NL8700027A - CHEMICAL CONNECTIONS. - Google Patents

Description

.> Ί VO 8528

Chemical connections.

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

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

There is therefore a need for a safe and effective drug for the treatment of migraine, which can be used either prophylactically or to relieve an existing headache, and a compound with a selective vasoconstrictor activity would fulfill such a role.

20 We have now found a group of indole derivatives with potent and selective vasoconstrictor activity.

The present invention provides an indole of the general formula 1 of the formula sheet, wherein R 1 represents a hydrogen atom, a 1-alkyl or 1-cycloalkyl group, or a phenyl or phenyl (C 1 -5) -alkyl group; R2 represents a hydrogen atom or a C 1-6 alkyl group; represents a hydrogen atom or an -alkyl group; And which may be the same or different each represent a hydrogen atom, a C 1-3 alkyl group or a 2-propenyl group; A represents -CO- or -SO2 ~; and n represents an integer from 2-5, (wherein R ^ does not represent hydrogen as A 30 represents -SO ^ -) and physiologically acceptable salts and solvates (e.g.

hydrates) thereof.

The invention encompasses within its scope all optical isomers of compounds of the formula I and their mixtures, including the racemic mixtures thereof.

8700027 ς>, -2-

With reference to the general formula 1, the alkyl groups can be straight chain or branched, such as methyl, ethyl or isopropyl groups. The cycloalkyl group can be, for example, a cyclopentyl or cyclohexyl group.

The alkyl portion of a phenyl (CL) alkyl group can be, for example, a methyl or ethyl group.

In one class of compounds of the formula 1, the group R may be a C 3 alkyl, phenyl or phenyl (CL) alkyl group.

1 1 — Ό 1—4

In general, the group is preferably a methyl or a phenyl group.

n in the compounds of formula 1 may be an integer 3, 4 or 5, but is preferably the integer 2.

A preferred class of compounds represented by the general formula 1 of the formula sheet is that in which R2 represents a hydrogen atom.

A further preferred group of compounds is that wherein R 1 represents a hydrogen atom.

An even more preferred class of compounds is that wherein R4 and R1. which may be the same or different each represent a hydrogen-20 atom or a methyl or ethyl group. It is preferred that the total number of carbon atoms in R 1 and R 5 is not greater than 2.

A particularly important compound of the invention is N- [2- [3- [2- (methylamino) ethyl] -1H-indol-5-ylethyl] methanesulfonainide and its physiologically acceptable salts and solvates (e.g. hydrates).

Suitable physiologically acceptable salts of the indoles of the general formula 1 include acid addition salts formed with inorganic or organic acids, for example, hydrogen chloride, hydrogen bromides, sulfates, nitrates, phosphates, oxalates, tartrates, citrates, fumarates, maleates, succinates and sulfonates such as mesylates. Other salts may be useful in 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 that are converted to the base compound in vivo. Examples of such equivalents include physiologically acceptable, metabolically labile N-acyl derivatives.

8700027 * -3-

Compounds of the invention selectively constrict the carotid arterial bed of the anesthetized dog, while having a negligible effect on blood pressure. Their selective vasodilatory activity has been demonstrated in vitro.

Compounds of the invention are useful for treating pain resulting from the dilation of the carotid vascular bed, especially migraine and cluster headache.

Therefore, the invention also provides pharmaceutical compositions suitable for use in human medicine, which comprises at least one compound of the formula 1 or a physiologically acceptable salt or solvate (eg hydrate) thereof and formulated for administration in any suitable manner. Such compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.

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

For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets or capsules prepared using conventional agents with pharmaceutically acceptable excipients such as binders (eg, pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); 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 in ways known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be present as a dry product for composition with water or other suitable vehicle for use. Such liquid preparations can be made in a conventional manner 870 0 02 7 -4-; v with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous carriers (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the compositions may be in the form of tablets or tablets formulated in known manner.

The compounds of the invention may be formulated for parenteral administration by injection. Formulations for injection 10 can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative.

The compositions may have forms as suspensions, solutions or emulsions in aqueous or oily carriers, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the powdered active ingredient may be present for formulation with a suitable carrier, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, for example with conventional suppository base such as cocoa butter or other glycerides.

For administration by inhalation, the compounds of the invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packages, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebulizer. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve 30 suitable for delivering a metered amount. For example, capsules and cartridges of gelatin for use in an inhaler or insuffler can be formulated with a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A proposed dosage of the compounds of the invention for oral, parenteral, buccal or rectal administration to humans 8700027 *> -5- (with an average body weight eg about 70 kg) for the treatment of migraine is 0.1 to 100 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. It will be understood that it may be necessary to make routine dose variations depending on the age and weight of the patient, as well as the severity of the condition being treated.

For oral administration, a unit dose will preferably contain from 2 to 50 mg of the active ingredient. A unit dose 10 for parenteral administration will preferably contain 0.2 to 5 mg of the active ingredient.

Aerosol formulations are preferably controlled so that each metered dose or "puff" delivered from a pressurized aerosol contains 0.2 to 2 mg of a compound of the invention and any dose administered via capsules or cartridges in an inhaler. or insuffler contains 0.2 to 20 mg. The total daily dose by inhalation will be in the range of 1 to 100 mg. The administration can take place a number of times a day, for example 2 to 8 times, while for example 1, 2 or 3 doses are given at a 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.

In another aspect of the invention, the compounds of the formula (I) and physiologically acceptable salts or solvates (eg, hydrates) can be prepared using the general methods given below. In the following processes, R 1, R 1, R 1, R, A and n have the meanings indicated for the general formula 1, unless indicated otherwise.

According to one general process (A), a compound of the general formula 1 can be prepared by reacting a compound of the general formula 2 of the formula or a salt thereof (eg an organic or inorganic acid addition salt such as the hydrochloride, hydrogen bromide , maleate, sulfate or creatinine sulfate adduct) or an N-silyl derivative thereof or a protected derivative thereof with a reagent which has the function of introducing the group R ^ A.

8700027 * ï -6-

Suitable reagents which have the function of introducing the group R 1 A include acids of the general formula R 1 AOH or acylating agents corresponding thereto.

Acylating agents suitable for use in the above-described method include acid halides (eg carboxylic acid chlorides and sulfonyl chlorides), alkyl esters (eg the methyl or ethyl ester), activated esters (eg the 2- (1-methylpyridinyl) ester), symmetrical anhydrides, mixed anhydrides or other activated carboxylic acid derivatives, such as those suitably used in peptide synthesis.

10 The. process can be carried out in a suitable aqueous or non-aqueous reaction medium, preferably at a temperature of -70 to + 150 ° C. Thus, the process using an acid halide, an activated ester or an anhydride can be carried out in a suitable reaction medium such as an amide (eg N, N-dimethylformamide) or hexamethyl-15 phosphoramide, an ether (eg tetrahydrofuran), an ester (eg ethyl acetate), a nitrile (eg acetonitrile), a haloalkane (eg dichloromethane) or mixtures thereof, optionally in the presence of an organic base, for example a tertiary amine such as triethylamine or pyridine, or an inorganic base such as potassium carbonate or sodium bicarbonate 20 carbonate. The organic base can also serve as a reaction solvent.

The reaction is preferably carried out at a temperature of -5 to + 25 ° C.

The reaction using an alkyl ester can be carried out in a suitable reaction medium such as an alcohol (eg methanol), an amide (eg dimethylformamide), an ether (eg tetrahydrofuran) or mixtures thereof and suitably at a temperature of 0 to 100 ° C .

When A represents -CO-, carboxylic acids of the formula R 1 COOH can also be used in the preparation of compounds of the formula 1 of the formula sheet. The reaction is preferably carried out in the presence of a coupling agent, for example N, N'-carbonyldiimidazole or a carbodiimide such as Ν, Ν'-dicyclohexylcarbodiimide. The reaction can be carried out in a suitable reaction medium such as a haloalkane (eg dichloromethane), a nitrile (eg acetonitrile), an amide (eg dimethylformamide) or an ether (eg tetrahydrofuran) suitable at a temperature of -50 to + 50 ° C. , preferably -5 to + 30 ° C. The reaction can also be carried out in the absence of a coupling agent in a suitable reaction medium such as a hydrocarbon (e.g. toluene or xylene) suitable at a temperature of from 50 to 120 ° C.

A compound of the general formula 1 wherein R 1 represents A -CHO can be prepared by heating a compound of the general formula 2 of the ethyl-formulated formula sheet optionally in the presence of a solvent such as ethanol.

Compounds of general formula 2 are new and include an additional aspect of the invention.

Compounds of general formula 2 wherein R2 is a hydrogen-10 atom can be prepared, for example, by reduction of a corresponding compound with a suitable reducible group as the substituent at the 5 position, such as “(CH2 ^ n I *” 11 a corresponding cyano-substituted alkenyl group The reduction may be by catalytic hydrogenation, or with a reducing agent such as lithium-aluminum hydride.

Such nitrile compounds are new and form a further aspect of the invention. These compounds can be prepared, for example, by cyclization of a suitable hydrazone, analogously according to the general method (B) described below. Alternatively, intermediates with a 5- (cyanoalkenyl) substituent can be prepared by reacting an appropriate indole-5-carboxaldehyde with a cyanoalkylphosphonate.

Compounds of the general formula 2 in which R 2 is an alkyl group can be prepared, for example, by reduction of a corresponding nitrile in the presence of an amine R 2 NH 2, or by reaction of a compound of the formula 2 wherein R 1 is a hydrogen atom with a suitable alkylating agent.

According to another general method (B), compounds of the formula 2 can be prepared by cyclizing a compound of the general formula 3 of the formula sheet wherein Q represents the group NR ^ R ^ (or a protected derivative thereof) or a leaving atom or group such as a halogen atom (eg chlorine or bromine) or an acyloxy group (eg a carboxyl or sulfonacyloxy group such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy) ).

The reaction may conveniently be carried out in aqueous or non-aqueous reaction media and at a temperature of from 20 to 200 ° C, preferably from 8700027 * * -8 to 50 ° C.

Particularly suitable embodiments of the method are described below.

When Q represents the group NR ^ R ^ (or a protected derivative thereof) -5, the process is most preferably carried out in the presence of a 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 can also be performed in an aqueous or non-aqueous reaction medium, in the presence of an acidic catalyst. When an aqueous medium is used, it can 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. The acidic catalyst can be, for example, an inorganic acid such as concentrated hydrochloric acid or sulfuric acid or an organic acid such as acetic acid. (In some cases, the acidic catalyst can also act as a reaction solvent). In an anhydrous reaction medium, which may include, for example, one or more ethers (e.g., as described above) or esters (e.g., ethyl acetate), the acidic catalyst will preferably be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride.

When Q is a leaving atom or group such as a chlorine or bromine atom, the reaction can take place in an aqueous organic solvent such as an aqueous alcohol (eg methanol, ethanol or isopropanol) in the absence of an acid catalyst, suitably at a temperature -30 temperature from 20 to 200 ° C, preferably 50 to 125 ° C. This process results in the formation of a compound of the formula 1 of the formula sheet, wherein R 4 and both are hydrogen atoms.

According to a particular embodiment of this method, compounds of the general formula 1 of the formula sheet can be prepared directly by the reaction of a compound of the general formula 4 of the formula sheet (where T is a group -NR 3 NH 2), or a salt thereof with 8700027 -9- a compound of the formula 5 of the formula sheet (wherein Q has the meaning given above) or a salt or protected derivative thereof (such as an acetal or ketal, eg formed with a suitable alkylortho format or diol, or protected as bisulfite addition complex) using the appropriate conditions as described above for the cyclization of compounds of the general formula 3. It will be appreciated that in this embodiment of the cyclization process (B) a compound of the general formula 3 is an intermediate is formed, and can be reacted in situ to form the desired compound of general formula 1.

Compounds of general formula 3 can, if desired, be isolated as intermediates during the process of preparing compounds of formula 1, wherein a compound of formula 4, or a salt or protected derivative thereof, is reacted with a compound of the formula 5, or a salt or protected derivative thereof, in water or in a suitable solvent, such as an aqueous alcohol (eg methanol) at a temperature of, for example, 20 to 30 ° C. When an acetal or ketal or compound of formula 5 is used, it may be necessary to carry out the reaction in the presence of an acid (e.g. acetic acid or hydrochloric acid).

Compounds of general formula 4 can be prepared, for example, from the corresponding nitro (i.e., wherein T is -NC> 2) compounds, using known procedures.

Another general method (C) for the preparation of compounds of the general formula 1 comprises reacting a compound of the general formula 6 of the formula sheet (wherein Y is an easily removable atom or group) or a protected derivative thereof with an amine of the formula R.R_NH.

4 5

The reaction may conveniently be carried out on those compounds of formula 6 wherein Y is a halogen atom (e.g. chlorine, bromine or iodine) or a group OR. where OR. for example, an acyloxy group which may be derived from a carboxylic or sulfonic acid such as an acetoxy, chloroacetoxydichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group.

The reaction may conveniently be conducted in an inert organic solvent, (optionally in the presence of water), examples of which 8700027 lead include alcohols, e.g. ethanol; cyclic ethers, e.g. dioxane or tetrahydrofuran; acyclic ethers, e.g. diethyl ether, esters, e.g. ethyl acetate; amides, e.g. Ν, Ν-dimethylformamide; and ketones such as 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 6 wherein Y is a halogen atom can be prepared by reacting a hydrazine of the general formula 4 with an aldehyde or ketone (or a protected derivative thereof) of the formula 5 wherein Q is a halogen atom, in an aqueous alcohol (eg methanol) containing an acid (eg acetic acid or hydrochloric acid). Compounds of formula 6 wherein Y is the group OR 4 can be prepared from the corresponding compound wherein Y is a hydroxyl group by acylation with the appropriately activated component (e.g. anhydride or sulfonyl chloride) using conventional techniques. The alcohol intermediate can be prepared by cyclization of a compound of formula 3 wherein Q is a hydroxyl group (or a protected derivative thereof) under standard conditions.

Compounds of formula 1 can also be prepared by another general method (D) comprising the reduction of a compound 20 of general formula 7 (wherein W is a group capable of being reduced to the desired - (CE2) 2NR4R5 ^ group or to provide a protected derivative of - (CH_) _ NR.R_; and B represents the group - (CH_) -, such as-2245 2n as defined herein or a group that can be reduced to - (CEL) -) or a salt or protected derivative thereof.

2 n 25 The desired - (CE ^) 2 «and“ NR ^ R ^ groups at the 3-position can be formed by reduction steps which take place separately or together in any desired manner.

Groups B, which can be reduced to the desired group - (CH 2) n - include corresponding unsaturated groups such as C 2-6 alkenyl-30 or alkynyl groups.

Examples of groups represented by the substituent W include - (CH2) 2NQ; -CH = CHNO2; - (C 1 H 2; -C 1 2 CN; -C 1 2 CHO; -COC 2 Z; -CH 2 CH = NOH; -CH. (QH) CH "NR.R_; - (CHJ. NO.C0R '; -COCONR.R_ and -OLCOZ (wherein Z is a 24 5 224 5 45 2 azido group or the group -NR ^ R ^ or a protected derivative thereof and R'g is a hydrogen atom or a methyl or ethyl group or R ', is the group OR7 where R7 is an alkyl or aralkyl group).

8700027

Groups that can be reduced to the - (CH2) 2 group include the corresponding unsaturated group and corresponding groups with one or more hydroxyl groups or carboxyl functions.

-11-

Groups which can be reduced to the group -NR ^ Rj. where -5 in R ^ and R ,. both are hydrogen include nitro, azido, hydroxyimino and nitrile groups. In the latter case, reduction gives the group -CH NH

6 C and thus provides a methylene group of the - (CH2) 2 group.

A compound of the general formula 1 in which R1 is a hydrogen atom can also be prepared by reduction of a corresponding compound wherein R1 is. a benzyl group, e.g. with hydrogen in the presence of a catalyst, e.g. 10% palladium or activated carbon.

The required -NR.R-group in which R. and / or R_ differ from water-4 D 4 O substance can be prepared by reduction of a nitrile -CH 2 CN or an aldehyde -CH 2 CH 2 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 2 is different from hydrogen is reductive alkylation of the corresponding compound in which R 4 and / or R 5 represent hydrogen with a suitable aldehyde or ketone (eg acetaldehyde or acetone) in the presence of a suitable reducing agent.

Suitable reducing agents for use in this process include hydrogen in the presence of a metal catalyst, or an alkali metal borohydride or cyanoborohydride (eg sodium borohydride or cyanoborohydride) using the conditions described below for the reduction of compounds of formula 7. In certain cases ( e.g.

For the introduction of the group R 1, where R 1 is ethyl), the alhyde (e.g., acetaldehyde) can be condensed with the amine and the intermediate thus formed can then be reduced using an appropriate reducing agent.

The required -NR ^ R ^ group in which R ^ and / or R ^ differ from hydrogen can also be prepared by reduction of a corresponding amide group, e.g. with the formula - (CH_) _ NR.COR'_ where R 'has the definition given above.

It will be understood that the choice of reducing agent and reaction conditions depends on the nature of the group W, B and other groups already present on the molecule. It will also be understood that if A represents -CO-, the group W will not contain an amide function.

8700027 -12- -¾ »

Suitable reducing agents which can be used in the above-described process for the reduction of compounds of the formula wherein W is, for example, the groups “(CH2 ^ 2NO2? -CH = CHNC> 2, - (CH2) 2N3, -CH2CN, -CH2CH = NOH and -CH (OH) CE ^ NR ^, 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 or rhodium, optionally present on a support for example, on activated carbon, kieselguhr or alumina.

In the case of Raney nickel, hydrazine can also be used as the source of hydrogen. This process can conveniently be performed in a solvent such as an alcohol e.g. ethanol, an ether, e.g. dioxane or tetrahydrofuran, an amide, e.g. dimethylformamide or an ester e.g. ethyl acetate, and at a temperature from -10 to + 50 ° C, preferably -5 to + 30 ° C.

The reduction process can also be effected on compounds of the formula 7 wherein W represents, for example, the groups - (CH2) 2NO2, -CH = CHNO, - (CH) N_, -CH (OH) CH NR R or -COCH.Z (where Z has the 2 223 2 4 O 2 meaning given above), using an alkali metal or alkaline earth metal borohydride or cyanoborohydride e.g. 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 10 to 100 ° C, preferably 50 to 100 ° C. In some cases, the reduction can be carried out using a borohydride in the presence of cobalt chloride.

When A represents -SO2_, the reduction of compounds of the formula 7 wherein W may be, for example, the groups - (CH2) 2NC> 2, -CH = CHNC> 2, - (CH2) 2N3, - (CH2) 2NR4COR'5; -CH2CH = NOH, -CHCOHJCH ^ R ^; -COCONR 2, -CH 2 CO 2 and -CO CH 2 Z (wherein R 1 and Z have the above definition) are also performed using a metal hydride such as lithium aluminum hydride. This process can be carried out in a solvent, for example an ether such as tetrahydrofuran, and suitably at a temperature of -10 to + 100 ° C, preferably 50 to 100 ° C.

A particular embodiment of the general process (D) comprises the reduction of a compound of the formula 7 wherein W represents the group -CH 2 CN, for example, by catalytic reduction with hydrogen in the presence of a catalyst such as palladium on carbon or rhodium 8700027 * * * -13- on alumina, optionally in the presence of an amine HNR ^ R ^.

Suitable reducing agents that can be used in group B reduction include hydrogen in the presence of a metal catalyst. Suitable metal catalysts and conditions for the reduction process have been described for the reduction of the group W.

The starting materials or intermediates of formula 7 may be prepared by analogous methods to those described in Laid-Open Publication No. 2,035,310 and in "A Chemistry of Heterocyclic Compounds - Indoles Part II"; Chapter VI, 10 published by W.J. Houlihan (1972) Wiley Interscience, New York.

Compounds of formula 7, wherein W represents the group -CH 1 CHO, can be prepared by oxidation (e.g., with Jones' reagent) of a compound of formula 6 wherein Y is a hydroxyl group. A compound of the formula 7 wherein W represents the group -CH 2 CH = NOH can be prepared by treating the corresponding aldehyde with hydroxy-xylamine hydrochloride under standard conditions.

The intermediate of the formula 7 wherein W is the group - (CH 2) 2 N 2 can be prepared from a compound of the formula 6 wherein Y is a halogen using standard procedures.

Standard reducing agents such as sodium borohydride can be used to prepare a compound of the formula 7 wherein W is the group -CH (OH) CH 2 R 1 R j. from the corresponding compound of the formula 7, wherein W is the group -COC ^ NR ^ R ,. is.

A compound of the formula 7 wherein W is the group - (CH2). ^ NR ^ COR ',. 25 can be prepared by acylation of the corresponding unsubstituted amine using conventional procedures.

The intermediates of formula 7 wherein B represents a C 1-4 alkenyl group can be prepared by reacting a compound of the general formula 8 of the formula sheet (wherein W has the definition given for formula 7 and n is zero or an integer from 1 to 3) with, for example, a suitable phosphonium salt, using standard conditions.

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

8700027 t - -14-

For example, a compound of the general formula 1, wherein one or more of R ^, R4 and / or R? alkyl groups are prepared from the corresponding compounds of formula I wherein one or more of R / R and R @ represent hydrogen atoms by reaction with a

5 suitable alkylating agent such as a compound of the formula RL (where R

X X

the desired R ^ - ^ or R ^ group and L represents a leaving atom or group such as a halogen atom or a tosylate group) or a sulfate (R) SO. Thus, the alkylating agent may be, for example, an alkyl-X ^ 4 halide (e.g. methyl or ethyl iodide), alkyl tosylate (such as methyl 10-tosylate) or dialkyl sulfate (e.g. dimethyl sulfate).

The alkylation reaction may conveniently be conducted in an inert organic solvent such as an amide (e.g. dimethylformamide), an ether (e.g. tetrahydrofuran) or an aromatic hydrocarbon (e.g. 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, alkali metal carbonates such as sodium carbonate or alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or t-butoxide or tetrabutyl ammonium fluoride. When an alkyl halide is used as the alkylating agent, the reaction can 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 to 100 ° C

Compounds of formula 1 wherein one or both of R 1 and R 4 represents propenyl may be prepared in the same manner using an appropriate compound of the formula R x L or (R 2) 2 ^ 4 ·

According to another general method (F), 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 a salt thereof to a reaction in order to form the protective group or delete groups.

Thus, at an earlier 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 in order to avoid undesired side reactions. For example, it may be necessary to protect the group NR 4 R 1, where R 4 and / or R 4 represents hydrogen by protonation or with 8700027-15 group which is easily removed at the end of the reaction sequence. Such groups may include, 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.

Cleaving of the protecting group or groups can be accomplished by conventional procedures. For example, an aralkyl group such as benzyl can be cleaved by hydrogenolysis in the presence of a catalyst (such as palladium on activated carbon) or sodium and liquid ammonia; an acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis, for example with hydrogen bromide in acetic acid or by. reduction, for example, by catalytic hydrogenation. The phthaloyl group can be removed by hydrazinolysis (such as by treatment with hydrazine hydrate) or by treatment with a primary amine (such as methylamine).

It will be understood that in some of the general methods (A) to (E) as described above it may be necessary or desirable to protect certain sensitive groups in the molecule in the manner described above. For example, a reaction step comprising removing protecting groups from a protected derivative of the general formula 1 or a salt thereof can be carried out after any of the above-described processes (A) to (E).

According to another aspect of the invention, therefore, the following reactions may be carried out in any suitable order if desired and / or necessary after any of the methods (A) to (E): (i) removal of certain protecting groups; and (ii) conversion of a compound of the general formula 1 or a salt thereof into a physiologically acceptable salt or solvate (e.g.

30 hydrate) thereof.

If it is desired to iso a compound of the invention. Learning as a salt, for example as an acid addition salt, this can be achieved by treating the free base of the general formula 1 with an appropriate acid, preferably with an equivalent amount of 35 or with creatinine sulfate in a suitable solvent (e.g. aqueous ethanol).

870 0 02 7 -16-

The starting materials or intermediates for the preparation of the compounds of the invention may be prepared by analogous methods to those described in Laid-Open Publication No. 2,035,310.

As used as the last major step in the preparation sequence, the general methods described above for the preparation of the compounds of the invention may also be used for the introduction of the desired groups during an intermediate stage in the preparation of the desired compound . For example, the desired group can be introduced in the 5-position before or after cyclization to form the indole core. It should therefore be appreciated that in such multistage processes the order of the reactions should be chosen in the order that the reaction conditions do not affect groups present in the molecule that are desired in the final product.

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

Chromatography was performed either in known manner using silica gel (Merck, Kieselgel 60, Art. 7734) or by "flash" chromatography (WC Still, M. Kahn and A. Mitra, J. Org. Chem. 2933, 43 , 1978) on silica (Merck 9385) and thin layer chromatography (tlc) on silica (Macherly-Nagel, Polygram) unless otherwise indicated. The following abbreviations define the eluents used for chromatography and t, ic: (A) Ethyl acetate-2-propanol-water-0.88 ammonia 25: 15: 8: 2, 25 (B) CH2Cl2-ethanol-0.88 ammonia 89 : 10: 1, (C) Ethyl acetate, (D) CH 2 Cl 2 -ethanol-0.88 ammonia 83: 5: 15: 1.5, (E) Ethyl acetate cyclohexane 1: 1, (F) Ether-methanol 9: 1, ( G) Ethyl acetate-methanol 9: 1, (H) Ether, (I) Ethyl acetate-2-propanol-water-0.88 ammonia 200: 15: 8: 2, (J) Ethyl acetate-2-propanol-water-0, 88 ammonia 100: 15: 8: 2, (K> Ethyl acetate-2-propanol-water-0.88 ammonia 50: 15: 8: 2, (L) CH Cl-ethanol-0.88 ammonia 87:12: 1.2, (M) CH Cl, ethanol-0.88 ammonia 95: 5: 0.5, (N) CH 2 Cl 2 ethanol-0.88 ammonia 91: 8: 0.8.

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

8700027 -17-

Proton (½) nuclear magnetic resonance (nmr) spectra were obtained either at 90 MHz using a Varian EM 390 device or at 250 MHz using a Bruker AM or WM 250 device, s = singlet, d = doublet, t = triplet, m = multiplet and q = quartet.

5 Intermediate 1 4-Hydrazinobenzeneacetonitrile hydrochloride

A solution of sodium nitrite (4.0 g) in water (34 ml) was added dropwise at a temperature of -5 to -2 ° to a suspension of 4-aminobenzeneacetonitrile (7.6 g) in concentrated salt-10 acid (80 ml) and stirring was continued at -2 ° for 20 minutes.

The mixture was filtered and filtrate added dropwise at 0 to 5 ° to a solution of tin (11) chloride dihydrate (65 g) in concentrated hydrochloric acid (130 ml). The mixture was allowed to come to room temperature overnight (17 hours) and the precipitate was filtered off, washed with concentrated hydrochloric acid, cold absolute ethanol and dry ether and dried to give the title salt as a powder (6.05 g), mp . 207-210 ° (foams).

Intermediate 2 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-aceto-20 nitrile

A mixture of intermediate 1 (3.15 g) and 4- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) butanaldiethyl acetal (4.95 g) in aqueous acetic acid (25%, 150 ml) was heated to reflux for 2 hours, cooled and the precipitate filtered off, washed with water (2 x 20 ml), then ether (100 ml). The crude product was triturated with ethyl acetate to give the title compound as a solid (3.2 g), mp. 185-186 °.

Intermediate 3 2- [2- [5- (2-Aminoethyl) -1H-indol-3-yl] ethyl3-1H-isoindole-1,3- (2H) -30 dione sulfate

A suspension of intermediate 2 (0.96 g) in methanol (100 ml) containing concentrated sulfuric acid (0.58 g) was hydrogenated over Pdo on activated charcoal (50% aqueous paste, 0.96 g) at room temperature and 70 psi. for 24 hours. The catalyst was filtered off, washed with methanol and the filtrate was evaporated to give the title compound as an oil (1.4 g).

8700027 -18-

Intermediate 4 2- [2- [5- (2-Aminoethyl) -1H-indol-3-yl] ethyl] -1H-isoindole-1,3- (2H) -dione hydrochloride

A solution of intermediate 2 (1.5 g) in methanol (400 ml) containing concentrated hydrochloric acid (0.6 ml) was hydrogenated over PdO on activated carbon (50% aqueous paste, 3.0 g) at room temperature and pressure for 24 hours. The catalyst was filtered off, washed with methanol and the filtrate was evaporated to give the title compound as a foam (1.2 g). T.l.c. (A) Rf 0.6.

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

Raney nickel (about 2 g) was added to a stirred solution of 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-carboni -15 vibrate (4.98 g) and sodium hypophosphite (10.6 g) in pyridine (100 ml), water (50 ml) and acetic acid (50 ml) added. The mixture was heated to about 50 ° for 6 hours, periodically adding additional Raney nickel (5 x about 2 g). After cooling, the mixture was filtered and the filtrate was diluted with water (1250ml) and extracted with ethyl acetate (3 x 500ml). The combined organic extract was washed with hydrochloric acid (2N; 2 x 500ml), dried (MgSO4), evaporated in vacuo, and azeotroped with toluene (2 x 100ml) to give the title aldehyde as a solid (4 6 g). A sample (0.53 g) was purified by chromatography (C) to give the pure title aldehyde as a solid (0.49 g), mp. 202-203 °.

Intermediate 6 (E) —3— [3— [2— (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yl] -2-propenitrile

A solution of diethyl cyanomethyl phosphonate (1.6 ml) in dry tetrahydrofuran (THF; 40 ml) was slowly added to a stirred suspension of NaH (80%; 0.30 g) in THF (40 ml) under nitrogen.

After 10 minutes, a solution of intermediate 5 (1.70 g) in THF (40 ml) was added to the obtained clear solution and the mixture was stirred at room temperature for 19 hours. The solution was then partitioned between hydrochloric acid (IN; 200 ml) containing NaCl (50 g) and ethyl acetate (3 x 150 ml). The combined organic extract was dried (MgSC> 4) and evaporated to dryness to yield a solid 8700027 -19- (1.53 g) which was purified by chromatography (E) to provide the title compound as a crystalline solid (1 , 13 g), mp.

232-234 °.

Intermediate 7 5 4- [2- [4- (Dimethylamino) butylidene] hydrazino] benzeneacetonitrile 4,4-Diethoxy-N, N-dimethylbutanamine (9.45 g) was then added to a stirred suspension of intermediate 1 (9.2 g) in deionized water (200ml) added at room temperature under nitrogen, 2N hydrochloric acid (22ml) was added (pH 2), and stirring was continued at room temperature for 5 hours. The clear solution was made basic with 8% aqueous NaHCO 2 (200 ml) and extracted with CHCl 2 (3 x 200 ml).

The organic layers were dried (MgSO4) and evaporated to give the title compound as an oil (15.6 g). T.l.c. (Silica, B)

Rf 0.35.

15 Intermediate 8 5- (Cyanomethyl) -N, N-dimethyl-1H-indole-3-ethanamine oxalate

Intermediate 7 (15.4 g) was heated to reflux with polyphosphate ester (108 g) in CHCl 3 (200 ml) with stirring under nitrogen for 8 minutes. The mixture was poured onto ice, 8% aqueous NaHCO 2 (500 ml) was added, and after stirring for 20 minutes, the mixtures were separated and the aqueous layer extracted with CHCl 2 (3 x 400 ml). The aqueous layer was further made basic to pH 9 with 2N Na 2 CO 2 (200 ml), solid NaCl was added and the mixture was extracted with CHCl 3 (3 x 400 ml). The combined organic layers were dried (MgSO4) and evaporated to give an oil (40.2 g). The oil was partitioned between ethyl acetate (200ml) and 2N hydrochloric acid (4 x 40ml); the aqueous layers were made basic (200 ml 2N and 20 ml 5N NaOH) and extracted with ethyl acetate (4 x 100 ml). The last organic layers were washed with brine, dried (MgSO4) and evaporated to give an oil (9.3 g). Purification by flash chromatography (B and D) gave a first crop (1.91 g) as an oil and a second crop (4.0 g) also as an oil. The second oil crop was dissolved in hot methanol (10 ml) and oxalic acid (1.59 g) in hot methanol was added. On cooling, crystals precipitated and after cooling on ice, the crystals were filtered, washed with methanol and dried to give the title compound (4.0 g), mp. 183.5-187 °.

870 0027.

-20-

Intermediate 9 N3 / N3-Dimethyl-1H-indole-3,5-diethaanamine dioxalate

Intermediate 8 (3.17 g) was partitioned between 8% aqueous NaHCO 4 (100 ml) and CH 2 Gl 4 (3 x 80 ml) and the organic layers were dried (MgSO 4) and evaporated to give the free base as an oil (2.41 g). The oil was hydrogenated at 45 ° and 70 psi over 5% rhodium on alumina (1.0 g) in 7% w / w ethanolic ammonia (200 ml) for 15.5 hours. The catalyst was filtered off and the solvent evaporated to give an oil (2.58 g). A portion (1.37 g) of the oil 10 was dissolved in methanol (6 ml), and oxalic acid (1.12 g) was added in methanol (2 ml). Addition of dry ether (80 ml) gave a gum, which was triturated with dry ether to give the title compound as a solid (1.79 g), mp. 160-170 ° (foams).

Intermediate 10 15 N3, N3-Dimethyl-1H-indole-3,5-diethaanamine dihydrochloride

Intermediate 8 (2.40 g) was hydrogenated at 55 psi over 10% palladium on activated carbon (50% paste with water; 1.2 g originally; an additional 2.4 g added after 25 hours and 1.2 g after 70 hour) in ethanol (240 ml) with concentrated hydrochloric acid (2.4 ml) for 138 hours. The catalyst was filtered off and the solvent evaporated to give a foam (2.81 g), a sample (about 0.7 g) thereof was partitioned between a saturated aqueous Na 2 CO 2 (100 ml) and butanone ( 3 x 70 ml).

The organic layers were washed with brine, dried (MgSO4) and evaporated to give an oil (0.57 g). A sample (169 mg) of the oil was purified by flash chromatography to give an oil (46 mg).

T.l.c. (A) Rf 0.35.

Example I

N- [2- [3- (2-Aminoethyl) -1H-indol-5-yl] ethyl] methanesulfonamide, compound with creatinine, sulfuric acid and water (1: 1; 1: 1) 30 (i) N- [2 - [3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yl3ethyl-methanesulfonamide

A solution of intermediate 3 (1.4 g) in pyridine (10 ml) at 5 ° was treated with methanesulfonyl chloride (0.46 ml). After 24 hours at room temperature, the mixture was poured onto concentrated hydrochloric acid ♦ (20 ml) and ice (100 g). The resulting solid was collected and purified by chromatography (F) to give the title compound as a foam (0.45 g). T.l.c. (C) Rf 0.2.

8700027 * ♦ -21- (ii) N- [2-C3- (2-Aminoethyl) -1H-indol-5-yl] ethylmethane sulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1)

A solution of the product from step (i) (0.29 g) in ethanol (5 ml) and tetrahydrofuran (2 ml) was treated with hydrazine hydrate 5 (0.2 ml) and heated under reflux for 3 hours. After cooling, the solution was evaporated to dryness, and the resulting solid was partitioned between ethyl acetate (50 ml) and a saturated solution (10 ml). The aqueous layer was extracted with ethyl acetate (3x50ml), and the organic layer was dried (MgSO4) and evaporated to give an oil. This was dissolved in a hot ethanol / water mixture (9: 1, 20 ml) and treated with an aqueous solution of creatinine and sulfuric acid (1: 1, 2M, 0.3 ml). After cooling, the title compound crystallized (0.16 g), mp. 209-210 °.

N.m.r. 6 (D20) includes 2.8-3.5 (14H, m, -CH2CH2NHSO2Me and CH2CH2NH2 and crea-tinin N-Me); 7.2 (1H, dd, indole-6) and 7.5-7.7 (2H, m, indole-4 and indole-7).

Example II

N- [2- [3- [2- (Methylamino) ethyl] 1H-indol-5-yl] ethyl] methanesulfonamide, compound with creatinine, sulfuric acid and water (2: 2: 2: 1) 20 (i) N- [2- [3- [2 - [(Methylsulfonyl) amino] ethyl] -1H-indol-5-yl] -ethyl] formamide guaterhydrate

A solution of the product of Example I as the free base (0.98 g) in ethyl format (50 ml) and ethanol (50 ml) was refluxed for 48 hours. The solvent was evaporated in vacuo and the residue partitioned between sulfuric acid (1N, 25ml) and ethyl acetate (50ml). The aqueous layer was extracted with ethyl acetate (25 ml) and the combined organic extracts were washed with brine (25 ml), dried (Na2 SO4) and evaporated in vacuo to give an oil. Purification by column chromatography (C and F) gave a foam. Trituration with ethyl acetate gave the title compound as a solid (0.15 g), mp. 89-91 °.

. 870 0 02 7 -22- (ü) N- [2- [3- [2- (Methylamino) ethyl] -1H-indol-5-yl] ethyl] methanesulfonamide, compound with creatinine, sulfuric acid and water (2 : 2: 2: 1)

A solution of the product from step 1 (0.6 g) in dry tetra-5 hydrofuran (THF) (20 ml) was added dropwise under nitrogen to a stirred suspension of LiAlH 2 (0.7 g) in dry THF (15 ml). The mixture was refluxed for 5 hours, cooled in ice and excess reagent decomposed by cautious addition of 10% water in THF. Brine (50ml) and ethyl acetate (100ml) were added, insolubles filtered off, and the aqueous layer was extracted with ethyl acetate (100ml). The combined organic extracts were washed with brine (50 ml), dried (Na 2 SO 4) and evaporated in vacuo to give an oil. The oil was dissolved in a hot mixture of ethanol (24ml) and water (3ml) and an aqueous solution of creatinine 15 and sulfuric acid (1: 1, 2M, 0.5ml) was added. Filtration of the cooled mixture gave the title compound as a solid (0.37 g), mp. 222-224 °.

N.m.r. <5 (D20) includes 2.6-3.6 (17H, m, CH2CH2NHMe and CH2CH2NHSO2Me and creatinine N-Me).

Example III

N- [3- [3- (2-Aminoethyl) -1H-indol-5-yl] propyl-3-methanesulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1) (i) 2- [2- [5 - (3-Aminopropyl) -1H-indol-3-yl] ethyl] -1H-isoindole-1,3- (2H) -dione hemisulfate 25 A solution of intermediate 6 (0.95 g) in methanol (550 ml) ) and sulfuric acid (1.0 ml) was hydrogenated at room temperature and press over pre-reduced 10% palladium on activated carbon (50% aqueous paste; 2.08 g) for 0.5 hours until hydrogen uptake (201 ml) was stopped . The catalyst was filtered off and the filtrate was evaporated in vacuo to give an oil (4.7 g). T.l.c. (A) Rf 0.3.

(ii) N- [3- [3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yl] propyl] methanesulfonamide

A mixture of the product from step (i) (4.7 g), methanesulfonyl chloride (1.0 ml), NaHCO 2 solution (8%; 300 ml) and ethyl acetate 35 (250 ml) was stirred vigorously at room temperature for 24 hours, adding an additional amount of methanesulfonyl chloride (1.0 ml) after 17 hours. The mixture (containing an insoluble solid) 8700027-23- was separated, and the aqueous phase was further extracted with ethyl acetate (2 x 200 ml). The combined organic extract was washed with hydrochloric acid (2N; 200 ml), dried (MgSO 4), and evaporated to yield an oil (0.49 g), which was purified by chromatography on a silica column (H). When the correct fractions were allowed to stand for a short time, the title compound crystallized out as a solid (0.1 g), mp. 165-167 °.

(iii) N-C3-C3- (2-Aminoethyl) -1H-indol-5-yl] propyl] methanesulfonamide, compound with creatinine, sulfuric acid and water (III; III). A solution of the product of step (ii) (0.48 g) in ethanol (100 ml) was treated with hydrazine hydrate (1.0 ml) and refluxed for 1 hour and 20 minutes. After cooling, the solution was evaporated in vacuo and azeotroped with ethanol (2 x 50 ml) to give a solid partitioned between Na 2 CO 2 -15 solution (2N; 100 ml) and ethyl acetate (3 x 100 ml). The combined organic extract was dried (mgSO4) and evaporated to dryness, yielding an oil which was dissolved in a hot mixture of ethanol (64 ml) and water (8 ml) and an aqueous solution of creatinine and sulfuric acid (1: 1, 2M, 0.56 ml) was added. After cooling, the title salt crystallized out (0.43 g), mp. 212-214 ° C.

N.m.r. <5 (DMSO-d.) Includes 2.6-3.2 (14H, m, CH.CH_CH-, NHSO Me, CH'CH'NH ,, and creatinine N-Me); 6.8-7.5 (4H, m, aromatic); and 10.9 (1H, d, indole-1). Example IV

N- [2- [3- (2-Aminoethyl) -1H-indol-5-yl] ethyl 3-acetamide, compound with creatinine, sulfuric acid and water (10:12:11:20) (i) N— [2— [ 3- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yljethy] acetamide quarterhydrate

A solution of intermediate 4 (0.3 g) in pyridine (10 ml) was cooled in an ice bath, and treated dropwise with stirring with acetic anhydride (0.3 ml). The solution was stirred at room temperature for 1 hour, diluted with water (15 ml) and stirred for 15 minutes. The resulting solution was poured into hydrochloric acid (2N, 50 ml), and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 2N hydrochloric acid (50ml), 2N Na ^ CQ ^ (50ml), dried (Na ^ SO ^) and evaporated in vacuo to give a foam which was purified by chromatography (C) to title compound as a solid (0.125 g), mp. 165-168 °.

870 0 02 7 -24- * *> 1 (ii) N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] acsetamide, compound with creatinine, sulfuric acid and water (10: 12:11:20)

A solution of the product of step (i) (0.5 g) in ethanol (100 ml) containing hydrazine hydrate (1.0 ml) was heated under reflux for 3 hours, evaporated in vacuo, and evaporated again with ethanol (2 x 20 ml). The solid obtained was partitioned between Na 2 O 2 solution (2N, 100 ml) and ethyl acetate (2 x 100 ml). The combined organic extracts were dried (Na 2 SO 4) and evaporated in vacuo to give an oil which was dissolved in a hot mixture of ethanol (16ml) and water (2ml) and treated with an aqueous creatinine and sulfuric acid solution (1: 1, 2M, 0.5 ml). After cooling, the title salt crystallized out (0.3 g), mp. 211-214 °.

N.m.r. <5 (D20) includes 2.95 (3H, s, NHCOMe); and 2.7-3.6 (11H, m, CH 2 CH 2 NHCO, CH 2 CH 2 NH, and creatinine N-Me).

—2 —2 2 -

Example V

N- [2- [3- [2- (Dimethylamino) ethyl] 1H-indol-5-yl] ethyl] acetamide oxalate Intermediate 10 (0.4 g) was added at room temperature to a stirred solution of triethylamine (0, 55 ml) in dry tetrahydrofuran (15 ml) under nitrogen and stirring was continued at room temperature for 5 minutes. The mixture was cooled to 0 °, acetic anhydride (0.15 ml) was added, and stirring was continued between 0 and 10 ° for 4 hours. The mixture was partitioned between saturated Na 2 O 2 solution (65 ml) and butanone (3 x 50 ml); the organic layers were washed with brine, dried (MgSO4) and evaporated to give an oil (0.64 g). Purification by flash chromatography (B and D) gave an oil (139 mg) which was dissolved in methanol (2 ml) and combined with another sample (57 mg) prepared in the same manner. Oxalic acid (77 mg) in methanol (0.5 ml) was added. Addition of dry ether gave a precipitate which was filtered off, washed with dry ether and dried to give the title compound as a solid (205 mg), mp. 85-93 ° (foams).

N.m.r. δ (DMSO) includes 1.81 (3H, s, NHCOMe)? 2.7-3.0 (8H, m, NMe2 and CONHCH2CH2); 3.08 (2H, t, CH 2 CH 2 NMe 2); 7.98 (1H, t, CONH) and 10.9 (1H, d, indole-1), 35 87 0 0 0 2 7 f * -25-

Example VI

N- [2- [3- [2- (Dimethylamino) ethyl] -1H-indol-5-yl] ethyl] methanesulfonamide oxalate

Intermediate 10 (0.905 g) was added to a stirred solution of triethylamine (1.26 ml) in dry Cl 2 Cl 2 (50 ml) at room temperature under nitrogen and stirring was continued at room temperature for 5 minutes. Methanesulfonyl chloride (0.282 ml) was added with cooling to 0 °, and the mixture was allowed to warm to room temperature with stirring for 5 hours. The mixture was poured into 2N 10 Na 2 O 2 solution (60 ml) and extracted with CH 2 Cl 2 (3 x 50 ml); the organic layers were dried (MgSC> 4) and evaporated to give a gum (0.85 g). The purification by short path chromatography (B, D, I, J and K) gave an oil (65 mg) which was dissolved in methanol (1 ml). Oxalic acid (25 mg) in methanol (0.5 ml) was added. Addition of dry ether gave a precipitate which was washed with dry ether and dried to give the title salt as a solid (38 mg), mp. 159-165 ° (foams).

N.m.r. <5 (DMSO) includes 2.9-3.0 (11H, m, NMe2 and MeSO2NHCH2CH2); 3.0-3.4 (6H, m, CH2CH2NMe2 and SO2NHGH2); 7.15 (1H, t, SO 2 NH) and 10.93 (1H, d, 20 indole-1).

Example VII

N-C2- [3- [2- (Dimethylamino) ethyl] -1H-indol-5-yl3ethyl] benzamide oxalate

Benzoyl chloride (0.53 ml) was added to a stirred solution of intermediate 9 as the free base (0.95 g) and triethylamine 25 (0.7 ml) in dry CH 2 Cl 2 (40 ml) at room temperature under nitrogen, and stirring was carried out. continued at room temperature for 1 hour 40 minutes. The mixture was washed with 8% aqueous NaHCO 3 (20 ml) and water (2 x 20 ml), dried (MgSC> 4) and the solvent was evaporated. The resulting oil (1.47 g) was combined with another portion prepared in the same manner and purified by flash chromatography (B and L) to give a foam which was dissolved in methanol (2 ml) and a solution of oxalic acid (230 mg) in methanol (1 ml) was added. Addition of dry ether (80 ml) gave a precipitate which was washed with dry ether and dried to give the title salt as a solid (0.873 g), mp. 158-160 °.

N.m.r. 6 (DMSO) includes 2.80 (6H, s, NMe2); 2.95 (2H, t, CONHCH.CH.); 870 0 02 7 -26-

3.06 (2H, m, CH CH 2 NMe) / 3.55 (2H, q, CONHCH 3 CH 3; 7.44-7.6 (4H, m, phenyl (m and p) and indole-4) 8 .63 (1H, t., CONH) and 10.95 (1H, d, indole-1) Example VIII

N- [2- [3- [2- (Dimethylamine) ethyl] -1H-indol-5-yl] ethyl] benzenesulfone-5 amide oxalate

Benzenesulfonyl chloride (0.61 ml) was added to a stirred solution of intermediate 9, as the free base (0.98 g) and triethyl amine (0.72 ml) in dry CHCl (40 ml) at room temperature under nitrogen. and dust, and stirring was continued at room temperature for 1 hour and 40 minutes. The mixture was washed with 8% aqueous NaHCO 3 (20 ml) and water (2 x 20 ml), dried (MgSO 4) and evaporated to give a foam (0.90 g). This was combined with similarly prepared material and the combined samples were purified by chromatography (M and N). The resulting foam (0.607 g) was dissolved in methanol (2 ml), and oxalic acid (154 mg) in methanol (1 ml) was added. Addition of dry ether (80 ml) gave a precipitate which was washed by pouring with dry ether, filtered, and dried to give the title salt as a solid (0.702 g), mp. about 80-90 ° (foams). N.m.r. fi (DMSO) includes 2.7-2.85 (8H, m, NMe2 and SO2NHCH2CH2); 2.95-3.1 20 (4H, m, SO2NHCH2CH2 and C ^ O ^ NMe ^; 7.37 (1H, brs, SO2NH); 7.55-7.7 (6H, m, Ph (m and £) ) and indole-4) and 10.9 (1H, s, indole-1).

Example IX

(i) N- [2- [3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yl] ethyl] benzamide, compound with ethyl acetate (2; 1). A solution of thionyl chloride (1.72 ml) in dry tetrahydrofuran (20 ml) was added dropwise under nitrogen to stirred, ice-cooled solution of benzoic acid (1.41 g) in a mixture of triethylamine (8.00 ml) and dry tetrahydrofuran (80 ml). The solution was stirred in ice for 1 hour, and intermediate 4 (2.13 g) was added and stirring was continued for 0.75 hours. The resulting suspension was partitioned between 2N Na 2 CO 3 (250ml) and ethyl acetate (2 x 250ml).

The combined organic extracts were washed with water (2 x 250 ml) and 2N Na 2 O 4 (250 ml), dried (Na 2 SO 4) and concentrated in vacuo. The residual oil (3.1 g) was chromatographed (E). The required fractions were combined and concentrated in vacuo to provide the title compound as a foam (0.92g), mp. 75-82 °.

870 0 02 7 # * -27- (ii) N- [2- [3- (2-Aminoethyl) -1H-indol-5-yl] ethyl] benzamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1)

A solution of hydrazine hydrate (0.90 ml) and the product of step (i) (0.67 g) in ethanol (25 ml) was stirred at reflux for 3.5 hours and then allowed to cool. The resulting suspension was concentrated in vacuo and the residual solid was partitioned between 2N Na 2 CO 2 (50ml) and ethyl acetate (3 x 50ml). The combined organic extracts were then dried (Na 2 SO 4) and concentrated in vacuo. The remaining gum (0.47 g) was dissolved in a hot mixture of ethanol (40 ml) and water (5 ml) and an aqueous solution of creatinine and sulfuric acid (1: 1; 2M; 0.76 ml) was added . The solid which crystallized on cooling was filtered off, washed successively with a mixture of ethanol and water (8: 1; 27 ml) and ethanol (10 ml) and dried at 60 ° for 8 hours to give the title compound as a solid substance (0.60 g), m.p. 228-229.5 °.

Nmr, <5 (D 2 O) includes 3.0-3.25 '(9H, m, CONHCH 2 CH 2, CH 2 CH 2 NH., And creatinine NMe; 3.68 (2H, t, CH CH NHCO); and 7, 4-7.64 (7H, m, phenyl, indole-4 and 11 "" "ώ indole-7).

Example X.

20 (i) N- [2- [3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-5-yl] ethyl] benzenesulfonamide

A solution of benzenesulfonyl chloride (1.38 ml) in dry dimethylformamide (25 ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of intermediate 4 (2.0 µm in a mixture of triethylamine (3.0 ml) , dry tetrahydrofuran (50ml) and dry dimethylformamide (25ml) and stirring was continued for 2.75 hours The suspension was then left overnight at room temperature and partitioned between 2N Na 2 CO 3 (500ml) and ethyl acetate (2 x 500ml) The combined organic extracts were washed with water (2 x 500 ml) and 2N Na 2 CO 3 (500 ml), dried (Na 2 SO) and concentrated in vacuo. The remaining foam (2.41 g) was chromatographed. Engraved (E) The required fractions were combined and concentrated in vacuo to afford the title compound as a solid (0.73g), mp 183-184 °.

35 8 7 Ö 0 0 2 7 f 4 / -28- (ii) N- [2- [3- (2-Aminoethyl) -1H-indol-5-yl] ethyl] benzenesulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1)

A suspension of the product of step (i) (0.60 g) and hydrazine hydrate (0.75 ml) in ethanol (30 ml) was stirred at reflux for 4.25 hours. The resulting suspension was evaporated in vacuo and the residual solid was partitioned between 2N Na 2 CO 3 (25 ml) and acetate (3 x 25 ml). The combined organic extracts were then dried (Na 2 SO 4) and concentrated in vacuo. The remaining gum (0.46 g) was dissolved in a hot mixture of ethanol (36 ml) and water (4.5 ml), and an aqueous solution of creatinine and sulfuric acid (1: 1; 2M, 0.68 ml ) was added. The solid which crystallized on cooling was filtered off, washed with a mixture of ethanol and water (8: 1; 2 x 5 ml) and ethanol (2x5 ml), then dried in vacuo at 60 ° for 6 hours to yield the title compound as solid 15 (0.48 g), m.p. 216-217.5 °.

N.m.r. S (DMSO) includes 2.78 (2H, t, SO HHCH CH); 2.85-3.2 (9H, m, SO 2 NHCH 2, CTCHNH and creatinine N-Me); 7.2-7.4 (3H, m, indole-2, indole-7 and SO NH)? 7.5-8.0 6H, m, phenyl and indole-4) and 10.9 (1H, s, indole-1).

The following examples illustrate pharmaceutical formulations of the invention containing 4- (acetylamino) -N- 2-3- 2- (dimethylamino) -ethyl-1H-indol-5-yl ethyl benzeneacetamide oxalate as the active ingredient. Other compounds of the invention can be formulated in a completely similar manner.

25 TABLETS FOR ORAL ADMINISTRATION Direct compression mg / tablet

Active ingredient 2.4

Calcium hydrogen phosphate 95.10 30 B.P. *

Croscarmellose sodium USP 2.00

Magnesium stearate, B.p. 0.50

Compression weight 100 mg * of a type suitable for direct compression 8700027 * * -29-

The active ingredient is sieved before application. The calcium hydrogen phosphate, croscarmellose sodium and the 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 then further mixed. The mixture is then compressed using a Manesty F3 tablet machine fitted with 5.5 mm beveled edge flatten punches, in tablets with a target compression weight of 100 mg.

Tablets can also be made using other conventional methods such as wet granulation.

Other strength tablets can be prepared by changing the ratio of the active ingredient to lactose or the compression weight, and using appropriate punches.

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

Injection for intravenous administration mg / ml 20 Active ingredient 0.6 mg

Sodium chloride B.P. as required

Water for injections B.P, up to 1.0 ml

Sodium chloride can be used to adjust the tonicity of the solution, and the pH can be adjusted using acid or caustic to that of optimal 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 acceptable cycles. It is also possible to sterilize the solution by filtration and fill into sterile ampoules under aseptic conditions. The solution can be packaged under an inert atmosphere of nitrogen or other suitable gas.

870 0 02 7.

Claims (11)

1 R 1 represents a C 1-8 alkyl, phenyl or phenyl (C 1-4) alkyl group. 1, Compounds of the general formula 1 of the formula sheet, wherein R 1 represents a hydrogen atom, a C 1 -alkyl or C-cycloalkyl group, or a phenyl or phenyl (C 1-4) alkyl group? R2 represents a hydrogen atom or a C 1-6 alkyl group; R3 represents a hydrogen atom or a C1 -C16 alkyl group; R 1 and which may be the same or different each represent a hydrogen atom, a 3-alkyl group or a 2-propenyl group; A represents -CO- or “SO ^ -; and n represents an integer from 2-5; (where R 1 does not represent hydrogen when A represents -SO 2 -) and physiologically acceptable salts and solvates thereof. Compounds according to claim 1, wherein in the general formula Compounds according to claim 2, wherein in the general formula 1 R 1 represents a methyl or phenyl group. Compounds according to any one of claims 1-3, wherein n corresponds to 2. Compounds according to any one of claims 1-4, wherein R2 represents a hydrogen atom. Compounds according to any one of claims 1-5, wherein represents a hydrogen atom. Compounds according to any one of claims 1-6, wherein R 1 and R 2, which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group. 8. N-C2- [3- [2- (methylamino) ethyl] -1H-indol-5-yl] ethyl] methanesulfonamide and its physiologically acceptable salts and solvates. Pharmaceutical composition comprising at least one compound of the general formula 1 or a physiologically acceptable salt or solvate thereof together with one or more physiologically acceptable carriers or excipients. 10. A process for the preparation of a compound of the general formula 1 as defined in claim 1 or a physiologically acceptable salt or solvate thereof comprising: (A) reacting a compound of the general formula 2 of the formula sheet (wherein R2, Ry R4, Rg and n are defined as in claim 1) or a salt thereof or an N-silyl derivative thereof or a protected derivative thereof, with a reagent having the function 870 0 02 7 J -31-t * the group R ^ A (where and A have the meaning as in claim 1)? or (B) cyclizing a compound of the general formula 3 of the formula sheet (wherein R ^, R ^, RA and n have the same meaning as 5 in claim 1 and Q the group NR ^ R ^ (where R4 and Rg are the same meaning as in claim 1) or a protected derivative thereof, or a leaving atom or group; or (C) reacting a compound of the general formula 6 of the formula sheet (wherein R 1, R 2, R 1, A, Y and n have the same meaning as in claim 1 and Y is an easily removable atom or group) or a protected derivative thereof, having an amine of the formula R.R_-NH (where R. and R_ have the same meaning as in claim 1 4- 5- or (D) reducing a compound of the general formula 7 of the formula sheet (wherein R 1, R 2, R 3 and A have the same meaning as in claim 1 and W is a group which can be reduced to the desired - (CH) NR.R group, where R. and R_ have the same meaning 2 2 4 b 4 b as in claim 1, or a protected derivative of "(0¾) 2NR4R5 and B represents the growth) ^ CH2 ^ n", wherein n has the same meaning as in claim 1, or a group that can be reduced to this group) or a salt or protected derivative thereof; or (E) in order to prepare one compound of the general formula 1 as defined in claim 1 or a physiologically acceptable salt or solvate thereof, subjecting another compound of the general formula 1 or a salt or solvate thereof to an inter conversion reaction; or (F) subjecting a protected derivative of the general formula 1 or a salt thereof to a reaction to remove the protecting group or groups; and if desired or necessary subjecting the compound obtained from any one of methods (A) to (E) to one or two additional reaction comprising: (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. 8700027 * '* -32- 11. Compounds of the general formula II of the formula sheet, wherein represents a hydrogen atom or a C 1-6 alkyl group; R 1 represents a hydrogen atom or a C 1-4 alkyl group; R 1 and R 1, which may be the same or different, each represent a hydrogen atom, a C 1-6 alkyl group, or a 2-propenyl group; and n represents an integer from 2-5, and salts thereof. 8700027 * ί COMPATIBLE PATENT OFFICES Dutch patent application no. 8700027 • RAVENHAC6 (Holland) beh. when writing dd. March 13, 1987 Ln / 657 IR v. D I, B, I 16 HST 1937 Improvement (s) of erratum (a) in the description associated with patent application No. 8700027 proposed by applicant (star) under date March 13, 1987 CC OC OC CC Cf cccc cc cc cccc cc cc cc. oc In formula 6 of the formula sheet, a nitrogen atom is missing in the side chain of the benzene ring. The side chain is changed to (CI ^) n 8700027 545 4 "** ί2 RrA-N (CH2) nW / .x 7 (0Η2) 2NRi + R5 R2NH (CH2} n \ / χ / CH2) 2NRltR5 I i“ Ü Γ ii — J \\ Λ ƒ \ Λ / '• 1 I, .2' t RrA-RN (CH-). R -ARN (CH2) x · 1 2 2n \ // \ 1 L 2n \ // \ • »· · I II I II 3 · \\ A t \ w \ NR3N = CH (CH2) 3Q · T ° HC (CH2) 3Q RrA-R2 (CH2). (CH2) 2Y 5 6 · · ï JQ w / \ / • N «3 RrA-R2N8w / \ / W 0HC (CH2> nN // Λ / · '· _« · · ___ · I ii ii 1 11 11 7 »· · Q · · · W / W o \\ / \ / «N · N« 3 y, 3 870 0027 Glaxo Group Limited