NL8503424A - INDOOL CONNECTIONS; METHOD FOR PREPARING THEREOF PHARMACEUTICAL PREPARATIONS. - Google Patents

Description

- \ "ΐ 't. *

J

VO 7529

Title: Indbol compounds; method for preparing them; pharmaceutical preparations.

The invention relates to indole derivatives, to methods for their preparation, to pharmaceutical compositions containing them and to their medical use, in particular to compounds of compositions for use in the treatment of migraine.

Migraine pain is associated with excessive widening of the blood vessels in the skull, and known treatments for migraine include the administration of compounds with vasoconstrictor properties, such as ergotamine. However, Ergotamine is a non-selective vasoconstrictor that narrows blood vessels throughout the body and has unwanted and dangerous side effects. Migraines can also be treated by the administration of an analgesic, usually in combination with an antiemetic, but such treatments are of limited value.

Accordingly, there is a need for a safe and effective drug for the treatment of migraine, which can be used prophylactically or used to relieve an existing headache, and a compound with a selective vasoconstrictor activity could play such a role.

A group of indole derivatives with strong and selective vasoconstrictor activity has now been found.

The present invention provides an indole compound of the general formula I wherein R 1 is a hydrogen atom, a C 1-8 alkyl group, C 1 -cycloalkyl group or C 1. alkenyl group, or represents a phenyl or phenyl (C 1 -6) alkyl group, wherein the phenyl ring is unsubstituted or substituted by one or two substituents selected from alkoxy, hydroxy, halogen, a group R 1, RgNCO-, wherein Rg and Rg ( which may be the same or different) each represent a hydrogen atom or an alkyl group, or a group R 1 RgN- wherein R 1? and Rg (which may be the same or different) each represents a hydrogen atom or an alkyl group, or R8 RgN- represents a saturated monocyclic 5-7 ring; R2 represents a hydrogen atom or a g alkyl group; or R 2 and R 2 together with the nitrogen atom to which they are attached form a saturated monocyclic 5-7 ring; y-. λ * - a § v i

Vei'L4'i *

T

- 2 - and R4, which may be the same or different, each represent a hydrogen atom, an alkyl group, or a 2-propenyl group; and n is an integer from 2-5; as well as physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The scope of the invention includes all optical isomers of compounds of formula I and their mixtures, including the racemic mixtures thereof. All geometric isomers of compounds of general formula I are also included in the invention.

With reference to the general formula I, the alkyl-10 groups may be straight or branched chain alkyl groups, such as methyl, ethyl or isopropyl groups. The cycloalkyl group can be, for example, a cyclopentyl or cyclohexyl group. Alkenyl groups which can be represented by R 1 include propenyl and butenyl groups. It will be clear that the double bond in such alkenyl groups is not adjacent to the nitrogen-15 atom.

When R 1 represents a substituted phenyl group or substituted phenyl (C 1 alkyl group), an alkoxy substituent may be, for example, methoxy, and a halogen substituent may be, for example, fluorine, chlorine or bromine. Substituents of the formula R 1 R 9 NCO 3 include N-methylcarbamoyl and examples of the substituents R 1, RgN- include amino, dimethylamino and pyrrolidino The substituent may be in the ortho, meta - or para - position.

The alkyl portion of the phenyl (C 1-6 alkyl group) may be, for example, a methyl or ethyl group.

A preferred class of compounds of general formula I.

consists of those wherein R 1 represents a hydrogen atom, an alkyl group, or C 1-6 alkenyl group, or a phenyl or phenyl (C 1) alkyl group, which may be substituted by the phenyl ring as previously described.

In the compounds of the general formula I, it is preferred that one of R 1 and R 1 represents a hydrogen atom.

A further preferred class of compounds is that wherein R8 and R19, which may be the same or different, each represent a hydrogen atom or an alkyl group.

Another preferred class of compounds of the invention is that wherein n equals 2 or 3.

8503424 * ............ - * - 3 -

When a substituted phenyl group or substituted phenyl (C 1 -alkyl group), preferred substituents C 1 include 2alkyl xy (e.g. methoxy), halogen (e.g. chlorine), a group R 1 RgNCO -, or a group R 1 RgNCO -. a group 5 R is RcNCO-, it is particularly preferred that R_ and R- independently represent a hydrogen atom or a methyl group When the substituent is a group R_R0N-, R_ and R which are the same or different , preferably a hydrogen atom or a methyl group, or together form a pyrrolidino ring.

A particularly preferred class of compounds within the scope of the general formula I is that in which an alkyl group (eg, "methyl"), an alkenyl group (eg, 2-propenyl) or a phenyl, Cl-2-yl, yl9Rep, represents wherein the phenyl ring may be unsubstituted or substituted as previously described; R 2 represents a hydrogen atom, R 1 and R 2, which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group; and n is equal to 2 or 3; as well as their physiologically acceptable salts and solvates (e.g. hydrates).

Preferred compounds of the invention include: 3- (2-aminoethyl) -N (phenylmethyl) -1H-indole-5-propanamide; 3- (2-aminoethyl) -N - ([4- (1-pyrrolidinyl) phenyl] methyl) -1H-indole-5-propanamide; 3- [2- (dimethylamino) ethyl] -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide; 3- (2-aminoethyl) -N- (2-propenyl) -1H-indole-5-propanamide; 3- (2-aminoethyl) -N - [(4-methoxyphenyl) methyl] -1 H -indole-5-propanamide; as well as physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Suitable physiologically acceptable salts of the indole compounds of the general formula (I) include acid addition salts formed with inorganic or organic acids, for example hydrochlorides, hydrobromides, sulfates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, maleates, succinates and sulfonates, for example mesylates. Other salts may be useful in the preparation of compounds of formula I, for example creatinine sulfate adducts.

85C5 ** 4 * - * s r - 4 -

It will be understood that the invention extends to other physiologically acceptable equivalents of the compounds of the invention, for example physiologically acceptable compounds which are converted to the mother compound in vivo. Examples of such equivalents include physiologically acceptable, metabolically labile N-acyl derivatives.

Compounds of the invention selectively narrow the cervical arterial bed of anesthetized dogs, while negligibly affecting blood pressure. The selective vasoconstrictor activity of compounds of the invention has been demonstrated in vitro.

Compounds of the invention are useful for treating pain resulting from widening of the blood vessels in the skull, especially migraine and cluster headache.

The invention therefore also provides a pharmaceutical composition suitable for use in human medicine, comprising at least one compound of formula I or a physiologically acceptable salt or solvate (eg hydrate) thereof and brought in a form for administration by any suitable away. Such formulations can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.

The compounds of the invention can therefore be brought into a form for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical preparations may be in the form of, for example, tablets or capsules, which have been prepared by conventional means using pharmaceutically acceptable excipients such as binders (eg pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g.

magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods known per se. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product 8503424-5 for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (eg sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g., almond oil / oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The liquid preparations may also contain conventional buffers, flavors, dyes and sweeteners as appropriate.

For buccal administration, the compositions may be in the form of tablets or lozenges, which are formulated in a conventional manner.

The compounds of the invention can be formulated for parenteral administration by injection or continuous infusion. Preparations for injection can be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative.

The compositions may be in forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending agents, stabilizers and / or dispersants, and / or agents to adjust the tonicity of the solution. Alternatively, the active ingredient may be in the form of a powder for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be found sases set in rectal preparations such as suppositories or retention clisms, eg containing conventional suppository bases such as cocoa butter or other glycerides.

For administration by inhalation, the compounds of the invention are conveniently provided in the form of an aerosol spray presentation from pressure packs, using a suitable propellant, eg dichloradifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or mister. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve capable of delivering a V O tr-6 measured amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated, containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or.

5 starch.

A proposed dose of the compounds of the invention for oral, parenteral, buccal, or rectal administration to humans (with an average body weight of, for example, about 70 kg) for the treatment of migraine is 0.1 to 100 mg of the active ingredient per dosage unit which, for example, could be administered up to 8 times a day, usually 1 to 4 times a day. It will be understood that routine dose variations may be required depending on the age and weight of the patient and the severity of the condition being treated.

For oral administration, a dosage unit will preferably contain 0.5 to 50 mg, for example 2 to 40 mg of the active ingredient. A dosage unit for parenteral administration will preferably contain 0.2 to 50 mg of the active ingredient.

Aerosol formulations are preferably controlled such that each metered dose or "puff" delivered from a pressurized aerosol contains 0.2 to 2 mg of a compound of the invention and each dose is administered via capsules or cartridges in an inhaler or insuffator. 2 to 20 mg. The total daily dose by inhalation will range from 1 mg to 100 mg. The administration * 25 may be several times a day, for example 2 to 8 times, with 1, 2 or 3 doses being given each time.

The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents such as analgesics, anti-inflammatory and anti-nausea agents.

According to another aspect of the invention, compounds of formula I and physiologically acceptable salts or solvates (e.g. hydrates) thereof can be prepared according to the general methods described below. In the following methods, R., R-, R_, R.

14 3 * «35 and n as defined for general formula I, unless otherwise indicated.

λ e; x.V. ^ i i · '' * u o. - - 7 -

According to one general method (A), a compound of the general formula I can be prepared by condensing an amine of the formula R ^ i ^ NH with an acid of the general formula II or a corresponding acylating agent, or a salt (e.g. an organic or inorganic acid addition salt such as the hydrochloride, hydrobromide, sulfate or maleate salt, or creatinine sulfate adduct) or a protected derivative thereof.

The reaction, which comprises a condensation of the amine with the acid of the general formula II, is preferably carried out in the presence of a coupling agent, for example carbonyldiimidazole or a carbodiimide such as Ν, Ν'-dicyclohexylcarbodiimide. The condensation reaction can be carried out in a suitable reaction medium, preferably an anhydrous medium, preferably at a temperature of -50 to + 50 ° C, most preferably -5 to + 30 ° C. Suitable solvents include halogenated hydrocarbons, eg dichloromethane, nitriles, eg acetonitrile, amides, eg N, N-dimethylformamide and ethers, eg tetrahydrofuran, as well as mixtures of two or more such solvents. The reaction can also be carried out in the absence of a coupling agent in a suitable reaction medium such as a hydrocarbon (eg toluene or xylene), preferably at a temperature of 50 to 120 ° C.

Acylating agents corresponding to the acid of the general formula II, and which can be used in the preparation of compounds of the formula I, include acid halides, for example acid chlorides.

Such acylating agents can be prepared by reacting an acid of the general formula II or a salt or protected derivative thereof with a halogenating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride. Other suitable acylating agents that can be used in the preparation of the compound of formula I include alkyl esters such as the methyl ester, activated esters (eg the 2- (1-methylpyridinyl) ester) and mixed anhydrides (eg formed with pivaloyl chloride, a sulfonyl halide such as methanesulfonyl chloride or a haloformate, e.g. a lower alkyl haloformate). Acids of formula II may themselves be prepared by, for example, cyclization of a suitable hydrazine compound, in an analogous manner to the method described below.

When an acylating agent corresponding to the acid of the general formula II is used, the condensation process can be carried out in aqueous or non-aqueous reaction media and preferably at a temperature of -70 to + 150 ° C. The condensation reaction using an acid halide, anhydride or activated ester can therefore be carried out in a suitable reaction medium such as an amide, for example Ν, Ν-dimethylformamide, an ether, for example tetrahydrofuran or diethyl ether, a nitrile for example acetonitrile, a halogenated hydrocarbon for example dichloromethane or mixtures thereof, optionally in the presence of a base such as a tertiary amine, for example triethylamine or pyridine, and preferably at a temperature of -5 to + 25 ° C. The condensation reaction using an alkyl ester can be carried out in a suitable reaction medium such as an alcohol, for example methanol, an amide for example dimethylformamide, an ether for example tetrahydrofuran or diethyl ether, or mixtures thereof and preferably at a temperature of 0 up to 100 ° C. In some cases, the amine HNR ^ I ^ itself can act as the reaction solvent.

If it is desired to prepare a compound of formula I, wherein R 1 and both represent hydrogen, the condensation can be carried out using ammonia, which can be used, for example, in the form of aqueous ammonia or in a solvent such as methanol.

25. Compounds of general formula II and corresponding acylating agents, such as the alkyl esters, are new compounds and form a further aspect of the present invention.

According to another general method B, compounds of formula I can be prepared by the cyclization of a compound of general formula III, wherein Q is the group NR ^ R ^ (or a protected derivative thereof) or represents a leaving group such as a a halogen atom (e.g., chlorine or bromine) or an acyloxy group (e.g., a carboxylic acid or sulfonic acid acyloxy group such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitro-35 benzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group).

Λ F · Λ “7 I 5-¾ t 'u o% l 4 - 9 -

The reaction can conveniently be conducted in aqueous or non-aqueous reaction media, and at temperatures from 20 to 200 ° C, preferably 50 to 125 ° C.

Particularly suitable embodiments of the method are described below.

When Q is the group NR ^ R ^ (or a protected derivative thereof), the process is preferably carried out in the presence of polyphosphate ester in a reaction medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane, or mixtures thereof. Polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the method described in "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sons 1967).

The cyclization, on the other hand, can be carried out in an aqueous or non-aqueous reaction medium, in the presence of an acidic catalyst. When an aqueous medium is used, it may be an aqueous organic solvent such as an aqueous alcohol (eg methanol, ethanol or isopropanol) or an aqueous ether (eg dioxane or 20-tetrahydrofuran) or mixtures of such solvents, and the acid catalyst may be eg an inorganic acid such as concentrated hydrochloric or sulfuric acid or an organic acid such as acetic acid (in some cases the acidic catalyst can also serve as the reaction solvent). In an anhydrous reaction medium, which may include one or more ethers (eg as previously described) or esters (eg ethyl acetate), the acidic catalyst will generally be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride.

When Q is a leaving group such as a chlorine or bromine-30 atom, the reaction can be carried out in an aqueous organic solvent, such as an aqueous alcohol (for example, methanol, ethanol or isopropanol), or an aqueous ether (for example, dioxane or tetrahydrofuran) in the absence of an acidic catalyst, preferably at a temperature of from 20 to 200 ° C, preferably from 50 to 125 ° C. This process leads to the formation of a compound of formula I wherein Η ”il V ü

Kt 3 ^ I ή) - - when R ^ are both hydrogen atoms.

According to a particular embodiment of this method, compounds of formula I can be prepared directly by reacting a compound of general formula IV or a salt thereof with a compound of formula V (wherein Q is as defined above) or a salt or protected derivative thereof (such as an acetal or ketal formed, for example, with an appropriate alkyl orthoformate or diol, or protected as a bisulfite addition complex) using the appropriate conditions described above for the cyclization of compounds of the general formula III. It will be understood that in this embodiment of the cyclization process B, a compound of the general formula III is formed as an intermediate, and can be reacted in situ to form the desired compound of the general formula I.

Compounds of general formula III may be isolated as intermediates, if desired, during the process of preparing compounds of formula I, wherein the compound of formula IV or a salt or protected derivative thereof is reacted with a compound of formula V, or a salt or protected derivative thereof, in a suitable solvent, such as an aqueous alcohol (eg methanol) at a temperature of eg 20 to 30 ° C. When an acetal or ketal of a compound of formula V is used, the reaction may need to be conducted in the presence of an acid (e.g. acetic acid or hydrochloric acid).

For example, compounds of general formula IV can be prepared from the corresponding nitro compounds, using the conventional procedures.

A further general method C for preparing compounds of the general formula I comprises a reaction of a compound of the general formula VI (wherein Y is an easily displaceable group) or a protected derivative thereof with an amine of the formula R 1 R ^ NH.

The displacement reaction may conveniently be carried out on that compound of formula VI wherein the substituent group Y is a halogen atom (eg chlorine, bromine or iodine) or a group ORg, wherein ORg represents, for example, an acyloxy group which may be derived from a. carboxylic acid or sulfonic acid, for example an acetoxy, chloroacetoxy,

ji * »7 *» Λ 9 T

- 11 - dichloroactoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyl oxy or Qethanesulfonyloxy group.

The displacement reaction can conveniently be carried out in an inert organic solvent (optionally in the presence of water), examples of which are alcohols, eg ethanol; cyclic ethers, for example dioxane or tetrahydrofuran; acyclic ethers, for example diethyl ether; esters, for example ethyl acetate; amides, for example N, N-dimethylformamide; and ketones, for example acetone or methyl ethyl ketone, at a temperature of from -10 to + 150 ° C, preferably from 20 to 50 ° C.

The compounds of the general formula VI wherein Y represents a halogen atom can be prepared by reacting a hydrazine of the general formula IV with an aldehyde or ketone (or a protected derivative thereof) of the formula V wherein Q represents a halogen atom , In an aqueous alkanol (eg methanol) containing an acid (eg acetic acid or hydrochloric acid). Compounds of formula VI wherein Y is the group ORg may be prepared from the corresponding compound wherein Y is a hydroxyl group by acylation or sulfonylation with the appropriate activated compounds (eg anhydride or sulfonyl chloride) using conventional techniques. The intermediate alcohol obtained can be prepared by cyclization of a compound of formula III, wherein Q is a hydroxyl group (or a protected derivative thereof) under standard conditions.

Compounds of the formula I can also be prepared according to another general method D which comprises a reduction of a compound of the general formula VII [wherein W is a group which can be reduced to form the required - (C 1 -N NR-1). R 1 group or to form a protected derivative of - (C 1 -N NRgR-1 and A represents the group - (CEt 1) - - as defined herein or is a group that can be reduced to - (CH 2) ) -3 or a salt or protected derivative thereof.

2 n

The 3-position - (CIL, -) and groups required can be formed by reduction steps that occur individually or together in any suitable manner.

The groups A that can be reduced to form the required group - (CH-) - include corresponding unsaturated groups, a n -PT. * * .T * * V - * - * - 12 - such as C2 g alkenyl groups.

Examples of groups represented by the substituent W include - (CH 2 NCy -CH = CHNO 2? -CH 2 CN; -CH 2 CHO; -COCH 2 Z; -CH 2 CH = NOH; and -CH (OH)? (Where Z is an azido group) or the group is -NR ^ R ^ or is a protected derivative thereof).

Groups that can be reduced to the - (CH2) 2 - group at the 3-position include the corresponding unsaturated group and corresponding groups containing a hydroxyl group or a carbonyl function.

Groups that can be reduced to the -NR 1 R 1 group where 10 and R 1 both represent hydrogen include nitro, azido, hydroxyimino and nitrile groups. In the latter case, reduction gives the group -CH2NH2 and thus provides a methylphen group for the - (CH2) 2 part.

The required -NR 1 R 2 group where R 1 and / or R 4 are other than hydrogen can be prepared by reduction of a nitrile -CH 2 CN or an aldehyde -CH 2 CHO in the presence of an amine, R 1 R 2 NH.

A particularly suitable method for preparing a compound of formula I in which R 1 and / or R 2 is other than hydrogen consists of a reductive alkylation of the corresponding compound in which R 2 and / or R 4 represents hydrogen with an appropriate aldehyde or ketone (e.g. formaldehyde or acetone) in the presence of a suitable reducing agent. In some cases (for example, for the introduction of the group or groups R and / or R when these represent methyl), the 4 aldehyde (eg formaldehyde) can be condensed with the amine and then the intermediate thus formed can be reduced using a suitable reducing agent.

It will be understood that the choice of reducing agent and reaction conditions will depend on the nature of the group W, as well as on the other groups already present in the molecule.

Suitable reducing agents which can be used in the above-mentioned process for the reduction of compounds of formula VII in which W for example the groups - (CH2) 2NO2, -CH = CHNO2, - (CH2) 2N3, -CH2CN, -CH2CH = NOH and -CH (OH) CH 2 NR 3 R 4 include hydrogen in the presence of a metal catalyst, for example, Raney Nickel or a noble metal catalyst such as platinum, platinum oxide, Ö 0 1 / - 13 palladium, palladium oxide or rhodium, which can be, for example, charcoal, kieselguhr or alumina can be worn. In the case of Raney Nickel, hydrazine can also be used as a hydrogen source. This process can conveniently be carried out in a solvent such as an alcohol, for example ethanol, an ether, for example dioxane or tetrahydrofuran, an amide, for example dimethylformamide or an ester, for example ethyl acetate, and at a temperature of -10 to + 50 ° C, preferably -5 to + 30 ° C.

The reduction process can also be carried out on compounds of formula VII in which, for example, W is the groups - (CEL,) 2NO2 "CH ^ CHNC ^ / - (CH ^) 2N3" CH (OH) Cl ^ NR ^ R ^ or - COC 2 Z (wherein Z is as previously defined) using an alkali or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, which process may conveniently be carried out in an alcohol such as propanol or ethanol, or a nitrile such as acetonitrile, and at a temperature of from 10 to 100 ° C, preferably from 50 to 100 ° C. In some cases, the reduction using a borohydride can be carried out in the presence of cobalt (II) chloride.

Reductive alkylation of a compound of formula VII can be carried out using an alkali or alkaline earth metal borohydride or cyanoborohydride. The reaction can be carried out in an aqueous or non-aqueous reaction medium, preferably in an alcohol (eg methanol or ethanol) or an ether (eg dioxane or tetrahydrofuran), optionally in the presence of water.

The reaction can conveniently be carried out at a temperature in the range of 0 to 100 ° C, preferably 5 to 50 ° C. .

A particular embodiment of the general process D comprises the reduction of a compound of formula VII wherein W represents the group 30 -C 1 CN, for example, by catalytic reduction with hydrogen in the presence of a catalyst such as palladium on charcoal or rhodium on alumina, optionally in presence of an amine HNR ^ Rj. The reduction can be carried out in a suitable solvent such as an alcohol, for example methanol or ethanol.

A compound of the general formula I wherein R ^ is a hydrogen-* »v- Λν -. can be prepared by hydrogenolysis of a corresponding compound in which there is a benzyl group, for example, with hydrogen in the presence of a catalyst, for example, 10% palladium on carbon.

5 Suitable reducing agents used in the reduction of group A.

can be used include hydrogen in the presence of a metal catalyst. Suitable metal catalysts and conditions for the reduction process are as described for the group W reduction.

The starting materials or intermediates of formula VII wherein 10 W represents - (CH2) 2NO2 · CH = CHNC> 2 / -CH2 CN or -C0CH2 Z may be prepared by analogous methods as described in British Patent Publication 2,035,310, and "A Chemistry of Heterocyclic Compounds -Indoles Part II", Chapter VI, published by WJ Houlihan (1972) Wiley Interscience, New York.

Compounds of formula VII wherein W represents the group -CH 2 CHO can be prepared by oxidation (eg with Jones' reagent) of a compound of formula VI wherein Y is a hydroxyl group. A compound of formula VII in which W represents a group -CH 2 CH = NOH can be prepared by treating the corresponding aldehyde with hydroxylamine hydrochloride under standard conditions.

The intermediate of formula VII wherein W represents the group ~ (CH2) 2N2 can be prepared from a compound of formula VI wherein Y is a halogen atom, using standard procedures.

Standard reducing agents such as sodium borohydride can be used to prepare a compound of formula VII wherein W represents the group -CH (OH) CH 2 NR 3 R 4, from the corresponding compound of formula VII, wherein W represents the group -COC 1 NR 1 R 4.

The intermediates of formula VII wherein A represents a C 1-4 alkenyl group may be prepared by a compound of the general formula VIII (wherein W is as defined for the general formula VII and p equals zero or an integer from 1 to 3) reacting with, for example, a suitable phosphonium salt, using standard conditions.

Compounds in which R 1 and R 2 both represent hydrogen atoms can be prepared according to a further general method E, which comprises 8503424-15 - a reaction of a nitrile of the general formula IX or a salt or a protected derivative thereof, with a suitable oxygen-containing compound . For example, a nitrile of the general formula IX can be hydrolyzed with an acid or a base under controlled conditions.

Acids and bases that can be used in this method include concentrated sulfuric acid; concentrated hydrochloric acid; a mixture of concentrated sulfuric acid, acetic acid and water (1: 1: 1); polyphosphoric acid; sodium t-butoxide in refluxing t-butanol; sodium hydroxide in aqueous ethanol in the presence of hydrogen peroxide; a base in the form of a resin; or boron trifluoride in acetic acid. The reaction can conveniently be carried out at temperatures from -10 to 100 ° C.

Compounds of general formula IX can themselves be prepared by, for example, cyclization of an appropriate hydrazone, in an analogous manner to Method B.

According to a further general method F, a compound of formula I according to the invention or a salt or protected derivative thereof can be converted into another compound of formula I according to conventional procedures.

For example, a compound of the general formula I wherein 20 represents one or more of the symbols R 1, R 1 and alkyl groups can be prepared from the corresponding compounds of formula I wherein one or more of R 1, R 2 / R 1 and R ^ represent hydrogen atoms, by reaction with a suitable alkylating agent such as a compound of formula R ^ L, (wherein R ^ represents the desired R ^, R2, or R ^ group and L represents a leaving group such as a halogen atom or a tosyl group ) or a sulfate (R) „SO ,. The alkylating agent can therefore be X 1, for example, an alkyl halide (for example, methyl or ethyl iodide), alkyl tosylate (for example, methyl tosylate) or dialkyl sulfate (for example, dimethyl sulfate).

The alkylation reaction can conveniently be conducted in an inert organic solvent such as an amide (eg dimethylformamide), an ether (eg tetrahydrofuran) or an aromatic hydrocarbon (eg toluene), preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides such as sodium or potassium hydride; alkali metal amides such as sodium amide; λ λ τ /. *) λ · * j- "J * v - 16 - alkali metal carbonates such as sodium carbonate; alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or t-butoxide; and tetra-butylammonium fluoride. When an alkyl halide is used as the alkylating agent, the reaction may also be conducted in the presence of an acid scavenger such as propylene or ethylene oxide. The reaction can conveniently be carried out at a temperature from -20 ° C to 100 ° C.

Compounds of formula I wherein a cycloalkyl, alkenyl or phenylalkyl group and / or one or both of a R 1 and propenyl may likewise be prepared using a suitable compound 10 of the formula R L or (R).

X X “

According to another general method G, a compound of the general formula I according to the invention or a salt thereof can be prepared by subjecting a protected derivative of the general formula I or a salt thereof to a reaction whereby the protecting group or groups be removed.

Thus, at an earlier stage in the reaction sequence for the preparation of a compound of the general formula I or a salt thereof, it may have been necessary or desirable to protect one or more sensitive groups in the molecule to avoid undesired side reactions. For example, it may be necessary to protect the group NR ^ R ^, where R ^ and / or R4 represent hydrogen, by protonation or with a group that can be easily removed at the end of the reaction sequence. Such groups can be, for example, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; or acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

In some cases, it may also be desirable for the indole nitrogen atom to be protected with, for example, an aralkyl group such as benzyl.

The subsequent cleavage of the protecting group or groups can be accomplished by conventional procedures. For example, an aralkyl group such as benzyl can be cleaved from a catalyst (e.g. palladium on charcoal) or sodium and liquid ammonia by hydrogenolysis; an acyl group such as N-benzyloxycarbonyl can be renewed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation. λ = - ï'i ’f -m J-5 'flil /' \ p 3 il ** -. , ut! Wü? J a-λ * -17- deleted. The phthaloyl group can be removed by hydrazinolysis (for example, by treatment with hydrazine hydrate) or by treatment with a primary amine (for example, methylaraine).

As will be appreciated, in some instances of the general methods A through F described above, it may be necessary or desirable to protect any sensitive groups in the molecule as just described. Therefore, a reaction step involving a deprotection of a protected derivative of the general formula I or a salt thereof can be carried out after any of the previously described methods A to F inclusive.

Therefore, according to a further aspect of the invention, the following reactions may be carried out in any suitable order if necessary and / or desired after any of the methods A to F: (i) removal of any protecting groups; and (ii) converting a compound of the general formula I or a salt thereof into a physiologically acceptable salt or solvate (eg hydrate) thereof.

When it is desired that a compound according to the invention be isolated in the form of a salt, for example in the form of an acid addition salt, this can be achieved by treating the free base of the general formula I with an appropriate acid, preferably with an equivalent amount, or with creatinine sulfate, in a suitable solvent (e.g. aqueous ethanol).

The starting materials or intermediates for the preparation of the compounds of the invention can be prepared by analogous methods as described in British Patent Publication 2,035,310.

As they can be used as the last major step in the preparation frequency, the general method mentioned above for the preparation of the compound of the invention can also be used for intermediate introduction of the desired groups into the preparation of the required compound. For example, the required group can be introduced in the 5-position before or after cyclization to form the indole core. It is therefore to be understood that in such multistage processes the order of reactions should be chosen so as not to interfere with the reaction conditions present in the molecule that are desired in the final product.

* - »^» i · »* - 18 -

The invention is further illustrated by the following examples. All temperatures are expressed in ° C.

Chromatography was performed either in the conventional manner with silica gel (Merck, Kieselgel 60, Art. 7734 or 7747) or by flash-5 chromatography (WC Still, M. Kahn and A. Mitra, J. Org. Chem. 1978, 43, 2933) to silica (Merck 9385) and thin layer chromatography (tlc) to silica (Macherly-Nagel, Polygram) unless otherwise indicated.

The following abbreviations define the eluent used for chromatography and t.l.c. 10 A) Dichloromethane-ethanol-0.88 ammonia 50: 8: 1 B) Dichloromethane-ethanol-0.88 ammonia 35: 8: 1 C) Dichloromethane-ethanol-0.88 ammonia 25: 8: 1 D ) Dichloromethane ethanol-0.88 ammonia 40: 8: 1 E) Dichloromethane ethanol-0.88 ammonia 20: 8: 1 15 F) dichloromethane ethanol-0.88 ammonia 100: 8: 1 G) Dichloromethane ethanol -0.88 ammonia 75: 8: 1 H) Ethyl acetate-cyclohexane-acetic acid 2: 4: 1 I) Ethyl acetate-ethanol-water-0.88 ammonia 25: 15: 1: 1 J) Ethyl acetate-ethanol- water-0.88 ammonia 25: 15: 8: 2 20 K) Toluene-ethanol-0.88 ammonia 78: 20: 2 L) Dichloromethane-ethanol-0.88 ammonia 78: 20: 2 M) Dichloromethane-ethanol- 0.88 ammonia 200: 8: 1 N) Toluene ethanol-0.88 ammonia 39: 10: 1

Intermediates were routinely checked for purity using t.l.c. using UV light for detection and spray reagent such as potassium permanganate (KMnO4). In addition, index intermediates were detected by spraying with aqueous cerium sulfate (CelV) and tryptamines by spraying with a solution of iodoplatinic acid (IPA) or cerium sulfate.

30 Protons (^ H) nuclear magnetic resonance (nmr) spectra were obtained at 90 MHz with a Varian EM 390 instrument or at 250 MHz with a Bruker AM or WM 250 instrument, s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, and br = wide.

t - 19 -

Reaction vials are 4 ml strong wall glass vials with a screw cap and Teflon surface disc supplied by Pierce and Warriner (UK) Ltd.

The following abbreviations are used in Tables 1 and 2: 5 TEA - triethylamine PC - pivaloyl chloride

EtOH ethanol

MeOH - methanol IPA - isopropanol 10 EtOAC - ethyl acetate IPAC - isopropyl acetate CH - cyclohexane Bu - butan-2-one AC - acetone 15 HH - hydrazine hydrate

Intermediate 1 4-Hydrazineobenzene-propanoic acid hydrochloride

To a stirred suspension of 4-aminobenzene-propanoic acid (3.30 g) in 25 ml of concentrated hydrochloric acid was added a solution of 20 1.45 g of sodium nitrite in 10 ml of water at a rate such that the temperature did not rise above + 3 ° C. When the addition was complete, the solution was stirred at 0 ° C for 10 minutes. The mixture was added to a stirred solution of 22.5 g of tin (II) chloride dihydrate in 15 ml of concentrated hydrochloric acid at -10 ° C at a rate such that the temperature did not rise above -5 ° C. The resulting suspension was allowed to warm to room temperature over a period of 1 hour. The solid was collected by filtration, washed with 50 ml of ethanol, 100 ml of ether and dried under reduced pressure to afford the title compound as a powder (3.9 g) mp 205-206 ° C (decomposition). Crystallization from 2-propanol gave an analytically pure sample with a melting point of 209-210 ° C (decomposition).

85 0 ·: i- v - 20 -

Intermediate 2 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindole-2-yl) ethyl] -1H-indole-5-propanoic acid

A mixture of intermediate 1 (5.8 g) and 2- (4,4-diethoxybutyl) -5 1H-isoindole-1,3 (2H) -dione (7.79 g) was refluxed in 150 ml of water 50 ml of acetic acid for 2 hours. The cooled suspension was extracted with 2 x 150 ml ethyl acetate, and the combined organic extracts were washed with 100 ml water and 100 ml brine. Evaporation of the solvent gave a gum which dissolved in ethyl acetate 10 and adsorbed on 30 g of silica. This was added to a column of silica and eluted (H). The appropriate fractions gave a powder which crystallized from 100 ml of ethyl acetate cyclohexane [1: 1] to give the title compound as a powder (5.0 g) mp 171-172 ° C.

15 Intermediate 3 4- Hydrazinobenzene butanoic acid, hydrochloride

To a stirred suspension of 5.37 g of 4-aminobenzenebutanoic acid in 37.5 ml of concentrated hydrochloric acid at -5 ° C was added a solution of 2.18 g of sodium nitrite in 15 ml of water at a rate such that the temperature does not exceed +2 ° C rose. When the addition was complete, the mixture was stirred for 10 minutes, then added to a stirred solution of 33.75 g of tin (II) chloride dihydrate in 25 ml of concentrated hydrochloric acid at -10 ° C at a rate such that the temperature did not rise above -5 ° C. After stirring the resulting suspension for 30 minutes, the solid was collected by filtration, washed with 100 ml of ether and dried. Crystallization from 100 ml of ethanol and 100 ml of isopropyl acetate gave the title compound as a powder (3.13 g), mp 199-201 ° C.

Intermediate 4 30 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindocL3r2-yl) ethyl] -1H-indole-5-butanoic acid

A mixture of 4-hydrazinobenzene butanoic acid (2.305 g) and 2- (4,4-diethoxybutyl) -1H-isoindole-1,3 (2H) -dione (2.91 g) was refluxed for 1 hour 8303424-21 in 112.5 ml of water and 37.5 ml of acetic acid.

The suspension was poured into 150 ml of ethyl acetate and the phases were separated. The organic phase was washed with 50 ml of brine, dried over Na 2 SO 4 and evaporated under reduced pressure to give a 5 gum. This was dissolved in 30 ml of tetrahydrofuran and adsorbed on 20 g of silica. The dried material was added to a column of silica and eluted (H). Suitable eluates were collected and evaporated under reduced pressure. Trituration of the residue with cyclohexane gave the title compound as a powder (2.35 g) with a melting point of 160-162 ° C.

Intermediate 5 (E) -Methyl 3- [4- [2- [2- (2-oxo-3-piperidinylidine)] hydrazino] phenyl 2-propenoate

To a suspension of (E) -methyl 3- (4-aminophenyl) -2-propenoate 15 (10.68 g) in 150 ml water and 12.5 ml concentrated hydrochloric acid at 0-2 ° C

a solution of 3.9 g of sodium nitrite in 12.5 ml of water was added. The mixture was stirred for 0.25 hours and a solution of 3-carbethoxy-2-piperidone (prepared from 3-carbethoxy-2-piperidone (8.55 g) and potassium hydroxy33 (3.0 g) in 100 ml of water left at 5 ° C for 72 hours) was added. The reaction mixture was adjusted to a pH of 4-5 with sodium acetate, allowed to warm to room temperature, and stirred for 18 hours. The precipitated solid was collected, washed with ethanol and ether and dried at 60 ° C under reduced pressure to afford the title compound as a solid (13.0 g), mp 209-209 ° C.

Intermediate 6 (E) -Methyl 3- (1,2,3,4-tetrahydro-1-oxo-9H-pyrido (3,4-b] indol-6-yl) -2-propenoate

Intermediate 5 (0.5 g) in 85% aqueous formic acid was refluxed for 2 hours and allowed to cool to room temperature. The mixture was filtered to give the title compound as a crystalline solid (0.22 µm, mp 258-259 ° C.

Λ? * Λ ^ '* H ^. . *: ·· ^ v »« j *.

- 22 -

Intermediate 7 (E) -3- (2-Aminoethyl) -5- (2-carboxyl-1-ethenyl) -1H-indole-2-carboxylic acid Intermediate 6 (2.0 g) was added in a 45 ml mixture 60 % aqueous ethanol and 7.5 g of potassium hydroxide heated at 60 ° C for 4 hours. The solution was cooled to 0 ° C and treated dropwise with 20% hydrochloric acid to a pH of 5. The precipitate was filtered, washed with water, ethanol and ether and dried to give the title compound as a solid (1.7 g). with a melting point of 292-295 ° C (decomposition).

10 Intermediate 8 3- (2-Aminoethyl) -5- (2-carboxyethyl) -1H-indole-2-carboxylic acid

Intermediate 7 (1.5 g), 10% palladium oxide on 200 mg of carbon and 50 ml of acetic acid were hydrogenated at atmospheric pressure for 5.5 hours (hydrogen uptake 148 ml). The reaction mixture was filtered, evaporated to dryness and crystallized from methanol / ether to give the title compound as a crystalline solid (1.1 g), mp 230-232 ° C.

Intermediate 9 3- (2-Aminoethyl) -1H-indole-5-propanoic acid 20 Intermediate 8 (0.9 g) was heated at 100 ° C for 60 hours in a mixture of 27 ml acetic acid and 20% aqueous hydrochloric acid . Evaporation to dryness gave the title compound as a crystalline solid (0.9 g) which was used in the next step without purification.

Intermediate 10 25 Ethyl 3- (2-aminoethyl) -1H-indole-5-propanoate, hydrochloride

Intermediate 9 (0.85 g) was added under nitrogen to a mixture of 10 ml thionyl chloride in 40 ml ethanol. The reaction mixture was refluxed for 4 hours, cooled to 50 ° C and 200 mL of ether was added. Filtration and evaporation of the mother liquids gave an oil which was chromatographed on silica gel. Elution (I) gave the tryptamine which was converted into the hydrochloride salt in a mixture of ethanol and ether, whereby the title compound was obtained as a crystalline solid (0.4 g), m.p. 182-185 ° C.

8r »Λ 3 Λ? 0 Ö 0 * 5 - 23 -

Intermediate 11 (E) and (Z) -Methyl 3- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] -2-propenoate 5-Bromo-N, N-dimethyl-1H-indoo1 -3-ethanamine (2.14g) was heated in an autoclave for 5 hours at 100 ° C with 0.90 ml methyl acrylate 18 mg palladium (II) acetate and 49 mg tri (o-tolyl) phosphine in 4 ml dry triethylamine . More palladium acetate (18 mg), tri (o-tolyl) phosphine (100 mg), methyl acrylate (0.9 ml) and trielethylamine (1.5 ml) were added, and heating was continued at 100 ° C for 16 hours. The mixture was partitioned between 20 ml of water and 20 ml of ethyl acetate. The water layer was extracted with 2 x 20 ml ethyl acetate, and the organic layers were washed with 2 x 15 ml brine, dried over MgSO 4 and evaporated to give the title compound as an oil (2.30 g) contaminated with starting material. This material was used in the next step without further purification.

Intermediate 12

Methyl 3- [2- (dimethylamino) ethyl] -1H-indole-5-propanoate

Intermediate 11 (2.08 g) in 100 ml of ethanol, containing 5 ml of 2N hydrochloric acid, was hydrogenated at room temperature and normal pressure over 10% palladium oxide on charcoal (50% paste with water, 0.4 g) until hydrogen uptake ceased (28 hours; further 400 mg portions of catalyst were added after 2 hours 20 minutes and after 17 hours). After filtration of the catalyst, the solvent was evaporated and the residue was made basic with 40 ml of 8% aqueous sodium bicarbonate and extracted with 4 x 50 ml of ethyl acetate. The organic layers were washed with brine, dried over MgSO 4 and evaporated to give the title compound as an oil (1.69 g).

T.l.c. (SiC 3) K Rf. 0.35 detection; u.v./IPA.

Intermediate 13 30 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-carboxaldehyde, quarter hydrate

Raney nickel (approx. 2 g) was added to a stirred solution of 4.98 grams of 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H- indole-5-carhonitrile and 10.06 g sodium hypophosphite in 100 ml pyridine, Τ '· * Λ "7 7 A f J * J * i = X fs' J -1 vv ϋ Λ * t' - 24 - 50 ml water and 50 ml acetic acid The mixture was heated at about 50 ° C for 6 hours, periodically adding further Raney nickel (5 x approx. 2 g) After cooling, the mixture was filtered, and the filtrate was diluted with 1250 ml water and extracted with 3 x 500 ml ethyl acetate The combined organic extracts were washed with 2 x 500 ml 2N hydrochloric acid, dried over MgSO 4, evaporated under reduced pressure and azeotroped with 2 x 100 ml toluene, with the title aldehyde as a solid (4.6 g) was obtained A 0.53 g sample was purified by chromatography on a silica column eluting with ethyl acetate to give pure title aldehyde as a solid (0, 49 g) with a melting point of 202-203 ° C.

Intermediate 14 (E) and (Z) -6- [3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl 3-1H-indol-5-yl] - 5-Hexenoic hydrate (4: 5). A solution of 4.39 g of (4-carboxybutyl) triphenylphosphonium bromide in 40 ml of dry dimethylformamide (DMF) was added dropwise over 3 minutes to a stirred suspension of 2.23 g of potassium tert-butoxide in 50 ml DMF under nitrogen. The resulting suspension was stirred at room temperature for 15 minutes, a solution of intermediate 13 (2.36 g) in 50 ml of DMF was added, and the resulting solution was heated to 100 ° C for 44 hours. After the emulsion was allowed to cool, it was partitioned between 1000 ml of 2N hydrochloric acid saturated with sodium chloride, and extracted with 3 x 500 ml of ethyl acetate. The combined organic extracts were washed with 4 x 500 ml water and 500 ml brine, dried over MgSO 4 and evaporated under reduced pressure to give a foam (5.98 g). This foam was purified by flash chromatography on silica eluting sequentially with 9000 ml chloroform-methanol 49: 1, 1000 ml 19: 1, 1000 ml 9: 1. the title acids being obtained as a foam, which coincided into a gum (0.45 g).

Analysis found: C: 68.2; H: 5.3; N: 6.1 C24H22N2O4 "1'25H2" calculated: C: 67.8; H: 5.8; N: 6.6% $ 5 Π 1k 9 Λ f 'J “* * - 25 -

Intermediate 15 * 3- [2- (1,3-Dihydro-1f3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-hexanoic acid compound with ethanol (2: 1)

A solution of intermediate 14 (1.30 g) in 170 ml of ethanol was hydrogenated at room temperature and normal pressure over pre-reduced 10% palladium oxide on charcoal (50% aqueous paste; 0.95 g) for 1 hour, then hydrogen uptake (69 ml) had ceased. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give the title acid as a solid (1.08 g) and mp 176-178 ° C.

Intermediate 16 3- (Cyanomethyl) -N- [4- (methoxyphenyl) methyl] -1H-indole-5-propenamide A mixture of N - [(4-methoxyphenyl) methyl] acrylamide (1.63 g), 5-bromo -3- (cyanomethyl) -1H-indole (2 g), palladium acetate (37 mg), 15 tri (o-tolyl) phosphine (109 mg) and triethylamine (2 ml) in 3 ml acetonitrile were heated at 100 ° C for 72 hours C heated in a reaction vial.

The cooled mixture was partitioned between 3 x 25 ml ethyl acetate and 25 ml water and the extracts were dried Ijeven MgSO 2 and evaporated. The residue was triturated with dichloromethane-ethanol-ammonia solution 20 (250: 8: 1) to afford the title compound as a powder (1.4 g) mp 108-110 ° C.

EXAMPLE I

3- (2-aminoethyl) -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide, hemisuccinate hydrate (4: 1) 25 (i) 3-fe- (1,3-Dihydro-1 , 3-dioxo-2H-isoindol-2-yl) ethyl] -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide

A solution of intermediate 2 (1.0 g) in 25 ml anhydrous THF containing 0.42 ml triethylamine was treated with 0.37 ml pivaloyl chloride and stirred at 0 ° C for 1 hour. A solution of 0.387 g of 4-methoxybenzenemethanamine in 10 ml of anhydrous THF

was added and the mixture was stirred at room temperature for 2.5 hours. The suspension was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was released with 30 ml of water and extracted with 2 x 50 ml of ethyl acetate. The combined organic extracts were evaporated under reduced pressure to yield about 2.0 g of a solid. Trituration with ether gave a powder (0.8 g) which was crystallized from butan-2-one / 5 cyclohexane to give the title compound as a powder (0.49 g) mp 196-199 ° C.

(ii) 3- (2-Aminoethyl) -N - [(4-methoxyphenyl) methyl 1 -1H-indole-5-propanamide, hemisuccinate hydrate (4: 1)

A stirred suspension of the product of step (i) (0.48 g) in 10 ml of ethanol containing 0.1 ml of hydrazine hydrate was refluxed for 3 hours. Hydrazine hydrate (0.05 ml) was added and the solution was refluxed for an additional 1 hour. After cooling, the solution was evaporated to dryness under reduced pressure. The residue was mixed with 60 ml of 2N sodium carbonate top solution, and extracted with 100 ml of methylene chloride. The extract was washed with 2 x 60 ml 2N sodium carbonate, dried over MgSO 4, and evaporated under reduced pressure to give a gum (0.25 g). This material was chromatographed on a column of silica gel (eluents A and B), and evaporation of the appropriate fractions gave the free base in the form of a gum (0.204 g). A solution of this material in 2 ml of hot isopropanol was treated with a hot solution of 0.0343 g of succinic acid in 2 ml of isopropanol. On cooling, the title compound crystallized from 25 as a powder (0.189 g) with a melting point of 185-187 ° C.

Found: C: 66.6; H: 7.0. N: 10, O, C 1, H -N O, 0.5C, H, 0.25H, O, calculated: C: 66.5; H: 6.9; N: 10.1% 21 20 32 4 o 4 2 N.m.r. (250MHz) δ (DMSO-dJ, includes 2.86-3.00 (6H, m, CHoCHoCO 6 —2 2 'and (CH2CH2NH2), 3.76 (3H, s, OCH3), 4.22 (2H, d, CH 2 NH), 6.96-7.10 30 (3H, m, H-6 and aromatics), 8.30 (1H, br.t, NHCO) and 10.84 (1H, br.s, indole NH ).

The following compounds were prepared by the same method as in Example I, with the appropriate amine starting material. The reaction conditions for steps (i) and (ii) are listed in Tables 1 and 2 below, respectively.

EXAMPLE II

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N- [4- (1-5 pyrrolidinyl) phenyl] -1H-indole- 5-propanamide m.p. 197-199 ° C.

(ii) 3- (2-Aminoethyl) -N- [4- (1-pyrrolidinyl) phenyl] -1H-indole-5-propane amide, hemisuccinate

mp. 222-223eC

Analysis found C: 68.8; H: 7.1; N: 12.6 C23H28n4O5.5C4H604, calculated: C: 68.9; H: 7.2? N: 12.9% N.m.r. (90 MHz) δ (DMSO-dg), includes 1.90 (4H, m, pyrrolidine -CH2CH2N), 2.50-2.75 (2H, m, CH2CH2CO), 2.78-3.05 (6H, m, CH2CH2CO and C12CH2NH2), 5.80 (2H br., NHg), 7.10-7.50 (5H, m, aromatics), 9.65 1H, br.s, IffiCO) and 10.70 ( 1H, br.s, indole NH).

EXAMPLE III

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N- (phenyl-methyl) -1H-indole-5-propanamide m.p. 142-143 ° C.

(Ii) 3- (2-Aminoethyl) -N- (1-enylmethyl) -1H-indole-5-propanamide,

hydrochloride mp. 205-205 ° C

n.m.r. (90 MHz) δ (DMSO-dg), includes 2.80-3.10 (6H, m, CH2CH2CO and CH2CH2NH2), 4.27 (2H, d, CH2Ph), 8.45 (1H, br.t, NHCO) and 10.90 (1H, br.s, indole NH).

EXAMPLE IV

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N- (phenyl-methyl) -1H-indole-5-butanamide m.p. 166-167 ° C.

(Ii) 3- (2-Aminoethyl) -N- (phenylmethyl) -1H-indole-5-butanamide,

hydrochloride mp. 195-198 ° C

85 C * o 4.2 4 - 28 - N.m.r. (90 MHz) § (DMSO-dg), includes 1.80 (2H, m, CH2CH2CH2), 3.00 (4H, s, CH2CH2NH2), 4.30 (2H, d, CH2Ph), 7.1-7 .40 (8H, m, aromatics), 8.40 (1H, t, NHCO) and 10.90 (1H, br.d, indole NH).

EXAMPLE V

5 (χ) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N- (4-methoxyphenyl) -1H-indole-5-propanamide mp. 184-186 ° C.

(ii) 3- (2-Aminoethyl) -N- (4-methoxyphenyl) -1H-indole-5-propanamide, hydrochloride 10 mp. 264-266 ° C

N.m.r. (90 MHz) δ (DMSO-dg), includes 2.80-3.10 (6H, m, CH2CH2CO and CH2CH2NH2), 3.70 (3H, s, OCH3), 7.2-7.70 (5H, m, CONH and aromatics) 8.20 (2H, br, NH 2) and 10.90 (1H, d, indole NH).

EXAMPLE VI

15 (i) N- [(4-Chlorophenyl) methyl] -3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5- propanamide m.p. 199.5-202 ° C.

(ii) 3- (2-Aminoethyl) -N - ((4-chlorophenyl) methyl] -1H-indole-5-propanamide, hemisuccinate, hydrate (4; 1) 20 mp 188-192 ° C

Analysis found: C: 63.1; H: 6.05; N: 9.8 C-H-ClN, 0.05C.HrO..0.25H0O, calculated: C: 63.0; H: 6.1; N: 10.2% 20 24 3 464 2 N.m.r. (250 MHz) δ (DMS0-dg), includes 2.90 (6H, m, CH2CH2CO and CH2CH2NH2), 4.25 (2H, d, CH2Ph), 7.0-7.40 (7H, m, aromatics) , 8.40 (1H, t, NHCO) and 10.80 (1H, br.s, indole NH).

EXAMPLE VII

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N-phenyl-1H-indole-5-butanamide m.p. 152-153 ° C.

(Ii) 3- (2-Aminoethyl) -N-phenyl-1 H -indole-5-butanamide, hydrochloride m.p. 222-224 ° C.

8503424 - 29 - N.m.r. (90 MHz) <5 (DMSO-d6), includes 2.0 (2H, m, CH2CH2CH2), 3.00 (4H, s, CH2CH2NH2), 6.90-7.70 (9H, m, aromatics, 10 10 (1H, br s, NHCO) and 10.90 (1H, br s, indole NH).

EXAMPLE VIII

(i) N- (4-Chlorophenyl) -3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-propanamide m.p. 200-203 ° C.

(ii) 3- (2-Aminoethyl) -N- (4-chlorophenyl) -1H-indole-5-propanamide hemisuccinate

mp. 216-218eC

Analysis found: C: 62.6; H: 5.8; N: 10.2.

C19 ^ 20C1N3 ° * 0 '^ C4H6 ° 4' calculated: C: 62.9; H: 5.8; N: 10.5%.

N.m.r. (250 MHz) 5 (DMS0-dg), 2.80-3.10 (6H, m, COCH2CH2 and CH2CH2NH2), 7.35.7.50 (3H, m, aromatics), 10.20 (1H, br.s , NHCO) and 10.80 (1H, br.s, indole NH).

EXAMPLE IX

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -N- [4-aminocarbonyl) phenyl] -1H-indole-5-propanamide mp. 238-240 ° C.

(ii) N- [4- (Aminocarbonyl) phenyl] -3- [2- (aminoethyl) 3-1H-indole-5-propanamide compound with creatinine, sulfuric acid and water (1: 1: 1: 1.5) mp . 205-208 ° C.

Analysis found C: 49.8; H: 6.0; N: 16.3; C21H24N402 * C4H7N3O * H2SO4 * 1.5H2 O 'calculated: C: 49.8; H: 6.0; N: 16.3% N.m.r. (250 MHz) <5 (DMSO-d ,.), 2.90-3.20 (9H, m and s, CH.CH.CO and o - ζ λ CH2CH2NH2), 4.30 (2H, d, CH2NHCO), 7.20-8.00 (9H, m, aromatics and CONH2), 8.40 (1H, t, NHCO) and 10.90 (1H, br.s, indole NH).

EXAMPLE X

(i) 3- [2- (1,3-Dihydro-1,3-dio% o-2H-isoindol-2-yl) ethyl] -N - [[4- (1-pyrrolidinyl) phenyl] methyl] - 1H-indole-5-propanamide m.p. 121-123 ° C.

Sr, I

- 30 - (ii) 3- (2-aminoethyl) -N - [[4- (1-pyrrolidinyl) phenyl] methyl] -1H-indole-5-propanamide, hemisuccinate m.p. 206-208 ° C.

Analysis found: C: 69.3; H: 7.4; N: 12.3; 5 C_.Η.-Ν.Ο.Ο, δΟ.Η-Ο ,, calculated: C: 69.5; H: 7.4; N: 12.5% 24 30 4 464 N.m.r. (250 MHz) <5 (DMSO-dg), includes 2.00 (4H, m, pyrrolidine -CH2CH2N), 2.80-3.00 (6H, m, CH2CH2CO and CH2CH2NH2), 3.20 (4H, m , pyrrolidine -CH2CH2N), 4.15 (2H, d, CH2NHCO), 6.40-7.00 (5H, m, aromatics and H-6), 8.20 (1H, t, NHCO) and 10.90 (1H, br.s, 10 indole NH).

EXAMPLE XI

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] - (2-propenyl) -1H-indole-5-propanamide m.p. 268-269 ° C.

15 (ii) 3- (2-Aminoethyl) -N- (2-propenyl) -1H-indole-5-propanamide, hydrochloride m.p. 230-231 ° C

Analysis found: 0: 62.3; H: 7.3; N: 13.5; C.-H-.N-0.HCl, calculated: C: 62.4; H: 7.2; N: 13.7% 16 21 3 20 N.m.r. (250 MHz) 6 (D20), includes 3.10 (2H, t, CH2CH2CO), 3.35 (2H, t, CH2CH2NH2), 3.70 (2H, m, NHCH2CH =), 4.90 (-, m, CH = CH 2) and 5.70 (1H, m, CH 2 CH = CH 2).

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EXAMPLE XII

3- (2-Aminoethyl) -1H-indole-5-propanamide, compound with creatinine sulfate, sulfuric acid and water (1: 1: 1: 1.25)

Ethyl 3- (2-aminoethyl) -1H-indole-5-propanoate (0.3 g) was heated at 38 ° C in 20 ml 0.880 d ammonia for 24 hours. Evaporation to dryness gave the crude amide which was purified by chromatography (eluent J) to give 130 mg of an oil. This was dissolved in ethanol and an aqueous solution, 1 molar in sulfuric acid and creatinine (0.28 ml) was added. Addition of acetone to the 80 ° C warm creatinine sulfate-10 solution until it became cloudy gave the title compound as a solid (120 mg), mp 218-220 ° C (decomposition).

Analysis found: C: 44.4; H: 6.05; N: 17.7; C13H17N30.C4H7N30.H2SO41.25H2 O Calcd C: 44.1; H: 6.2; N: 18.1%

EXAMPLE XIII

15 3- (2-Aminoethyl) -N-methyl-1H-indole-5-propanamide, hydrochloride

To a solution of intermediate 2 (1.0 g) in 25 ml dry tetrahydrofuran containing 0.42 ml triethylamine, 0.37 ml pivaloyl chloride was added at 0 ° C. After stirring for 10 minutes, the suspension was filtered and the filtrate was evaporated under reduced pressure. 20 ml of 33% ethanolic methylamine was added to the oily residue and the resulting solution was stirred for 18 hours. Evaporation of the solvent gave a solid which was partitioned between 10 ml of 2N hydrochloric acid and 25 ml of ethyl acetate. The organic phase was separated and extracted again with 10 ml of 2N hydrochloric acid. The combined aqueous extracts were saturated with potassium carbonate and extracted with 4 x 50 ml ethyl acetate. Evaporation of the combined extracts dried over Na2 SO4 gave a solid which was dissolved in 10 ml of 2N methanolic hydrochloric acid and evaporated again to dryness. Crystallization of the residue from propan-2-ol and isopropyl acetate [2: 1] (10 ml) gave 0.27 g of the title compound, mp 224-226 ° C.

Analysis found: C: 59.3; H: 7.2; N: 14.6;

C14 H19 N3 ° HCl / calculated - C: 59.7; H: 7.2; N: 14.9% N.m.r. (90 MHz) 5 (DMS0-dr), includes 2.90 (2H, m, CH-CH_CO), 3.10 O-2 λ (4H, br.s, CI12CH2NH2), 7.10-7.50 ( 3H, m, aromatics), 7.80 (1H, q, NHCH 3), 8.20 (2H, br, NH 2) and 11.00 (1H, br.s, indole NH).

"f '. *' * -Ί <*‘ <- 34 -

EXAMPLE XIV

3- [2- (Dimethylamino) ethyl] -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide hydrochloride

To a stirred solution of the product of Example I (ii) (0.2 g) 5 in 5 ml n-propanol at 0 ° C, 0.26 ml of a 37-40% aqueous formaldehyde solution was added and the mixture was stirred for 15 minutes. 0.11 g of sodium borohydride was added in portions over a period of 5 minutes, keeping the temperature at 0 ° C. After 30 minutes, the mixture was acidified with 5 ml of 2N hydrochloric acid and diluted with 25 ml of water. The solution was washed with 2 x 10 ml ethyl acetate and then made basic with 8 ml 2N sodium carbonate. The cloudy solution was extracted with 3 x 25 ml ethyl acetate and the extracts evaporated under reduced pressure. The residue (0.2 g) was chromatographed on silica (G) to give 45 mg of an oil. This oil was dissolved in 2 ml absolute ethanol and 5 ml hydrogen chloride solution in ether was added. Then, 15 ml of ethyl acetate was added and the resulting solid was collected and dried to give the title compound as a powder (37 mg), mp 94-96 ° C.

Analysis found ~ r: C: 64.2; H: 7.3; N: 9.1; C 3 H 21 N 3 O. BC 1 .0.6 CH 3 CH 2 O 2 CH 3, calculated: C: 64.5; H: 7.6? N: 9.1%.

N.m.r. (250 MHz) <$ (DMS0-dg), includes 2.80 (6H, s, NMe2), 2.95 (2H, t, CH2CH2CO), 3.00-3.30 (4H, m, CH2CH2NMe2), 3, 70 (3H, s, OCH3). 4.20 (2H, d, CH 2 NHCO), 7.0-7.50 (6H, m, aromatics), 8.30 (1H, t, NHCO) and 10.90 (1H, br, s, indole NH).

EXAMPLE XV

3- [2- (Dimethylamino) ethyl] -1H-indole-5-propanamide oxalate Intermediate 12 (1.54 g) was heated in a capped glass bottle at 75 ° C for 26 hours with 880 ammonia (1 ml) and 1.2 ml of methanol. Methanol was partially evaporated, more 880 ammonia (1 ml) was added, and heating was continued at 75 ° C for 24 hours. Evaporation of the solvent gave 1.32 g of a foam, which was purified by flash chromatography (eluent L) to 0.507 g of an oil. A portion of this (481 mg) was dissolved in 2 ml of methanol and 175 mg of oxalic acid in methanol was added. Addition of dry 7 ° * 7 1 -A * tvi ύλ i 1 - 1 * 1 - * f & J ii v; Ether-35 gave a gummy precipitate / which was triturated with dry ether to give the title compound as a solid (0.401 g) mp 139-142 ° C.

Analysis found: C: 58.1; H: 6.8; N: 1.17; 5C15H21N3 ° * C2H2 ° 4 'calculated: C: 58.4; H: 6.6; N: 12.0%.

N.m.r. (90MHz) δ (DMS0-dg), includes 2.7-3.40 (12H, m, CH2CH2CO, CH2CH2NH2 and NMe ^), 6.70 (1H, br.s, CONHH), 7.10-7, 50 (4H, m, aromatics and CONffi) and 10.90 (1H, br.s, indole NH).

EXAMPLE XVI

10 3- [2- (Dimethylamino) ethyl] -N, N-dimethyl-1H-indole-5-propanamide succinate

A mixture of dimethylamine in ethanol (33% w / v, 4 ml) and intermediate 12 (0.75 gO was heated in a reaction vial at 100 ° C for 24 hours. The solution was then evaporated under reduced pressure and the residue was chromatographed on silica (F and G) to give an oil (0.112 g), this oil was dissolved in 2 ml of hot isopropanol and a solution of succinic acid (46 mg) in hot isopropanol was added dropwise to isopropyl acetate. the hot mixture was added until a cloudy solution was obtained The solid obtained on cooling was recrystallized from isopropanol to give the title compound as a powder (75 mg), mp 131-133 ° C.

N.m.r. (90 MHz) 5 (DSM0-dg), includes 2.40 2.7-3.40 (12H, m, CH2CH2CO, CH2qi2NH2 and NMeJ, 6.70 (1H, br.s, CONHH), 7.10- 7.50 (4H, m, aromatics and CONHH) and 10.90 (1H, br.s, indole NH).

Analysis found: C: 61.4; H: 8.0; N: 9.8.

C._H__N_0.C .Η, .0. 0.25HO, calculated: C: 61.5; H: 7.7; N: 10.2.

17 25 3464 £ N.m.r. (250 MHz) δ (DMS0-dg), includes 2.80-3.00 (14H, m, NMe2, CONMe2 and CH2CH2CO), 3.00-3.40 (4H, m, CH2CH2NMe2) and 10.90 ( 1H, br.s, indole NH).

EXAMPLE XVII

3- [2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-propanamide hydrochloride

A mixture of methylamine in ethanol (33% w / v, 4 ml) and intermediate 12 (0.56 g) was heated in a reaction vial at 75 ° C for 24 hours.

85 0 3. > - 36 -

The cooled solution was evaporated under reduced pressure and the residue was chromatographed on silica (M and F) to give 220 mg of an oil. This oil was dissolved in 5 ml of ethanolic hydrogen chloride and the solution was evaporated under reduced pressure to obtain a gum. Grinding the gum with about 15 ml of ethyl acetate gave a solid which was collected and dried. (0.18 g) melting point 73-75 ° C.

Analysis found: C: 58.4; H: 7.9; N: 12.4.

C16H23N3 ° "HCl" H2 ° "calculated: C: 58.6; H: 7.9; N: 12.8%.

10 N.m.r. (250 MHz) 6 (DMSO-dJ, includes 2.60 (3H, d, NHCH_), 2.85 6-3 (6H, s, NMe2), 2.90 (2H, t, CH2CH2C01 3.10-3 .40 (4H, m, CH2CH2NMe2), 7.90 (1H, br.q, NHCH3) and 10.90 (1H, br.s, indole NH).

EXAMPLE XVIII

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-15 hexanamide

Pivaloyl chloride (0.38 ml) was added to a solution of 1.31 g of intermediate 15 and 0.43 ml of triethylamine in 100 ml of dry tetrahydrofuran, and the mixture was stirred at room temperature for 1 hour, after 40 minutes more 0.10 ml of triethylamine and 0.05 ml of pivaloyl chloride were added. A saturated solution of ammonia in tetrahydrofuran (60ml) was added, and the mixture was stirred in a sealed bottle at room temperature for 3.5 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give an oil, which was partitioned between 150 ml of 25N sodium carbonate solution and 3 x 100 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to yield 0.99 g of a solid. This material was partially purified by flash chromatography, eluting with ethyl acetate-methanol (19: 1). 0.84 g of a solid were obtained. A sample of this material (0.117 g) was suspended in 10 ml of water for 1 hour at 90 ° C.

The precipitate was filtered off, washed with 5 ml of boiling water, and dried under reduced pressure at 50 ° C to afford the title compound as a solid (0.075 g), mp 177-179 ° C.

v *, «* - 37 - (ii) 3- (2-Aminoethyl) -1H-indole-5-hexanamide, compound with creatinine, sulfuric acid / water and ethanol (10: 10: 10: 5; 2)

A mixture of the product of step (i) (0.59 g), 1.5 ml hydrazine hydrate and 50 ml ethanol was refluxed for 1.75 hours, allowed to cool, and evaporated to dryness. The solid obtained was azeotroped with 2 x 50 ml absolute ethanol, then partitioned between 50 ml 2N sodium carbonate and 3 x 50 ml ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure to give the title base as an oil (0.43 g). The oil was dissolved in a hot mixture of 48 ml ethanol and 6 ml water, and was treated with an aqueous solution of creatinine and sulfuric acid (1: 1; 2M; 0.75 ml). On cooling, the title compound crystallized out as a solid (0.49 g), mp 188-193 ° C. (decomposition).

Analysis found: C: 49.0; H: 7, l? N: 16.8; C. -N 0, C LN 0.H.SO. 0.5H 0.0.2C HoO, calculated: C: 48.7; H: 6.9; N: 16.7% 16 23 34732422ο N.m.r. (90 MHz) δDMSO-dg) includes 1.20-1.80 (6H, m, -CH2 (CH2) 3CH2-), 2.10 (2H, t, CH2CH2CO), 2.90 (3H, s, NCH3 ), 3.00 (4H, br.s, CH2CH2NH2) and 10.90 (1H, brs, indole NH).

EXAMPLE XIX

3- [2- (Dimethylamino) ethyl] -N- (2-propenyl) -1H-indole-5-propanamide oxalate

A mixture of intermediate 12 (0.75 g) and 3.5 ml of allylamine in 1.5 ml of methanol was stirred in a reaction vial at room temperature for 96 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica (eluent N). The appropriate fractions were collected and evaporated under reduced pressure to obtain 0.142 g of an oil, which was dissolved in 2 ml of methanol and a solution of 44 mg of oxalic acid in 1 ml of methanol was added. Ethyl acetate (about 20 ml) was added and the resulting solid was collected and dried to obtain 0.13 g of a powder, mp 68-70 ° C.

Analysis found: C: 60.8; H: 7.5; N: 10.2.

C.oH._N, 0. (C: O, H). 0.33 EtOAc, calculated: C: 61.2; H: 7, l? N: 10.0%. lo 25 2 22:} λ V V. · * «! * '* T - 38 -

EXAMPLE XX

(i) 3-Cyanomethyl) -N- [4- (methoxyphenyl) methyl] -1H-indole-5-propanamide A solution of intermediate 16 (1.4 g) in 50 ml of methanol was added to a previously reduced suspension of 10 % palladium oxide on charcoal (50% paste with water, 300mg) in 20ml of methanol and the mixture was hydrogenated until uptake ceased (about 95ml).

The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to obtain 1.2 g of an oil.

10 T.l.c. (M) Rf 0.40, detection u.v / KMnO ^.

(ii) 3- [2- (Ethylamino) ethyl] -N- [4- (methoxyphenyl) methyl] -1H-indole-5-propanamide oxalate salt

A mixture of the product of step (i) (0.6 g) and ethanolic ethyl amine solution (30 ml, 30% w / v) in 100 ml ethanol was added to a pre-reduced suspension of 10% palladium oxide on charcoal (50% paste with water, 0.6 g) and the mixture was hydrogenated until uptake ceased. A further amount of catalyst (0.6 g) was added and the mixture was hydrogenated again until the uptake ceased. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure to obtain 0.59 g of an oil. This oil was dissolved in 2 ml of methanol and a solution of 140 mg of oxalic acid in 5 ml of ethyl acetate was added. The solution was diluted with about 50 ml of ethyl acetate and the resulting solid was collected, washed well with about 25 ml of diethyl ether and dried to yield the title compound as a powder (0.47 g), mp 104-106 ° C.

Analysis found: C: 62.6; H: 6.8; N: 8.8 C23H29N3 ° 2 * (CO2H) 2.0.5H2 °, C: 62.8; H: 6.7; N: 8.8%

Water analysis showed 0.4 moles of water.

The following examples show pharmaceutical compositions according to the invention, containing 3- (2-aminoethyl) -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide hemisuccinate hydrate (4: 1) as the activation ingredient. Other compounds of the invention can be formulated in a very similar manner.

15 0 ^ ^ 4 sr. .

- 39 -

TABLETS FOR ORAL ADMINISTRATION DIRECT PRESS

mg / tablet

Active ingredient 8.4

Calcium hydrogen phosphate 89.1 5 B.P *

Croscarmellose sodium ÜSP 2.00

Magnesium stearate, B.P. 0.50 press weight 100 mg * of a quality suitable for direct pressing 10 The active ingredient is sieved before use. The calcium hydrogen phosphate, croscarmellose sodium and active ingredient are weighed into a clean polythene bag. The powders are mixed by vigorous shaking, then the magnesium stearate is weighed out and added to the mixture, which is further mixed. The mixture is then compressed using a Manesty F3 tablet machine, equipped with 5.5 mm flat, beveled edge punches, into tablets with a target press weight of 100 mg.

Tablets can also be prepared by other conventional means, for example, by wet granulation.

Tablets of other strengths can be prepared by changing the ratio of active ingredient to lactose or changing the press weight and using suitable stamps.

The tablets can be film-coated using suitable film-forming materials, such as hydroxypropyl-methylcellulose, using standard techniques. The tablets can also be coated with sugar.

CAPSULES mg / capsule

Active ingredient 8.4 * Starch 1500 190.6 30 Magnesium stearate BP 1.00

Fill weight 200.00 pounds

A form of directly pressable starch.

'5 2 4 * * t - 40 -

The active ingredient is sieved and mixed with the excipients. The mixture is filled into No. 2 hard gelatin capsules using suitable equipment. Other doses can be prepared by changing the fill weight and changing the capsule size as needed.

SYRUP

mg / 5 ml dose

Active ingredient 8.4

Buffer)

Flavor (10 Color) as required

Preservative)

Thickener)

Sweetener)

Purified water to 5.00 ml. The active ingredient, buffer, flavor, colorant, preservative, thickener and sweetener are dissolved in a little water, the solution is made up to volume and mixed. The syrup obtained is clarified by filtration.

SUPPOSITORY FOR RECTAL ADMINISTRATION

20 Active Ingredient 8.4 mg * Witepsol Hl5 to 1.0 g £

A branded product of Adeps Solidus Ph. EUR.

A suspension of the active ingredient in melted Witepsol is prepared and filled into 1 g size suppositories using suitable equipment.

INJECTION FOR INTRAVENOUS ADMINISTRATION

mg / ml 'Active ingredient 2/1

Sodium chloride BP as needed

Water for injections BP up to 1.0 ml 8S A -U 5 '

J V 'J -i £ “V

ί - 41 -

Sodium chloride can be added to adjust the tonicity of the solution and the pH adjusted with acid or alkali to provide optimum stability and / or to facilitate dissolution of the active ingredient. Suitable buffer salts can also be used.

The solution is prepared, clarified and filled into appropriately sized ampoules which are sealed by melting the glass. The injection is sterilized by autoclaving using one of the accepted cycles. The solution can also be sterilized by filtration and placed in sterile ampoules under aseptic conditions. The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

-03 - :: 4

Claims (9)

1. Indole compounds of the general formula I in which R represents a hydrogen atom, a C 1 alkyl, C 1 cycloalkyl or C 1 alkenyl 110 3 / Jb group, or a phenyl or phenyl (C 1 alkyl group in which the phenyl ring may be unsubstituted or substituted by one or two substituents selected from C 1 -alkoxy, hydroxy, halogen, a group R 1, R 2 NCO- wherein R 1 and R 9 (which may be the same or different) each have a hydrogen atom or a C 1 alkyl group or a group R_RQN-, wherein R_ and R. (which may be the same or different) each represent / o / o a hydrogen atom or a C 1-4 alkyl group, or R_RQN- a lo / 10 10 saturated monocyclic 5-7 ring represents; R2 represents a hydrogen atom or a C 1-8 alkyl group; or and R 2 together with the nitrogen atom to which they are attached form a saturated monocyclic 5-7 ring; R 9 and R 8 which may be the same or different, each a hydrogen atom, 15 represent a C 1-4 alkyl group, or a 2-propenyl group; and n is an integer from 2-5; as well as physiologically acceptable salts and solvates thereof. 2. Indole compounds according to claim 1, wherein R 1 represents a hydrogen atom, a C 1-6 alkyl or C 1-6 galkenyl group, or a phenyl or phenyl (C 1-6) alkyl group, wherein the phenyl ring may be unsubstituted or substituted by one or two substituents as defined in claim 1. Indole compounds according to claim 1 or 2, wherein one of R 1 and R 2 represents a hydrogen atom. Indole compounds according to any one of claims 1 to 3, wherein R 1 and R 2, which may be the same or different, each represent a hydrogen atom or a C 1 alkyl group. Indole compounds according to any one of claims 1-4, wherein n equals 2 or 3. 6. Indole compounds according to claim 1, wherein R 1 represents a C 1-8 alkyl group, a C 1-6 alkenyl group or a phenyl (C 1-6) alkyl group, wherein 1 to 2 wherein the phenyl ring may be unsubstituted or substituted by 3 42 4 One or two substituents as defined in claim 1; represents a hydrogen atom; and R 4, which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group; and n equals 2 or 3. Indole compounds according to claim 1 selected from 3- (2-aminoethyl) -N- (phenylmethyl) -1H-indole-5-propanamide; 3- (2-aminoethyl) -N - {[4- (1-pyrrolidinyl) phenyl] methyl) -1H-indole-5-propanamide; 3- [2- (dimethylamino) ethyl] -N - [(4-methoxyphenyl) methyl] -1H-indole-10 5-propanamide; 3- (2-aminoethyl) -N- (2-propenyl) -1H-indole-5-propanamide; and 3- (2-aminoethyl) -N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide; as well as the physiologically acceptable salts and solvates thereof. A pharmaceutical composition comprising as an active ingredient an effective amount of at least one indole of the general formula I according to claim 1 or a physiologically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers or excipients. A process for preparing an indole of the general formula I according to claim 1 or a salt or solvate thereof, comprising (A) condensing an amine of the formula R ^ NH (wherein R ^ and R2 as in claim 1 defined) with an acid of the general formula II (wherein R 1, R 1, and n are as defined in claim 1) or a corresponding acylating agent, or a salt or a protected derivative thereof; or (B) cyclizing a compound of the general formula III (wherein R ^, and n2 ° are as defined in claim 1 and Q is the group NR ^ R ^ (wherein R ^ and R4 are as defined in claim 1) Or a protected derivative thereof or a leaving group; or (C) reacting a compound of the general formula VI (wherein R 1, R 2 and n are as defined in claim 1 and Y is an easily displaceable group) or a protected derivative thereof, having an amine of the formula RR.NH (wherein R 1 and R are as defined in claim 1 3 4 34 35) or 4 24 7 1 *? - 44 - (D) reducing a compound of the general formula VII (wherein and R 2 as defined in claim 1 and W is a group which can be reduced to form the required group or a protected derivative thereof (wherein R 1 and R 45 are as defined in claim 1 ) and A represents the group - (CH-) - ~ XI or a group that can be reduced to - (Ci ^) n ~ eerd (wherein n is as defined in claim 1), or a salt or protected derivative thereof; or (E) reacting a nitrile of the general formula IX 10 (wherein R 1, R 4 and n are as defined in claim 1) or a salt or protected derivative thereof, with a suitable oxygen-containing compound; or (F) converting a compound of the general formula I as defined in claim 1, or a salt or protected derivative thereof into another compound of the general formula I; or (G) subjecting a protected derivative of the general formula I as defined in claim 1 or a salt thereof to a reaction to remove the protecting group or groups; and, if necessary and / or desired, conducting one or two further reactions after one of the methods A-F, comprising (i) removing any protecting groups; and (ii) converting a compound of the general formula I or a salt thereof into a physiologically acceptable salt or solvate thereof. a S