NL8701372A - INDOOL DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF, AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE DERIVATIVES AS AN ACTIVE COMPONENT. - Google Patents

Description

t i VO 9195

Title: Indole derivatives, process for their preparation as well as pharmaceutical preparations containing these derivatives as active component.

This invention relates to indole derivatives, to methods of preparation thereof, to pharmaceutical preparations containing these derivatives as active component and the medical use thereof, in particular to compounds and preparations for use in the 5; fight against migraines.

The pain caused by migraines. is associated with excessive dilation of the cranial vasculature, and the known method of combating migraine therefore includes the administration of compounds with vasodilatory properties, such as ergotamine. However, Ergotamine is a non-selective vasoconstrictor that narrows blood vessels throughout the body causing unwanted and dangerous side effects. Migraines have also been treated by the administration of an analgesic, usually in combination with an anti-emetic, but such treatment is of limited value.

Thus, there is a need for a safe and effective drug for the treatment of migraine, which can be used either preventively or to relieve a persistent headache, where a compound with a selective vasoconstrictor activity could play such a role.

A number of classes of compounds with selective vasodilatory activity have been described.

For example, British Patent No. 2,035,310 describes a large number of 5-carboxamido and thioamido-substituted indole derivatives. The compounds are said to have antihypersensive activity while it is further described that certain compounds of the invention are also potentially useful for the treatment of migraine.

British Patent No. 2,082,175 discloses various 5-acetamido and 5-thioamido-substituted indole derivatives having selective vasoconstrictor activity. As indicated in this British Patent, these compounds have a selective narrowing action on the anesthetic dog's arterial bed making them potentially useful for the treatment of migraines.

A new group of indole derivatives with a potent and selective vasoconstrictor activity has now been found. Thus, the present invention provides an indole of the general formula 1 of the formula sheet, wherein R. is a group RR ^ N-, a group R10 -C (CH_) -, a group R11, NCO (CH) -, a group R ^ CONH (CEL) represents a group R_R.NSO „(CH) -5 o 2 po 2 p 5622p or a group R ^ SC ^ NHiC ^) ^ -, (where R, - and Rg which may be the same or different, each represent a hydrogen atom or an alkyl group 10, or Re and R ', together with the nitrogen atom to which they are

3 O

confirmed to form a saturated monocyclic 5- to 7-ring; R represents a C alkyl group and p is zero or one); R represents a hydrogen atom or a C 1-6 alkyl group; R 1 and R 2 which may be the same or different each represent a hydrogen atom, an alkyl group, or a 2-propenyl group; m is zero or an integer from 1 to 4 and n is zero or one (provided that m and n are both not zero); as well as physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The invention encompasses within its scope all optical isomers of compounds of formula (1) and their mixtures including the racemic mixtures thereof. All geometric isomers of the compounds of the general formula (1) are also within the scope of the invention.

In the compounds of formula (1), the substituent R 4 may be present at the ortho, meta or para site, as is evident.

In the general formula (1), the alkyl groups can be straight or branched groups, such as methyl, ethyl or isopropyl. The substituent R1 can take the ortho, meta or para position.

Preferred compounds represented by the general formula (1) are those in which R 1, R 1, R 1, R 1, m and n have the aforementioned meanings and R 1 a growth RR N -, RcO - C (CH) -, R, .RrNC0 (CHo) -, RrCONH (CH ") -, 1 -56 5 2 2 p 56 2 p 5 2p RR.NSO- (CH") - or a group R_S0oNH (CH.), Where Rr and Rc are 5 6 2 2- p 3 ^ 7 2 2 p 5 6 may be the same or different, each representing a hydrogen atom or an alkyl group, wherein R 1 and p have the aforementioned meanings.

a * - 3 -

A preferred class of compounds represented by the general formula (1) is that where a hydrogen atom or a methyl group represents.

In the compounds of the general formula (1), m may be zero 5 or an integer from 1 to 4, preferably 2.

Another preferred class of compounds of the general formula (1) is those in which and which may be the same or different each represent a hydrogen atom or a C 1-3 alkyl group, for example a methyl or ethyl group.

IQ In the compounds of the general formula (1) wherein R ^ is a R_RCN-, R-0oC (CH2) -, RcR_NCO (CH2) -, R; CONH (CH0) - or RR NSO. (CEL) - ob 52 2 p 56 2 p 5 2 p 5622p group are preferably Rc and R, which are the same or different

v O

each can be a hydrogen atom or a methyl group. When R1 and R2 together form a saturated monocyclic 5 to 7 ring, this will preferably be a pyrrolidino ring.

In the compounds of the general formula (1), wherein R 1 is the group R 7 SO 2 NH (CH 2) - R? preferably a methyl group.

Suitable substituents in compounds of the general formula (1) include, for example, the groups H 2 NCOCH 2 -, CH 2 SO 2 NH-, H 2 NCO -, (CH 3) 2n -, ch 3 O 2 C -, pyrrolidino and CH 3 NHSO 2 CH 2 -.

The substituent in compounds of the general formula (1) is preferably in the meta or para position.

A particularly preferred group of compounds that fall within the scope of the general formula (1) is that in which R2 represents a hydrogen-25 atom; R 3 and R 3, which may be the same or different, each represent a hydrogen atom or a methyl group; m represents a whole 2; Rt represents the group H 2 NCCO 2-, C 1 -SC 4 EIH-, CH-CONH-, H 2 NCO-, {CH 3) 2N-, CH 3 O 2 C-, CH 3 NHSO 2 CH 2 - or a pyrrolidino ring; wherein the R 1 substituent is attached to the phenyl ring in the meta or para position.

Particularly preferred compounds of the general formula (1) which fall within this group are those in which R 1 represents the group (CH 3) 2N-, CH 3 O 2 C-, H 2 NCOCH 2 - or CH 3 CONH and the group R 1 is in the para position.

Preferred compounds of the invention include: 3- (2-aminoethyl) -N- [2- [4- (dimethylamino) phenyl] ethyl] -1H-indole-5-carboxylamino-5 u-4- methyl 4- [2 - [[[3- (2-aminoethyl) -1H-indol-5-yl] carbonyl] amino] -ethyl] benzoate, and its physiologically acceptable salts and solvates (e.g. hydrates).

Suitable physiologically acceptable salts of the indoles of the general formula (1) include saline 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 are sometimes useful for the preparation of compounds of formula (1), for example creatinine sulfate adducts.

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

The compounds of the invention selectively disclose the anesthetized arterial bed, having a negligible effect on blood pressure. The selective vasoconstrictor activity of the compounds of the invention has also been demonstrated in vitro.

Compounds of the invention are useful for the treatment of pain resulting from dilation of the cranial vasculature, especially migraine and Horton syndrome.

Thus, the invention also provides a pharmaceutical composition adapted for use as a human medicine, such that it comprises at least one compound of formula (1) or a physiologically acceptable salt or solvate (eg hydrate) thereof and which is formulated in any suitable route can be administered. Such formulations can be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.

Thus, the compounds of the invention can be formulated into compositions 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 -5--.

taking, for example, tablets or capsules obtained by conventional methods with pharmaceutically acceptable excipients such as binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (for example, 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 in the art. Liquid preparations for oral administration are in the form of, for example, solutions, syrups or suspensions, or they consist of a dry product which is prepared with water or another suitable carrier just before use. Such liquid preparations can be conventionally obtained with pharmaceutically acceptable additives, such as suspending agents (eg sorbitol syrup, methyl cellulose or cured edible fats); emulsifiers (e.g. lecithin or acacia); non-aqueous carriers (for example, almond oil, oily esters or ethyl alcohol), * and preservatives (for example, methyl or propyl p-hydroxybenzates or sorbic acid). The liquid preparations may also contain customary buffers, flavors, colors and sweeteners as required.

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

The compounds of the invention may also be formulated for parenteral administration by injection or continuous infusion. An injection composition can be provided in unit dosage form, for example, 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 carriers, wherein they may contain auxiliary agents such as suspending agents, stabilizers and / or dispersing agents, and / or agents that adjust the tonicity of the solution. Optionally, the active component can be in powder form and just for use with a suitable carrier, for example sterile-6-r? '' pyrogen-free water is produced.

The compounds of the invention may also be formulated as rectal compositions such as suppositories or enamels, which may contain, for example, conventional suppository bases such as cocoa butter or other glycerides.

For administration by inhalation, the compounds of the invention are conveniently delivered in the form of an aerosol spray in a pressure package, using an appropriate propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro-ethane, carbon dioxide or other suitable gas, or atomizer.

In an aerosol, the dosage unit can be determined by means of a valve that dispenses a dosed amount. Capsules and cartridges of, for example, a gelatin for use in an inhaler or blower may be formulated containing a powdered mixture of a compound of the invention and a suitable powder base such as lactose or 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 - 100 mg of active ingredient per unit dose , which, for example, can be administered up to 8 times a day, but usually 1 to 4 times a day. Obviously, one can sometimes make routine dose variations depending on the age, weight of the patient, and severity of the condition to be treated.

For oral administration, a unit dose preferably contains 0.5 to 50 mg, for example 2 to 40 mg of the active component.

A unit dose for parenteral administration preferably contains 0.2 to 5 mg of the active component.

Aerosol compositions are preferably formulated such that each delivered dose or "syringe" from an aerosol contains 0.2 to 2 mg of a compound of the invention while each dose administered via capsules or cartridges into an inhaler or blower 0.2 up to 20 mg. The total daily dose by inhalation will be in the range of 1 mg to 100 mg. The administration can be different a; ? *? «, - * 3,, /. / y

• - 'V

* X

- 7 - times a day, for example 2 to 8 times, for example, where 1, 2 or 3 doses are given.

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

According to another aspect of the invention, the compounds of formula C1) and their physiologically acceptable salts or solvates (e.g. hydrates) thereof can be prepared by the general methods indicated below. In the following methods, R 1, R 1, m and n 10 have the meanings of the general formula (1) unless otherwise indicated.

According to one general method (A), a compound of the general formula (1) can be prepared by condensing an amine of the formula (2) of the formula sheet with an acid of the general formula (3) of the formula sheet, or an acylating agent corresponding thereto, or a salt (for example, 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 involving the condensation of the amine of the formula (2) with the acid of the general formula (3) is best carried out in the presence of a coupling agent, for example carbonyl diimidazole or a carbodiimide, such as Ν, Ν ' -dicyclohexylcarbodiimide.

The condensation reaction can be carried out in a suitable reaction medium, such as an anhydrous medium, suitably at a temperature of -50 to + 50 ° C, preferably -5 to + 30 ° C. Suitable solvents 25. include halogenated hydrocarbons, for example dichloromethane, nitriles, for example acetonitrile, amides, for example N, N-dimethylformamide and ethers, for example tetrahydrofuran, as well as mixtures of two or more of such solvents. The reaction can also be conveniently conducted in the absence of a coupling agent in a suitable reaction medium such as hydrocarbon (eg toluene or xylene) at a temperature of 50 to 120 ° C.

Acylating agents corresponding to the acid of the general formula (3) which are useful for the preparation of the compounds of formula (1) include acid halides, for example acid chlorides.

Such acylating agents can be prepared by reaction of an acid ·; · ►> · ·> - ». Ia

ï V

Of the general formula (3), or a salt or a protected derivative thereof / with a halogenating agent such as phosphorus pentachloride, thionyl chloride, or oxalyl chloride. Other suitable acylating agents useful for the preparation of compounds of formula (1) include alkyl-5 esters such as the methyl ester, activated esters (e.g. the 2- (1-methylpyridinyl) ester) and mixed anhydrides (e.g. formed with pivaloyl chloride, a sulfonyl halide such as methanesulfonyl chloride or a haloformate, such as a lower alkyl haloformate).

For example, acids of formula (3) can themselves be prepared by cyclizing an appropriate hydrazine compound, analogously to the method (3) to be described below.

When an acylating agent corresponding to the acid of the general formula (3) is used, the condensation process can be carried out in aqueous or non-aqueous reaction media suitably at a temperature of -70 to + 150 ° C. Thus, the condensation reaction with an acid halide, anhydride or activated ester 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 are optionally carried out in the presence of a base such as a tertiary amine, for example triethyl amine 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, suitably at a temperature of 0 to 100 ° C . In some cases, the amine of formula (2) itself may act as the reaction solvent.

According to another general method (B), compounds of formula (1) can be prepared by cyclizing a compound of the general formula (4) of the formula sheet, wherein Q is the group NR- ^ R ^ (or a protected derivative thereof ) or a branching atom or branching group such as a halogen atom (e.g. chlorine or bromine) or an acyloxy group (e.g. a carboxylic acid or sulfonic acid acyloxy-35 group such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy,

"·" * "V · tM

* - * - 9 - p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group).

The reaction may conveniently be carried out in aqueous or non-aqueous reaction media at temperatures from 20 to 200 ° C, preferably from 50 to 125 ° C.

Particularly suitable embodiments of the general method (B) are described below.

When Q is the group NR ^ R ^ (or a protected derivative thereof) it is desirable to carry out the process in the presence of a polyphosphate ester in a reaction medium containing one or more organic solvents, preferably halogenated hydrocarbons, such as chloroform , dichloromethane, dichloroethane, dichlorodifluoromethane, or mixtures thereof. The polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform by the method described in "Reagents for Organic Synthesis", 15 (Fieser and Fieser, John Wiley and Sons 1967).

Optionally, the cyclization can be carried out in an aqueous or non-aqueous reaction medium, in the presence of an acid 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 tetrahydrofuran) as well as mixtures of such solvents, while the acid catalyst is for example an inorganic acidic such as concentrated hydrochloric acid or sulfuric acid or an organic acid such as acetic acid. (In some cases, the acidic catalyst can also function as a reaction solvent). In an anhydrous reaction medium that may include one or more ethers (e.g., as previously described) or esters (e.g., ethyl acetate), the acidic catalyst is generally a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride.

When Q is a cleavable group such as a chlorine or bromine-30 atom, the reaction can be in an aqueous organic solvent, such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran) in the absence of an acidic catalyst, suitably at a temperature of from 20 to 200 ° C, preferably from 50 to 125 ° C. This process results in the formation of a compound of formula (1) in which? -1 * ***

* »V

R 10 and R 2 are both hydrogen atoms.

According to a particular embodiment of the general method (B), compounds of formula (1) can be prepared directly by the reaction of a compound of the general formula (5) of the formula-5 sheet, or a salt thereof with a compound of formula (6) of the formula sheet (wherein Q has the aforementioned meaning) or a salt or a protected derivative thereof (such as an acetal or ketal formed, for example, with a suitable alkyl orthoformate or suitable diol, or protected as a bisulfite addition complex) using the suitable conditions as described above for the cyclization of the compounds of the general formula (4). It will be understood that in this embodiment of the cyclization process (B) a compound of the general formula (4) is formed as an intermediate, which can be reacted in situ to form the desired compound of the general formula (1).

Compounds of the general formula (4) may be isolated if desired as intermediates during the process for the preparation of compounds of formula (1), wherein a compound of formula (5), or a salt or a protected derivative thereof, with the Bond of formula (6), or a salt or a protected derivative thereof, in a suitable solvent, such as an aqueous alcohol (eg methanol), is reacted at a temperature of eg 20 to 30 ° C. When an acetal or ketal of a compound of formula (6) is used, it is sometimes necessary to carry out the reaction in the presence of an acid (eg acetic acid or hydrochloric acid).

For example, compounds of the general formula (5) can be prepared from the corresponding nitro compounds by conventional procedures.

A further general method (c) for preparing compounds of the general formula (1) involves the reaction of a compound of the general formula (7) of the formula sheet (wherein Y is an easily replaceable group) or a protected derivative thereof with an amine of the formula R ^ R ^ NH.

The substitution reaction may suitably to those compounds according to -. *; * -¾,; v - 11 - formula (7) can be carried out, in which the substituent group Y is a halogen atom (for example chlorine, bromine or iodine) or a group ORg in which 0Ro for example an acyloxy group derived from a carboxylic acid or sulphone- acid, such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoro-acetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyl oxy group.

The replacement reaction may conveniently be conducted in an inert organic solvent (optionally in the presence of water), examples of which include alcohols, e.g. ethanol; cyclic ethers, for example dioxane or tetrahydrofuran; acyclic ethers, for example diethyl ether; esters, for example ethyl acetate; amides, for example, Ν, Ν-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 (7) wherein Y is a halogen-15 atom can be prepared by a hydrazine of the general formula. (5) reacting with an aldehyde or ketone (or a protected derivative thereof) of formula (6), wherein Q is a halogen atom, in an aqueous alkanol (e.g. methanol) containing an acid (e.g. acetic acid or hydrochloric acid) contains. Compounds according to formula (7), wherein Y is the group OR- can be from the corresponding compound

"O

bond, wherein Y is a hydroxy group, are prepared by acylation or sulfonylation with the appropriate activated compound type (e.g., anhydride or sulfonyl chloride) using conventional techniques. The intermediate alcohol can be prepared by a compound.

Thing of formula (4), wherein Q is a hydroxyl group (or a protected derivative thereof) to be cyclized under standard conditions.

Compounds according to formula. (1) can also be prepared according to another general method (D), which involves the reduction of a compound of the general formula (8) of the formula sheet 30 (of which W is a group that can be reduced to the required - (CH ^) ^ NR ^ R ^ group or which is a protected derivative of - (CH ^) or a salt or protected derivative thereof.

The required (CS ^ 2 ~ and "^ 3 ^ 4 groups in 5th 3 position) can be formed by reduction steps that run individually or together in any suitable manner.

* -i - 12 -

Examples of groups represented by the substituent w include - (CH 2) 2 NO 2; -CH = CHNO2; - (CH ^ N ^ · -C ^ CN; -C ^ CHO; -COC ^ Z; -CH2CH = NOH; and -CH (OH) C ^ NR ^ R ^; (where Z is an azido group or the -NR group ^ R ^ or a protected derivative thereof).

Groups which can be reduced to the - (CH2) 2 moiety in the 3-position include the corresponding unsaturated group and the corresponding groups having a hydroxyl group or a carbonyl function.

Groups which can be reduced to the group -NR 1 R 2, where R 1 and R 2 are both hydrogen, include nitro, azido, hydroxyimino and nitrile groups. In the latter case, the reduction yields the group -CH2NH2 and a methylene group of the - (CH2) 2 unit is thus obtained.

The required -NR ^ R ^ group, wherein R ^ and / or R ^ are other than hydrogen, can be prepared by reduction of a nitrile -CH2CN or an aldehyde -CH2CHO in the presence of an amine, R ^ R ^ NH.

A particularly suitable process for the preparation of a compound of formula (1), wherein R 1 and / or R 1 is other than hydrogen, involves reductive alkylation of the corresponding compound, wherein R 1 and / or R 1 represent hydrogen with a suitable aldehyde or ketone (eg, formaldehyde or acetone) in the presence of a suitable reducing agent. In some cases (eg for entering the groups R 1 and / or R 3 when these represent methyl) the aldehyde (eg formaldehyde) can be condensed with the amine and the intermediate thus formed can then be reduced with a suitable reducing agent .

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

Suitable reducing agents used in the above method for the reduction of compounds of the formula (8), wherein W is, for example, the groups - (CH ^ NC ^, -CH = CHNC> 2, - (CHj) Ng, -CH2CN, -CH2CH = NOH and -CH (OH) CH2NR3R4 are useful include hydrogen in the presence of a metal catalyst, for example Raney Nickel or a noble metal catalyst such as platinum, platinum oxide, palladium, palladium oxide, 35 or rhodium, which can be carried, for example - on charcoal, kieselguhr - 13 - or alumina In the case of Raney Nickel, hydrazine can also be used as hydrogen, This process may suitably be in a solvent such as an alcohol, for example ethanol, an ether, for example dioxane or tetrahydrofuran, an amide, for example dimethylformamide 5 or a ester, for example ethyl acetate, at a temperature of from -10 to +50 ° C, preferably -5 to +30 ° C.

The reduction process can also be carried out on compounds of formula (8), wherein W is, for example, the groups - (CH ^), -CH = CHNO2, - (CH2) 2 ^, -CH (OH) C ^ NR ^ R ^ or -COCI-Z (wherein Z has the aforementioned meaning-10 s), using an alkali metal or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, which process is suitable for an alcohol such as propanol or ethanol, or a nitrile such as acetonitrile, is carried out at a temperature of 10 to 100 ° C, preferably 50 to 100 ° C. In some cases, the reduction with borohydride can be carried out in the presence of cobalt chloride.

The reductive alkylation of a compound of formula (8) can be carried out with; an alkali metal or alkaline earth metal borohydride or cyanoborohydride. The reaction can be carried out in an aqueous or non-aqueous reaction medium, suitably in an alcohol (e.g. methanol or ethanol) or an ether (e.g. dioxane or tetrahydrofuran) optionally in the presence of water. The reaction is conveniently conducted 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 (8), wherein W is the group -Ci-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 the presence of an amine HNR ^ R ^ 30 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) in which R 1 is a hydrogen atom can also be prepared by hydrogenolysis of a corresponding compound in which R 1 is a benzyl group, for example with hydrogen in the presence of a catalyst, for example 10% palladium-op- cabbage.

.-j * »* - 14 -

The starting materials or intermediates of formula (8), wherein W represents - (CH 2) 2 NO 2, -CH = CHNO 2, -CH 2 CN or -COCH 2 Z, may be according to methods analogous to those described in British Patent Application No. 2,035,310 and in "A Chemistry or Heterocyclic Compounds - Indoles 5 Part II "/ Chapter VI, published by WJ Houlihan (1972) Wiley Interscience, New York.

Compounds of the formula (8), wherein W is the group -CH 2 CHO, can be prepared by oxidation (e.g. with Jones' reagent) of a compound of the formula (7), wherein Y is a hydroxyl group.

A compound of formula (8), wherein W is the group -CH 1 CH 2 NOH, can be prepared by treatment of the corresponding aldehyde with hydroxylamine hydrochloride under standard conditions.

The intermediate of formula (8), wherein W is the group - (C 1) 2 N 2, can be prepared from a compound of formula (7), wherein Y is a halogen atom under standard procedures.

Standard reducing agents such as sodium borohydride can be used to prepare a compound of formula (8), in which W is the group -CH (OH) CH 1 N 2 R 1 R from the corresponding compound of formula (8), wherein W is the group -COCH 1 jNR ^ R ^ is.

According to a further general method (E), a compound of formula (1) according to the invention, or a salt or a protected derivative thereof, can be converted into another compound of formula (1) using conventional procedures.

For example, a compound of the general formula (1), wherein one or more of R 2, R 1, and R 1, are alkyl groups, from the corresponding compounds of formula (1), wherein one or more of R 2, R 1, and R 1 represents hydrogen atoms, prepare by reaction with a suitable alkylating agent such as a compound of formula R L (wherein R is the

X X

desired R2, R1 or R1 group and L represents a cleavable group such as a halogen atom or a tosylate group) or a sulfate (R1) 2 ^ 0 ^. Thus, the alkylating agent may be, for example, an alkyl halide (e.g. methyl or ethyl iodide), alkyl tosylate (e.g. methyl tosylate) or dialkyl sulfate (e.g. dimethyl sulfate).

The alkylation reaction may suitably be in an inert organic solvent, such as an amide (eg dimethylformamide), an ether * * * fc * V / / .m> - 15 - (eg tetrahydrofuran) or an aromatic hydrocarbon (e.g., toluene) preferably be conducted 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; 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 can also be carried out in the presence of an acid binding agent such as propylene or ethylene oxide.

The reaction is suitably carried out at a temperature from -20 to +100 ° C.

Compounds of formula (1) wherein R 2 and R 2 represent only or both propenyl may be prepared in a similar manner using a suitable compound of formula R 1 L or (R 2 SO 2).

According to another embodiment of the general method (E), compounds of the general formula (1) wherein R 1 represents a group R 2 CONH (CH 2) - or a group R 1 SO 2 N (CH 2) can be prepared by o 2 p * K 7 2 2 p a corresponding compound of the general formula (1) / wherein R ^ HgNiC ^) - proposes to react with a reactant serving to introduce the group R ^ CO- or R ^ SQ ^ -. Suitable reactants include acids of the formula R 2 COOR and acylating derivatives thereof, as well as sulfonylating agents corresponding to acids of the formula R-SO.H.

/ 3

Derivatives of the acids R 2 COOH and R 2 SO 4 H useful in this embodiment of the general process (E) include acid halides, for example, carboxylic acid chlorides and sulfonyl chlorides; mixed anhydrides; alkyl esters; and activated esters, for example the 2- (1-methylpyridinyl) ester; as previously described for the general procedure (A). The acylation reaction with an acid of the formula R 2 COOH or an acylating derivative thereof or a sulfonylating agent corresponding to the acid R 2 SO 2 H can be carried out under similar reaction conditions as those described above for the general process (A).

According to a further embodiment of the general method (E), compounds of the general formula (1) can contain a group

1 V

- 16 -

RrR..NCO (CH2) - are prepared by reacting a corresponding compound of the general formula (1) wherein R ^ RgC ^ C ^ C ^) ^ - with a amine RCR NH. The replacement reaction with an amine of the formula R 1 RgNH can be carried out under similar reaction conditions as those described above for the general process (C).

Compounds of the general formula (1), wherein R 1 represents HjN-, may also be prepared by a further general method (F), comprising the reduction of a compound of the general formula (10) from the formula sheet.

The reduction can, for example, be carried out with hydrogen in the presence of a metal catalyst. Useful catalysts include Raney Nickel, or a noble metal catalyst such as platinum, platinum oxide, palladium, palladium oxide or rhodium, which may be, for example, based on charcoal, kieselguhr or alumina. Hydrazine can also be used as a hydrogen source for Raney Nickel. The reduction according to the general method (F) may suitably be in a solvent such as alcohol, for example ethanol; an ether, for example dioxane or tetrahydrofuran; an amide, for example dimethylformamide; or an ester, for example ethyl acetate. The reduction can be carried out at a temperature in the range from -10 to + 50 ° C, preferably -5 to + 30 ° C.

Compounds of the general formula (10) can be prepared by cyclizing a corresponding hydrazone, as described in method (B). Optionally, one can prepare compounds of formula (10), wherein n is zero, by an indole of the general formula (11) of the formula sheet (wherein X represents a cleavable atom or cleavable group such as a halogen atom, eg bromine or iodine atom ) reacting with a compound of formula (12) of the formula sheet in the presence of carbon monoxide and a palladium catalyst.

The reaction can also be carried out in the presence of a base. For example, the palladium catalyst can be a palladium salt derived from an organic acid, for example, an acetate, or derived from an inorganic acid, for example, a chloride or bromide; a paladium complex such as a triarylphosphine complex, for example a triphenylphosphine or tri (2-methylphenyl) phosphine palladium complex, or finely divided palladium metal, such as palladium on charcoal. One can • . Forming a triarylphosphine palladium complex in situ by reacting a palladium salt, for example palladium acetate or palladium chloride, with the appropriate triaryl phosphine. The reaction can be carried out in the presence or absence of a solvent.

Suitable solvents include nitriles, eg acetonitrile? alcohols, for example, methanol or ethanol; amides, for example dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, and water. The reaction can conveniently be carried out at a temperature of from -10 to + 150 ° C.

According to another general method (G), a compound of the general formula (1) according to the invention, or a salt thereof, can be prepared by subjecting a protected derivative of the general formula (1) or salt thereof to a reaction in which the protecting group or groups are removed.

Thus, at an early stage of the reaction sequence for the preparation of a compound of the general formula (1) 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 1 R 3, where R 1 and / or 20 R 2 represents hydrogen, by protonation or with a group that is easily removable at the end of the reaction sequence. Such groups contain, 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 to protect the indole nitrogen with, for example, an aralkyl group such as benzyl.

The subsequent cleavage of the protecting group or groups can be prepared according to conventional procedures. Thus, an aralkyl group such as benzyl can be cleaved off by hydrogenolysis in the presence of a catalyst (eg palladium on charcoal) or sodium and liquid ammonia; an acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example, by catalytic hygenation. The phthaloyl group can be removed by hyrazineolysis (eg by treatment with hydrazine hydrate) or by treatment with a primary am-amine (eg methylamine).

It will be appreciated that in some of the general methods (A) through (F) as previously described it may be necessary or desirable to protect any sensitive groups in the molecule as just described. Thus, a reaction step involves the removal of the protecting group from a protected derivative of the general formula (1) or a salt thereof which can be carried out after any of the previously described processes (A) to (F).

Thus, according to a further aspect of the invention, the following 10 'reactions may be carried out in any suitable order, if necessary and / or if desired, after any of methods (A) to (F): (i) removal of all protecting groups; and (ii) conversion of a compound of the general formula (1) or a salt thereof into a physiologically acceptable salt or solvate (eg hydrate) thereof.

% <; · 1-1 - <· »♦ -« f -19-

When it is desirable to isolate a compound of the invention as a salt, for example an acid addition salt, this can be accomplished by treating the free base of the general formula (1) with a suitable acid, preferably with an equivalent amount or with creatinine sulfate in a suitable solvent (eg aqueous ethanol).

The starting materials or intermediates for the preparation of the compounds of the invention may be prepared according to methods analogous to those described in British Patent No. 2035310.

The general process as indicated above for the preparation of the compound of the invention, except as the last major step in the preparation order, may also be used to introduce the desired groups at an intermediate stage in the preparation of the required compound. Thus, for example, the required group can be introduced at the 5-position before or after cyclization to form the indole core.

It will therefore be apparent in such multistage processes that the order of the reactions should be chosen so that no groups present in the molecule, which are desired in the final product, are affected at the respective reaction conditions.

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

The chromatography was performed either in the usual manner with silica gel (Merck, Kieselgel 60, Art. 7734) or by flash chromatography on 25: silica (Merck 9385) and thin layer chromatography (tlc) on silica (Macherly-Nagel, Polygram) except when otherwise indicated.

Intermediate 1 J

3- [2- (Dimethyl) ethyl] N- [2- (nitrophenyl) ethyl] -1H-indole-5-carboxamide 30 A solution of 5-iodo-N, N-dimethyl-1H-indole-3-ethanamine ( 100 mg), p-nitrophenethylamine (80 mg), tributylamine (0.3 ml) and dichlorobis (triphenylphosphine) palladium (II) (24 mg) in dry acetonitrile (5 ml) under a carbon monoxide atmosphere at the reflux temperature for Stirred at room temperature overnight (16 hours). The solvent was removed under reduced pressure in the presence of silica gel (Merck 9385). The impregnated silica was applied to a silica column as a 1 µl-20 plug (Merck 9385) and eluting with dichloromethane-ethanol-ammonia (75: 8: 1). The title compound as an oil (47 mg ).

T.l.c. silica dichloromethane-ethanol-aqueous ammonia (75: 8: 1) 5 Rf 0.19 (main) detection u.v., IPA, KMnO4.

Intermediate 2 3-f2- (Dimethylamino) ethyl1-1H-indole-5-acetic acid.

A suspension of 3- [2- (dimethylamino) ethyl] -1 H -indole-5-carbonitrile oxalate (5.6 g) in 2N sodium hydroxide (80 ml) was heated at 80 ° for 10 hours. The reaction mixture was neutralized to pH 7 by dropwise addition of concentrated hydrochloric acid and the reaction mixture was evaporated in vacuo. The residue was extracted with a mixture of methanol-chloroform (1:10), filtered and concentrated in vacuo to a foam (4.0 g).

15 Analysis found: C 66.1; H 8.0; N 10.3; CL. H10 N_0, .0.2H-0.0.3CoH, O requires: C 66.5; H 7.7; N 10.6% 14 lo 2 2 2. 2 o HO determination contains 1.5% HO w / w a 0.2 mol HO 2 2 2

EXAMPLE I

N-L2- (4-Aminophenyl) ethyl3-3-1-2- (dimethylamino) ethyl] -1H-indole-5-carboxylamide.

A suspension of 10% PdO / C (34 mg of a 50% paste with ^ 0) in absolute ethanol (10 ml) was stirred under a hydrogen atmosphere at room temperature and pressure for 0.5 hour. A solution of intermediate (1) (98 mg) in ethanol (7 ml) was added and the mixture stirred for 4 hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give an oil (ca 100 mg) which was purified by column chromatography over silica gel (Merck Art, 9385). Elution with isopropyl alcohol-diethyl ether-aqueous ammonia (20: 20: 8: 1) gave the title compound as a foam (50 mg).

T.L.c. Silica-isopropyl alcohol-ether-water ammonia (20: 20: 8: 1) Rf 0.30 detection u.v., IPA.

Nmrδ (DMSO-dg includes 22.30 (6-H-, s. NMe2); 2.60 (2H, brt, -CH2 NMe2); 2.70 (2H, brt, PhCH2 ~); 2.90 (2H , brt, -CH2CH2NMe2), 4.86 (brs, NH2), 8.38 (1H, brt, NHCO, and 11.04 (1H brs indole NH).

♦ 1 *. '·· <-21-

7QORBESLD II

H-C 2- [4- (Acetylamino) phenyl] ethyl] -3- [2- (dimethylamino) ethyl! 1 H -indole-5-carboxamide.

Acetyl chloride (0.32 ml) was added dropwise for 10 min.

5 to a stirred solution of the product of Example I (1.6 g) in pyridine (10 ml) at 0 ° C under a nitrogen atmosphere. The solution was allowed to warm to room temperature and stirring was continued for 17 hours. The reaction was quenched by adding ice and the resulting solution was stirred for 0.5 hour. The solution. The agent was removed under reduced pressure (last traces of water under azeotrope formation with toluene) and the residue dissolved in methanol (20 ml). Concentration of the solution under vacuum in the presence of silica gel (Merck Art. 7734) gave a powder which was applied as a plug to the silica column (Merck Art. 9385)). Elution with dichloromethane-ethanol-. Aqueous ammonia (50: 8: 1) gave the title compound as a foam (634 mg), which was further purified by HPLC to provide the title compound as a foam (174 mg).

T.1, c. Silica dichloromethane-ethanol-aqueous ammonia (25: 8: 1), Rf 0.38 detection u.v., IPA.

20 Analysis found: C 66.9; H 7.2; N 13.2

CooHnoN.0_.0.3 C-K-O.0.8HO requires: C 67.4; H 7.5; N 13.3% 23 28 4 2 26 2

example 'III

3- [2- (Dimethylamino) ethyl] -N- [2- [4- [(methylsulfonyl) amino] phenyl3-ethyl] -25H-indole-5-carboxamide.

To a cold (ca. 10 °) stirred solution of the product of Example I (694 mg) in pyridine (15 ml), methanesulfonyl chloride (0.28 ml) was added under a nitrogen atmosphere. Stirring was continued at room temperature for 26 hours. The solvent was removed under vacuum and the residue dissolved in ethanol (approx. 20 ml). Water (approx.

10 ml) was added to the solution, followed by solid potassium carbonate until two layers were observed. The water phase was extracted with ethanol (2x10 ml), after which the combined organic phases were concentrated under reduced pressure to obtain an oil (about 1.5 g). Purification by column chromatography on deactivated alumina using iso- ».

-22- propyl alcohol-diethyl ether-aqueous ammonia (65: 120: 16: 2) as an eluent as an crude title compound in the form of an oil (364 mg) and a pure title compound in the form of an oil which when triturated with dry ether yielded a solid (150 mg) mp 106-109 ° (decomposition).

T.l.c. alumina isopropyl alcohol-diethyl ether-water-ammonia (65: 120: 16: 2) Rf 0.7 detection u.v., IPA.

Analysis found C 58.6; H 6.7; N 12.0 C „H_QN.0, S.0.5C_Hc0.o.95 HO requires: C 59.0; H 7.0? N 12.0% 22 28 4 3 2 b 2

EXAMPLE IV

Methyl 4- [2 - [[[3- (2-aminoethyl) -1H-indol-5-ylcarbonyl] amino] ethyl] -benzoate hemisuccinate hydrate (4: 2: 3).

(i) Methyl-4- [2 - [[[3- [2 - [[(phenylmethoxy) carbonyl] amino] ethyl] -1H-indol-5-yl] carbonyl] amino methyl benzoate.

A solution of 3- [2 - [[(phenylmethoxy) carbonyl] aminojethyl] -1H-indole-5-carboxylic acid was treated with 1,1'-carbonyldiimidazole (0.324 g) and stirred at room temperature for 2 hours. (Solution A). A suspension of methyl 4- (2-aminoethyl) benzoate hydrochloride (0.435 g) in anhydrous tetrahydrofuran (20 ml) was treated with triethylamine (0.28 ml) and stirred at room temperature for 1 hour (suspension B).

Suspension (B) was added to solution (A) and stirred at room temperature for 48 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to obtain a gum (1.3 g) which was chromatographed on silica gel (Merck 7734) and eluted with isopropyl acetate. The product which separated as crystals from the appropriate fractions was collected and dried to give the title compound (0.34 g) mp 151-153 °.

(ii) Methyl-4- [2 - [[[3- (aminoethyl) -1H-indol-5-yl] carbonyl] aminoethyl] benzoate hemisuccinate hydrate (4: 2: 3).

A suspension of 10% palladium oxide on charcoal (0.35 g of a 50% paste with water) in ethanol was pre-reduced by stirring under hydrogen atmosphere for 0.5 hour. A solution of the product of step (i) (0.333 g) in ethanol (25 ml) was added to the catalyst suspension and the mixture was stirred under a hydrogen atomosphere for 0.75 h until hydrogen uptake ceased (18 ml). The catalyst (d4) and the solvent were removed by filtration and rotary evaporation, respectively, to give a free base as a gum (0.22 g).

The free base (0.22 g) in hot isopropanol (2 ml) was treated with a hot solution of 12 succinic acid (0.037 g) in hot isopropanol (2 ml). After removing the solvent (by evaporation under reduced pressure), the residue was triturated with anhydrous ether to give the title compound as a powder (0.225 g) mp 170-5 °.

T.l.c. Silica dichloromethane / ethanol / axonmonium hydroxide (35/8/1) Rf 0.4 detection UV (IPA

10 Analysis found C 63.0? H 6.05; N 8.99 C-.H-.N-CL.O.SC.H 0.75 H 2 O requires C 63.07; H 6.33; N 9.59%.

21 23 3 3 4 6 4 2 EXAMPLE V.

3- (2-Aminoethyl) -N - [- 2- [4- (dimethylamino) phenyl] ethyl 3-1 H -indole-5-carboxamide dihydrochloride.

(I) PhenylmethylC2- [5-C C2- (4-dimethylaminophenyl) ethyl] amino] carbonyl-3H-indol-3-yl) ethylcarbamate hemihydrate.

A solution of 3- [2- [[(phenylmethoxy) carbonyl] amino jet'nyl] -1H-indole-5-carboxylic acid (1.69 g) in anhydrous tetrahydrofuran (25 ml) was mixed with N, N'-carbonyldiimidazooK0, 89 g) treated and stirred under reflux for 1 hour. A solution of 2- (4-dimethylaminophenyl) ethylamine (0.82 g) in anhydrous tetrahydrofuran (10 ml) was added to the solution and the mixture stirred at room temperature for 20 hours. The solution was evaporated under reduced pressure and the residue was mixed with water (150 ml) and extracted with ethyl acetate (4 x 40 ml). The combined organic extracts were washed with 8% aqueous sodium bicarbonate solution (3 x 30 ml), dried (MgSO 2) and evaporated to give a gum (2.5 g). This material was chromatographed on silica gel (200 g, Merck 7734) eluting with isopropyl acetate / petroleum ether (bp 60-80 °) (1: 1) followed by isopropyl acetate. Evaporation of the appropriate fraction gave a solid (2.3 g) which was triturated with anhydrous ether to give the title compound as a powder (1.86 g) mp 139-142 °.

T.l.c. Silica, dichloromethane / ethanol / 0.88 ammonium hydroxide (100: 8: 1)

Rf 0.45 detection: u.v. IPA.

1% ». · 2 - 1 - · - · - <- -24- (ii) 3- (-Aminoethyl9-N- [2- [4- (dimethvlamino) phenyl] ethyl] -1H-indole-5-carboxamide dihydrochloride.

A suspension of 10% palladium oxide on charcoal (1.0 g of a 50% water paste) (50 ml) was pre-reduced by stirring in a nitrogen atmosphere for 0.5 hour. The product of step (i) (1.0 g) in ethanol (100 ml) was added to the pre-reduced catalyst and the mixture was stirred under nitrogen for 1.5 hours until nitrogen uptake was stopped (60 ml). The catalyst and solvent were removed by filtration and rotary evaporation, respectively, to give a gum (0.9 g) which was chromatographed on a column of silica gel (100 g of Merck 7734) eluting with dichloromethane / ethanol / 0.88. ammonium hydroxide (50: 8: 1). Evaporation of the appropriate fractions produced the free base of the title compound in the form of a gum (0.65 g). This material (0.65 g) was dissolved in hot ethanol (20 ml), treated with excess ethereal hydrogen chloride and diluted with ethyl acetate (20 ml). The solution was concentrated until it became cloudy, then allowed to cool and a solid was crystallized. After the solid was collected by filtration, it was washed with ethyl acetate (10ml) and then dried to afford the title compound as a powder (0.415g) mp 210-212 °.

T.l.c. Silica, dichloromethane / ethanol / 0.88 ammonium hydroxide (25/8/1)

Rf 0.45. Detection, u.v. IPA.

Analysis found: C 55.83; H 6.34; N 12.01; Cl, 18.64, C, HNN.2.2HC1.0.6H 0.0.4HC1 requires: C 56.20; H 6.65; N 12.48; Cl 18.95 21 264 2

EXAMPLE VI

3- (2-Aminoethyl) -N-CC4- (1-pyrrolidinyl) phenyl] methyl] -1H-indole-5-carboxamide hemisuccinate.

(i) Phenylmethyl [2- [5 [[[[4- (1-pyrrolidinyl) phenyl] methyl] amino] carbonyl] -1H-indol-3-yl ethyl carbamate.

A solution of 3— [2-CC (phenylmethoxy) carbonyl] amino] ethyl] -1H-indole-5-carboxylic acid (1.69 g) in anhydrous tetrahydrofuran (25 ml) was added with 1,1-carbonyldiimidazole (0, 89 g) treated and refluxed for 1 hour. A solution of 4- (1-pyrrolidinyl) phenyl-methylamine (0.88 g) in anhydrous tetrahydrofuran (10 ml) was added and the resulting solution at room temperature for 48 hours; Stirred. The mixture was evaporated to dryness under reduced pressure to give a foam (2.4 g) which was eluted by chromatography with petroleum ether ( b.p. 60-80 °) and petroleum ether (b.p. 60-80 °) / isopropyl acetate (1: 1) was purified Evaporation of the appropriate fraction of 5-5 yielded the title compound in the form of a powder (0.85 g) mp 154-157 °.

(ii) 3- (2-Aminoethyl9-N- [[4- (1-pyrrolidone) phenyl] methyl] -1H-indole-5-carboxamide hemisuccinate.

A suspension of 10% palladium oxide on charcoal (0.8 g of a 50% paste with water) in ethanol (25 ml) was stirred under an aqueous atmosphere for 0.5 hour. A solution of the product of stage (i) (0.75 g) in ethanol (100 ml) was added to the pre-reduced catalyst suspension and the resulting mixture was stirred under a hydrogen atmosphere for 4 hours. The suspension was filtered and the filtrate evaporated under reduced pressure to obtain a gum (0.35 g) which was chromatographed on a column of silica eluting with dichloromethane / ethanol / 0.88 ammonium hydroxide mixture (200/8/1 - 25/8/1). Evaporation of the appropriate fractions gave the free base of the title compound in the form of a gum which solidified to a solid (0.079 g). The free base (0.079 g) was taken in a hot mixture of isopropanol (2 ml) and methanol ( 3 ml) and treated with a hot solution of succinic acid (0.0134 g) in isopropanol (2 ml). By concentrating and subsequently cooling the solution, the title salt crystallized as a solid (0.056 g) melting point (234-8 °).

Analysis found: C 67.99; H 7.08, N 13.03 C.XJ.O.C LO requires C 68.39; H 6.93; N 13.29% 22 26 4 2 3 2

EXAMPLE VII

N-2- [4-C (2-Amino-2-oxoethyl) phenylethyl] -3- [2- (dimethylamino) ethyl] -1H-30 indole-5-carboxamide oxalate (i) 4- (Cyanomethyl) benzenacetic acid.

A suspension of 4 - [(aminocarbonyl) methylbenzene acetic acid (1.58 g) in dry 1,4-dioxane (50 ml) was cooled to below 15 ° and treated with dry pyridine (1.3 ml) followed by trifluoroacetic acid-anhydride (2.31 ml). The resulting solution was stirred under 15 ° under nitrogen atmosphere for 1.5 hours. Water (10 ml) was added to the solution and the solvent was removed in vacuo. The residue was partitioned between water (100ml) and ethyl acetate (100ml) and the aqueous layer was separated and extracted with ethyl acetate (100ml).

The combined extracts were dried (MgSC> 4) and concentrated under reduced pressure to give a solid (approx. 3 g) which was purified by flash chromatography. The elution with 1% acetic acid in dichloromethane gave two samples of the title compound (200 mg) mp 116-117 °, (500 mg) mp 115-117 ° as crystalline solids.

(Ii) 4- (cyanomethyl) benzene acetamide

To a stirred fine suspension of the product from step (i) (115 mg) in dry tetrahydrofuran was added triechylamine (0.175 ml) followed by diphenylphosphorylazide (0.28 ml) under nitrogen atmosphere at room temperature. A saturated solution of ammonia in dry tetra-hydrofuran (10ml) was added to the reaction mixture and stirring continued for 5 hours. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with a 10% acetic acid solution in dichloromethane to afford the title compound as a solid (approximately 30mg), mp 158-160 ° ( decomposition).

(iii) 4- (2-aminoethyl) benzeneacetamide hydrochloride)

The product of step (ii) (136 mg) in ethanolic hydrogen chloride (10 ml) was hydrogenated under one atmosphere of hydrogen at room temperature for 30 hours over pre-reduced 10% palladium-on-25 carbon (150 mg of a 50% strength pasta with water). The catalyst was removed by filtration and the filtrate evaporated in vacuo to give crude title compound as a solid (approximately 40mg).

The catalyst was washed with hot ethanol (100ml) and the ethanolic solution concentrated in vacuo to further obtain a pure title-30 compound as a crystalline solid (133mg).

T.l.c. Silica, dichloromethane-ethanol-acetic acid (150: 8: 1), Rf 0.08, detection UV, IPA.

- 27 - (iv) N- £ 2- [4- (2-amino-2-oxoethyl) phenyl] ethyl] -3- [2- (dimethylamine) ethyl] -1H-indcol-5-carboxamide oxalate

Diphenylphosphorylazide (0.27 ml) was added to a stirred suspension of 3 - [(2-dimethylamino) ethyl] -1 H -indole-5-carboxylic acid (144 mg) and the product of step (iii) (133 mg) in triethylamine (0.2 ml) and dry dimethylformamide (10 ml) added at 0 ° under a nitrogen atmosphere.

The reaction mixture was slowly warmed to room temperature and stirred for 25.5 hours. The resulting solution was concentrated under vacuum (to approximately 1.5 ml) and applied directly to a silica gel column (Merck Art 9385; 2.5 cm diameter). The elution with dichloromethane-ethanol-aqueous ammonia (25: 8: 1) gave the free base of the title compound as a foam (179 mg).

T.l.c., Silica, dichloromethane-ethanol-aqueous ammonia (25: 8: 1)

Rf 0.31, detection u.v., IPA.

The foam (169 mg) was dissolved in absolute ethanol (1 ml) and added to a solution of oxalic acid (39 mg) in ethanol (0.5 ml). Ether (30 ml) was then added to the resulting precipitate.

The solvent was decanted and the solid washed with ether (30 ml) and dried at room temperature under vacuum for 30 hours to yield the title compound in the form of a fine powder (202 mg, 97%), mp 70-72 ° (foamed).

Analysis found: C 60.3; H 6.4; N 10.9.

C23H28N4O2 * C2H2O4'0.6S H2 ° requires: c 60.7; H 6'4? N 11 / -3%.

H 2 O determination: 2.46% H 2 O w / w * 0.68 mol.

EXAMPLE VIII

3- [2- (dimethylamino) ethyl] -N- [2- [4 - [(methylsulfonyl) amino] phenyl] ethyl] -1 H -indole-5-acetamide oxalate

Diphenylphosphoryl azide (1.73 ml) was added to a cooled (ice bath) solution of intermediate 2 (1.0 g), and N- [4- (2-aminoethyl) phenyl] -methanesulfone-30 amide (0.87 g) in dimethylformamide (140 ml) and triethylamine (1.13 ml) were added and the mixture stirred for 62 hours. The resulting solution was evaporated to dryness under vacuum and the residue was pre-adsorbed on silica (7734.5g). Purification by flash chromatography eluting with dichloromethane-ethanol-aqueous ammonia (100: 8: 1) to give the V- * 28 title compound as a free base in the form of an oil (1.0 g) which was dissolved in hot ethanol (7 ml), after which a solution of oxanoic acid _3 (0.25 g, 2.78x10 mol) in ethanol (2 ml) was added added. The solvent was evaporated in vacuo to give a foam which was triturated with ether 5 (50ml) to give the title compound as a foam (0.92g).

T.l.c. Silica, dichloromethane-ethanol-aqueous ammonia (50: 8: 1) Rf 0.5 Detection u.v. + IPA.

Analysis Found: C 54.8; H 6.1; N 9.9.

10 'C23H30N4O3S.C2H2O4.0,7H2O requires: C 55.1; H 6.2; N 10.3%.

H2O analysis found: 1.83% H2 <0 w / w 0.55 mole equiv. H2Q '.

EXAMPLE IX

3- [2- (dimethylamino) ethyl] -N- [4- [f (methylamino) sulfonyl] methyl] -phenyl] -1H-indole-5-acetamide oxalate 15 Trimethylacetyl chloride (0.27 ml) was cooled ( 5 °) suspension of intermediate 2 (0.5 g) in dichloromethane (100 ml) and triethylamina (0.71 ml) added and the mixture stirred for 30 minutes. Then 4-amino-N-methyl-benzenemethanesulfonarnide hydrochloride (0.48 g) was added and the mixture was stirred overnight.

Methanol (50 ml) was added to the resulting solution and the mixture was stirred for 10 minutes. The solvents were evaporated under vacuum and the residue was pre-adsorbed on silica (7734.5 g). Purification by flash chromatography under elution with dichloromethane-ethanol-aqueous ammonia (75: 8: 1) gave the title compound as a free base in the form of a colorless oil (0.6 g) which was dissolved in hot ethanol (20 ml) and then a solution of oxalic acid (0.13 g) in ethanol (3 ml) was added. On cooling, the title compound crystallized from the solution as a solid (0.59 g), mp 210-213 ° (foam). Analysis found: C 55.2; H 6.0; N 0.5 requires C22H28N4 ° 3S * C2H2 ° 4: C 55.6; H 5.8; N 10.8%.

* «- 29 -

EXAMPLE X

N- [2- [4- (acetylaaino) phenyl] ethyl] -3- [2- (dimethylamino) ethyl] -1H-indole-5-acetamido hydrochloride (i) 3- [2- (dimethylamino) ethyl] -N -E2- (4-nitrophenyl) ethyl] -1H-indole-5-5 acetamido hydrochloride

Diphenylphosphorylazide (2.1 ml) was added to a cooled (ice bath) solution of intermediate 2 (1.2 g) and 4-nitrophenetylamine hydrochloride (1.0 g) in dimethylformamide (200 ml) and triethylamine (1.4 ml) and the mixture was stirred for 1 hour. The solution was allowed to warm to room temperature and stirring was continued for a further 12 hours. The resulting solution was evaporated to dryness under vacuum and the residue was pre-absorbed on silica (9385.3 g). Purification by column chromatography (Silica 7747, 125 g) eluting with dichloromethane-ethanol-aqueous ammonia (50: 8: 1) gave the crude title-15 compound as a free base. A second column (Silica 7747, 50 g) with eluent dichloromethane-ethanol-aqueous ammonia (100: 8: 1) gave the pure title compound as a free base in the form of an oil (0.8 g), part of which ( 0.20 g) was dissolved in a mixture of ethanol (1 ml) and isopropanol (8 ml). Etheric hydrochloride was added to pH 1. Addition of diethyl ether gave the title compound in the form of a foam (0.20 g).

T.l.c. Silica, dichloromethane-ethanol-aqueous ammonia (50: 8: 1) Rf 0.5 Detection u.v. + IPA.

(ii) N- [2- [4-acetlamino) phenyl] ethyl] -3- [2- (dimethylamino) ethyl] -1H-25 indole-5-acetamide hydrochloride

A solution of the free base of the product of step (i) (0.5 g) in ethanol (35 ml) and ethanolic hydrogen chloride (6 ml) was stirred over 10% palladium at room temperature and atmospheric pressure for 30 minutes. - charcoal (50% paste with water, 0.5 g) hydrogenated. The catalyst was filtered off and washed with methanol (20 ml).

The combined filtrates were evaporated to dryness under vacuum and the residue was pre-adsorbed on silica (7734, 2 g). Purification by chromatography eluting with dichloromethane-ethanol-aqueous ammonia (50: 8: 1) gave N- [2- (4-aminophenyl) ethyl] -3- [2- (dimethylamino) ethyl] -1H-indcol- 5-r * -30-acetamide (0.39 g). To a solution of this amine (0.37 g) and triethylamine (0.17 ml) in dichloromethane (40 ml), acetyl chloride (0.087 ml) was added and the mixture stirred for 30 minutes. A further amount of acetyl chloride (0.02 ml) was added and stirring continued for 30 minutes. Methanol (20 ral) was added to the mixture which was then stirred for 10 min. The solution was evaporated to dryness under vacuum and the residue on silica (7734, 1 g): pre-adsorbed. Purification by chromatography eluting with dichloromethane-ethanol-aqueous ammonia (50: 8: 1) afforded the pure title compound as a free base in the form of an oil (0.35 g) in a mixture of ethanol (3 ml) and isopropanol (10 ml) was dissolved.

Ethereal hydrogen chloride was added to pH 1, the title compound precipitating in the form of a foam (0.27 g) after addition of diethyl ether.

15 T.l.c., Silica, dichloromethane-ethanol-aqueous ammonia (50: 8: 1) R £ 0.2

Detection u.v. + IPA.

Analysis found: C 62.4; H 7.2; N 12.1 C H N ° HCl • 0, 9H ° requires: C 62.8; H 7.2; N 12.2%.

Jv “Γ £ L * 1 ^ 0 analysis found 3.70% H ^ O w / w = 0.9 mol equiv. H ^ O.

EXAMPLE XI

N- [3- [4- (aminocarbonyl) phenyl] propyl] -3- [2- (dimethylamino) ethyl] -1H-5-carboxamide oxalate (i) 3-12- (dimethylamino) ethyl] -N- (2 -propyl) -1H-indole-5-carboxamide oxalate 25 3- [2- (dimethylamino) ethyl] -1H-indole-5-carboxylic acid (2.0 g) in a mixture of dry pyridine (130 ml) and dry dissolved dimethylformamide (20ml) in a nitrogen atmosphere (it is necessary to heat to achieve a complete solution). The solution was cooled in an ice bath and thionyl chloride (1.25 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours after which t.l.c. demonstrate an incomplete reaction over silica (diethyl ether-isopropyl alcohol-water-aqueous ammonia 20: 20: 8: 1). The reaction mixture was again cooled in an ice bath and further thionyl chloride (0.3 ml) was added, followed by propargylamine hydro- * v v. * - 31 - chloride (2.36 g). The resulting solution was stirred at room temperature for 16 hours - T.l.c. using the same solvent system as before showed some starting material to be present while further adding thionyl chloride (0.3ml) and propargylamine hydrochloride (0.4g). The mixture was stirred at room temperature for 20 hours. The solvents were evaporated in vacuo to give a viscous oil which was mixed with dichloromethane-ethanol-aqueous ammonia (50: 8: 1) and applied to a silica column. "Evaporation" elution using the same solvent system 10 'gave the title compound as a free base in the form of a foam (880 mg). A further less pure sample of the title compound as a free base (0.214 g) was also obtained. Part of the title compound as a free base (50mg) was dissolved in methanol (0.5ml) and oxalic acid (16.5mg) was added as a solid Diethyl ether (10ml) was added to obtain a gummy precipitate The large gummy droplets were removed with a spatula, and the residual material was stirred at room temperature for 6 hours to obtain a precipitate The precipitate was removed by filtration but immediately formed a gum. Dryed under vacuum at 60 ° C for 10 hours to afford the title compound as a foam, 20 mg.

Analysis found: C 59.4; H 6.2; N 11.2.

C Η. N O.C H.O..0.2HO4 requires: C 59.6; H 5.9; N 11.6%.

16 19 3 224 2 (ii) Methyl 4- [3 - [[[3- [2- (dimethylamino) ethyl] -1H-indol-5-yl ·] carbonyl] -25 :: amino] -2-propynyl] benzoate oxalate

Methyl 4-iodobenzoate (731mg), the free base of the product from step (i) (826mg) and bis (triphenylphosphine) palladium dichloride (63mg) were dissolved in a mixture of diethylamine (50ml) and tetrahydrofuran (50ml) . Copper (I) iodide (38 mg) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvents were evaporated in vacuo to give an oil, which was dissolved in dichloromethane-ethanol-aqueous ammonia (75: 8: 1) and applied to a silica column (Merck Art 9385). "Evaporation" elution with the same solvent system gave the title compound in the form of a foam 35 (998 mg), part of which (104 mg) was dissolved in methanol (3.5 a1) - 1 - 32 - after which a solution of oxalic acid (23 mg) in methanol (0.5 ml) was added. Diethyl ether (100 ml) was added and the title compound was isolated as a solid (97 mg), m.p. 163-7 CO (decomposition).

5 (iii) Methyl-4- [3 - [[[3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] carbonyl] -amino] propyl] benzoate oxalate

The product of step (ii) as a free base (173 mg) was dissolved in methanol (40 ml) and activated charcoal (150 mg) was added. The mixture was heated to reflux for 2 hours and the charcoal was removed from the hot solution by filtration over a wad of cotton wool. The cool (room temperature) filtrate was added to a pre-reduced suspension of 10% palladium oxide on charcoal (50% aqueous paste, 80mg) in ethanol (40ml). The mixture was hydrogenated at 1 atmosphere of hydrogen for 4 hours. The catalyst was removed by filtration through "hyflo" and the solvent was evaporated in vacuo to give a gum which was dissolved in dichloromethane-ethanol-aqueous ammonia (50: 8: 1) and applied to a silica column (Merck Art 9385) . "Evaporation" elution using the same solvent system gave the title compound as a free base in the form of a foam (111 mg). Part of the title compound as a free base (99 mg) was dissolved in methanol (3 ml) and a solution of oxalic acid (22 mg) in methanol (0.5 ml) was added. Diethyl ether (50 ml) was added to give a suspension, which was stirred at room temperature for 6 hours. The title compound was isolated by filtration as a gummy solid under vacuum at 60 ° C

was dried for 20 hours and yielded a foam (94 mg).

Analysis found: C 63.0; H 6.6; N 8.7.

CHNaN0.0 HO requires: C 62.8; H 6.3; N 8.5%.

24 29 <5 3 2 2 4 (iv) N- [3- [4- (aminocarbonyl) phenyl] propyl] -3- [2- (dimethylamino) ethyl] -30 1H-indole-5-carboxamide oxalate

The product of step (iii) in the form of a free base (560 mg) was dissolved in methanol (30 ml) and the solution saturated with gaseous ammonia. The mixture was heated in an autoclave at 110 ° C for 72 hours. The solvent was evaporated in vacuo to give an oil dissolved in methylene chloride-ethanol-aqueous ammonia (50: 8: 1) and applied to a silica column (Merck Art 9385, 4 cm diameter x 6 in). "Evaporation" elutions using the same solvent system gave starting material 261 mg and the free base of the title compound 218 mg, part of which (207 mg) was dissolved in methanol (2 ml) followed by a solution of oxalic acid (47 .5 mg, 0.53 mmol) in methanol (0.5 ml) was added. Diethyl ether (50 ml) was added and the resulting gummy precipitate was stirred at room temperature for 6 hours to give the title compound as a solid, 10 (215 mg), melting point foaming 70 °, melting 133-143 ° C.

Analysis found: C 62.0; H 6.6; N 11.2, C23H28N4 ° 2 * C2H2 ° 4 requires: C 62.2; H 6.3; N 11.6%.

T.l.c. Silica, dichloromethane-ethanol-aqueous ammonia (50: 8: 1)

Rf 0.07.

EXAMPLE XII

3- [2- (dimethylamino) ethyl] -N- [2- [3- [(methylsulfonyl) amino] phenyl] -ethyl] -1H-indole-5-carboxamide oxalate (i) 3-C2- (dimethylamino) ethyl ] -N- [2- (3-nitrophenyl) ethyl] -1H-indole-5-carboxamide 20 A suspension of 3 - [(2-dimethylamino) ethyl] -1H-indole-5-carboxylic acid (0, 15 g) in anhydrous pyridine (7 ml) at -12 ° (cooling bath temperature) was treated with thionyl chloride (0.052 ml) and stirred at about -12 ° for 0.5 hour. The resulting mixture was allowed to warm to about 0 ° over a period of 1.5 hours. The suspension was again cooled to about -12 ° and treated with a solution of m-nitrophenethylamine (0.107 g) in anhydrous pyridine (1 ml). Stirring at -12 ° for 0.5 hour was allowed the resulting solution to reach room temperature over a 1.5 hour period and then stirred at room temperature for 18 hours. Two further portions of thionyl-30 chloride (0.02 ml and 0.052 ml) were added at about -12 ° over a period of 4 hours. Stirring was continued at room temperature for 3 days. The solvent was removed by rotary evaporation and the residue purified by flash chromatography eluting with dichloromethane-ethanol-0.88 aqueous ammonia (100: 8: 1). Rotary evaporation of the appropriate fractions gave the title compound in the form of a gum (0.4 g).

T.l.c. Silica, dichloromethane-ethanol-0.88 aqueous ammonia (100: 8: 1) Rf 0.2 uv / IPA.

5 (ii) N- [2- (3-aminophenyl) ethyl] -3- (2-dimethylaminoethyl) -1H-indole-5-carboxamide dihydrochloride

A solution of the product of step (i) (0.26 g) in ethanol (15 ml) was pre-reduced in the presence of 10% palladium oxide on charcoal (0.4 g of a 50% paste in water) in ethanol (15 ml) hydrogenated until hydrogen uptake ceased The catalyst and solvent were removed to give a gum (0.3 g) which was evaporated by flash chromatography eluting with dichloromethane-ethanol-0.88 aqueous ammonia (50: 8: 1) was purified Rotary evaporation of the appropriate fractions gave the free base in the form of a foam (0.13 g).

15 T.l.c. Silica, dichloromethane-ethanol-0.88 aqueous ammonia (25: 8: 1)

Rf 0.6 Detection: UV / IPA.

A solution of the free base (0.12 g) in ethanol (10 ml) was treated with excess ethereal hydrogen chloride and the resulting solution was evaporated to dryness to give the title compound as a hygroscopic foam (0.115 g).

T.l.c. Silica, Sichloromethane-ethanol-0.88 aqueous ammonia (25: 8: 1)

Rf 0.6. Detection: UV / IPA.

(iii) 3- [2- (dimethylamino) ethyl] -N- (2- (3 - ((methylsulfonyl) amino) -phenyl] -ethyl] -1H-indole-5-carboxamide oxalate (1: 1) 25 A stirred cold (-15 °) solution of the free base of the product of step (ii) (0.23 g) in anhydrous pyridine (9 ml) was treated with methanesulfonyl chloride (0.05 ml) and the resulting solution was left for reach room temperature for about 2 hours After stirring at room temperature for about 24 hours, the solution was cooled to approximately 11 ° and treated with further methanesulfonyl chloride (0.05 ml) and further stirred at room temperature for 20 hours. by rotary evaporation and the remaining gum was evaporated by flash chromatography under V- - ^ - V- ...- .. ¾ · / ·. · - 35 elution with dichloromethane-ethanal-0.88 aqueous ammonia (50: 8: 1) Purified Rotary evaporation of the appropriate fractions gave the title compound as a free base in the form of a gum (0.155 g).

T.l.c. Silica, dichloromethane-ethanol-0.88 aqueous ammonia (25: 8: 1) 5 Rf 0.6 u.v./IPA.

A hot solution of the free base (0.155 g) in absolute alcohol (2 ml) was treated with a hot solution of oxalic acid (0.0325 g) in hot absolute alcohol (2 ml). Methanol (5 ml) was added to redissolve the precipitated gummy salt. Rotary evaporation of the solvent gave the title compound as a foam. (0.12 g), mp 140-150 ° (shrinks at 80 °).

T.l.c. Silica, dichloromethane-ethanol-0.88 aqueous ammonia (25: 8: 1)

Rf 0.6 u.v./IPA.

Analysis found: C 55.1; H 5.9; N 10.5.

15 C22H28N4 ° 3S2C2H2 ° 4 0.1 S2 ° requirement: C 55/4; H 5.8; N 10.8%.

The following example illustrates a pharmaceutical composition according to the invention containing 3- (2-aminoethyl) -N- [2- [4- (dimethylamino) -phenyl] ethyl] -1H-indole-5-carboxamide dihydrochloride as active component. Other compounds of the invention can be formulated in a similar manner.

Tablets for oral administration mg / tablet

Active component 10

Magnesium stearate BP ·. 0.5 25 Lactose anhydrous 99

The active component is sieved and mixed with the anhydrous lactose and magnesium stearate. The mixture is then pressed into tablets using a Manasty tablet machine equipped with 8.0 mm concave punches.

V. * * * - 36 -

Injection for intravenous administration mg / ml

Active component> 0.6 mg

Sodium chloride BP as required 5 Injection water BP 1.0 ml

Sodium chloride can be added to adjust the tonicity of the solution while the pH can be adjusted with acid or base to that of optimal stability and / or to facilitate dissolution of the active component. Optionally, suitable buffer salts can be used.

The solution is prepared, clarified and filled into appropriately sized ampoules which are sealed by melting the glass.

The injection liquid is sterilized by heating the whole in an autoclave according to one of the acceptable sterilization cycles.

Optionally, the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions.

The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

** ** "" ". * '* "J V ·"!

* £ I

Claims (12)

1. Compounds of the general formula 1, in which a group R ^ RN-, a group RcO „C (CH„) a group R_RcNCO (CH „) a group o 6 5 2 2 p 5 o 2 p R_CONH (CH_) a group R_R_NSO_ (CEL) - or a group R_SO „NH. (CH) O 2 p 5 oz 2 p / 2 2 o (where Rg and Rg, which may be the same or different, each represent a hydrogen atom or a C ^ _3 alkyl group or Rg and Rg together with the nitrogen atom to which they are attached form a saturated monocyclic 5 to 7 ring: R 1 represents a C 1 -3 alkyl group and p 0 or 1); R2 represents a hydrogen atom or a C1-3 alkyl group, R2 and R2, which may be the same or different, each represent a hydrogen atom, a C1-3 alkyl group or a 2-propenyl group; m is zero or an integer from 1 to 4; and n is zero or one (provided that m and n are not both zero); and physiologically acceptable salts and solvates thereof. Compounds according to claim 1, characterized in that R. is a group • X 15 RRN-, RcO_C (CH „) -, R_RcNC0 (CHo) -, R ^ CONH (CH„) -, R R_NS0o (CH-) -56 52 2 p 56 2 po 2 p 56 2 2 p or a group R ^ SO ^ NH (CH ^) ^, wherein Rg and Rg, which may be the same or different, each represent a hydrogen atom or a C 1-3 alkyl group. Compounds according to claim 1, characterized in that a 20. RN-, RO-C (CH) -, RH NCO (CH) -, R_CONH (CH V - or RR.NSO (CHj -56 52 2 p 56 2 p- 5 2 p 56 2 2 p where R and R5, which may be the same or different, each represent 5 o a hydrogen atom or a methyl group. Compounds according to claim 1, characterized in that R ^ represents a group selected from H ^ NCOCH ^ -, CH ^ SO ^ NH-, H ^ NCO-, (CH ^ J ^ N-, CH 3 O 2 C -pyrrolidino and CH 3 NHSO 2 CH 2 -. Compounds according to any one of claims 1 to 4, characterized in that R 2 represents a hydrogen atom or a methyl group. Compounds according to any one of claims 1 to 5, characterized in that m is 2. Compounds according to any one of claims 1 to 6, characterized in that R 3 and R 3, which may be the same or different, each represent a hydrogen atom or a 3 alkyl group. - 38 - Compounds according to claim 1, characterized in that it represents a hydrogen atom; and, which may be the same or different, each represent a hydrogen atom or a methyl group; m represents an integer 2; the group H2NCOGH2 ~, CH3SC> 2NH-, CH3CONH-, H2NCO-, (CH3) 2N-, CH2 O ^ C-, CH3NHSO2CH2- or a pyrrolidino ring; wherein the substituent R 2 on the phenyl ring is present at the meta or para site. 9. Compounds according to claim 8, characterized in that R 1 represents the group ('CH 3) 2N-, CH 3 O 2 C-, H 2 NCOCH 2 - or CH 3 CONH - and the group is located at the para site. 10. 3- (2-aminoethyl) -N- [2- [4- (dimethylamino) phenyl] -ethyl] -1H-indole-5-carboxamide; methyl 4- [2 - [[[3- (2-aminoethyl) -1H-indol-5-yl] -carbonyl] -amino] ethylbenzoate; and physiologically acceptable salts and solvates thereof. A pharmaceutical composition comprising at least one compound of formula (1) according to any one of claims 1 to 10 or a physiologically acceptable salt or solvate thereof together with one or more physiologically acceptable carriers or diluents. 12. A method of preparing a compound of the general formula (1) as claimed in any one of claims 1 to 10 or a physiologically acceptable salt or solvate thereof, comprising: (A) condensing an amine of the general formula (2 ) with an acid of the general formula (3) or an acylating agent corresponding thereto, or a salt or a protected derivative thereof; or 251 (B) cyclizing a compound of the general formula (4), wherein Q is the group NR 3 R 3 (or a protected derivative thereof) or a cleavable atom or cleavable group; or (C) reacting a compound of the general formula (7) (wherein Y is an easily replaceable group) or a protected derivative thereof, with an amine of the formula R 3 R 1 NH; or (D) reducing a compound of the general formula (8) (wherein W is a group which can be reduced to the required - (CH2) 2 NRjR4 group or gives a protected derivative of - (CH2) 2NR3R ^) or a salt or a protected derivative thereof; or ,, ** ν ·· * '* \ ^ t- s. 1 - 39 - (E) for the preparation of a compound of the general formula (1) subjecting another compound of the general formula (1) or a salt or a protected derivative thereof to an internal reaction; or 5 (F) for the preparation of a compound of the general formula (1) wherein H 1 N - represents reducing a compound of the general formula (10); or (G) subjecting a protected derivative of a compound of the general formula (1) or a salt thereof to a reaction to remove one or more protecting groups; and subjecting the compound resulting from any of steps (A) to (F) to one or more further reactions as necessary or desired if desired (H) (i) removing any protecting groups; and (ii) converting a compound of the general formula (1) or a salt thereof into a physiologically acceptable salt or solvate thereof. \ -: € R1 1 'Q—. \, - (CH2) NC0 (CH2) s XCHJ ^ R, \ __ / i m n \ // \ / J 4 • _ · · · _ · I II I! • · \\ / \ / • N H \ 2 3 V - ’\\ f2. - (CHo) NHHO 2 C (CH 2). (CH2) 2NR, Rk \ / 1 m * n \ // \ / ^ z J 4 • · · · ____ »I II II • I · \\ / \ /. NH »» 1 \ -W f2 V / »- (ch2) nco (ch2) x ... '_ / mn \ // \ • -» · · /.-nhn=ch(ch2)3q * Ri 5 9 2 5 * \ __ / - (CH2) mNC0 (CH2) n χ //. Χ 0HC (CH2) 3Q · __ · · · I II \ / -ΝΗΝΗ2 \, · - \\? 2 .7 \ '.- (CH,) NCOtCH,) · (CH2) 2Y \ / mn \ // \ / • - · · · _ · '- I li s II «· · \\ / \ / • NH / i.' a: j f £ Glaxo Group Limited 3 - «\ · R 2 \ - (CH,) n_co (ch2). , W \ / 2 m 2 n \ // \ / • - · · · _ · - i II II • * · \\ / \ / • NH 10 Ν ° 2 ~ -χ - \\? 2 V ".— (CH2) _Ν_ £ 0- (εΗ2) v / CHj ^ RgR. \ _ / M zn \ // \ / i * * * * _ · · * ------- * I II II • · · \\ / \ / • NH 11 \ / x / CH2) 2NR3R, • · _ · I II II • · · \\ / \ / • NH 12 NO, ._. 2v <\\, O, · - (ch2 ) nh, \ _ / m • «·· / ·; ·.,) / <« Glaxo Group Limited