
`If desired the aminolysis may be effected in the pres-
`ence of a base, such as an alkali metal carbonate or
`bicarbonate (e. g. sodium or potassium carbonate or
`bicarbonate); a tertiary amine (e. g.
`triethylamine or
`pyridine); an alkoxide (e. g. sodium t-butoxide) or a
`hydride (e.g. sodium hydride).
`The reaction may conveniently be effected at a tem-
`perature of from -20” to +150" C.
`formula (IX)
`The starting materials of general
`wherein X represents a group OR11 may be prepared for
`
`30
`
`35
`
`45
`
`S0
`
`S5
`
`65
`
`

`
`11
`
`5,037,845
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`presence of an acid scavenger such as propylene or
`ethylene oxide. The reaction may conveniently be ef-
`fected at temperatures of from 0° to 60° C., preferably
`20° to 40° C.
`
`The compound of formula (XI) may be prepared by
`any of the processes (A)—(E) described herein, or as
`described in UK Published Patent Application No.
`2124-210A.
`
`According to a further general process (F), the com-
`pound of formula (I) may be prepared by dealkylation
`of a quaternary ammonium salt of formula (XII):
`
`I-I3C
`
`\
`
`NSOp_CH2
`
`H
`
`(XII)
`
`CH3
`
`45/
`Cl-IzCHzN<R15 E9
`CH3
`
`NH
`
`or
`group
`a methyl
`represents
`R15
`(wherein
`—CH2Cl-I2R15 where R15 is an electron-withdrawing
`group, and E9 is an anion e.g. a halide ion).
`Electron-withdrawing groups R15 include —SO3R0,
`—CO2‘7, COR“, CH0 and CN, where R” is a hydro-
`carbyl group, e.g. an alkyl, aryl or aralkyl group. R15is
`preferably a phenoxysulphonyl group.
`Where R15 represents a methyl group the dea1l<yla-
`tion may be effected by heating the compound (XII) in
`aqueous ethanolamine, at a temperature in the range 50°
`to 200° C. A group —CH2CH2R15 may be removed by
`treatment with a base such as an alkali metal carbonate,
`e. g. sodium carbonate or an alkali metal hydroxide e.g.
`sodium hydroxide.
`Compounds of formula (XII) where R15 represents a
`methyl group may be prepared by alkylating the 3-
`aminoethyl or 3-methylaminoethyl compound corre-
`sponding to compound (I), for example as described for
`general process (E).
`Compounds of formula (XII) in which R15 represents
`the group