CH671017A5 - - Google Patents

Description

671,017

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DESCRIPTION

1. Compounds of general formula (I): Ro rra-n (ch2)

n \ H \

(ch2) 2nr „r5

(I)

• • •

NX / Y

in which

R represents a hydrogen atom, a C1-C6 alkyl or C3-C7 cycloalkyl group, or a phenyl or phenylalkyl group (Q-C4);

R2 represents a hydrogen atom or a Cj- alkyl group

c3;

R3 represents a hydrogen atom or a C 1 -C alkyl group -

c3;

R4 and R5, similar or different, each represents a hydrogen atom, a Q-C3 alkyl group or a 2-pro-penyl group;

A represents —CO— or - S02—, and n represents an integer from 2 to 5, provided that Rj does not represent a hydrogen when A represents - S02—,

their physiologically acceptable salts and solvates.

2. Compounds according to claim 1, characterized in that Rt represents a C1-C6 alkyl, phenyl or phenylalkyl (Cr

Q) -

3. Compounds according to claim 2, characterized in that Rj represents a methyl or phenyl group.

4. Compounds according to claim 1, characterized in that n represents the integer 2.

5. Compounds according to claim 1, characterized in that R2 represents a hydrogen atom.

6. Compounds according to claim 1, characterized in that R3 represents a hydrogen atom.

7. Compounds according to claim 1, characterized in that R4 and R5, similar or different, each represent a hydrogen atom or a methyl or ethyl group.

8. N- [2- [3- [2- (methylamino) ethyl] -1H-indole-5-yl] ethyl] methane-sulfonamide according to claim 1 and its physiologically acceptable salts and solvates.

9. Pharmaceutical composition, characterized in that it comprises at least one compound of general formula (I) according to claim 1, or a physiologically acceptable salt or solvate with at least one physiologically acceptable carrier or excipient.

10. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its physiologically acceptable salts or solvates, characterized in that a compound of general formula (II) is reacted:

r2nh (ch2) n x ^ / (ch2) 2nr4rs

The present invention relates to indole derivatives useful as medicaments and a process for their preparation. The invention relates in particular to compounds and compositions useful for the treatment of migraine.

Migraine pain is associated with excessive dilation of the cranial vascular system, and known treatments for migraine include the administration of compounds with vasoconstrictive properties, such as ergotamine. However, ergotamine is a non-selective vasoconstrictor that contracts blood vessels throughout the body and has unwanted and dangerous side effects. Migraine can also be treated by the administration of a pain reliever, usually in combination with an anti-emetic, but these treatments are of limited value.

We are therefore looking for a safe and effective drug for the treatment of migraine that can be used prophylactically or to relieve an established headache and a compound having selective vasoconstrictor activity playing this role.

We have discovered a group of indole derivatives having potent and selective vasoconstrictive activity.

The invention relates to indole derivatives of general formula I:

(II)

\\ / \ / • NOT

in which R2, R3, R4, Rs and n are as defined in claim 1, or one of its salts or one of its N-silyl derivatives or one of its protected derivatives, in which case the protective group is removed, with a reagent for introducing the group Ri A, where Rt and A are as defined in claim 1, the compound being, if desired, isolated as a salt or solvate acceptable for therapeutic use, or transformed into another salt or solvate acceptable.

Rj-A-N (CH2)

(ch2) 2nr4r5

(I)

n \ Ì! \

I II II "" <

\\ / \ / • NOT

in which:

R! represents a hydrogen atom, a C1-C6 alkyl or C3-C7 cycloalkyl group, or a phenyl or phenylalkyl (Cj-35 c4) group;

R2 represents a hydrogen atom or a C1-C4 alkyl group

C3;

R3 represents a hydrogen atom or a Ct- alkyl group

C3;

40 R4 and R5, which may be the same or different, each represents a hydrogen atom, a C 1 -C 3 alkyl group or a 2-propenyl group;

A represents —CO— or - S02—, and n represents an integer from 2 to 5, provided that Rj does not represent hydrogen when A represents - S02 -,

and physiologically acceptable salts and solvates (eg hydrates) thereof.

The invention covers all the optical isomers of the compounds of formula I and their mixtures, including their racemic mixtures. n / a In general formula I, the alkyl groups can be straight chain or branched chain alkyl groups, such as methyl, ethyl or isopropyl groups. The cycloalkyl group can for example be a cyclopentyl or cyclohexyl group.

The alkyl fragment of a phenylalkyl group (C1-C4) can be, for example, a methyl or ethyl fragment.

In a category of compounds of formula I, the group Rt can be a Ct-C6 alkyl, phenyl or phenylalkyl group (Q-

Q) -

In general, the group R 1 is preferably a methyl or phenyl group.

In the compounds of formula I, n can be one of the integers 3, 4 or 5, but preferably the integer 2.

A preferred category of the compounds represented by the general formula I is that in which R2 represents a hydro-65 gene atom. Another preferred category of compounds is that in which R3 represents a hydrogen atom.

Another preferred category of compounds is that in which R4 and R5, which may be the same or different, represent

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each a hydrogen atom or a methyl or ethyl group. It is preferred that the total number of carbon atoms in R4 and R5 does not exceed 2.

A particularly important compound according to the invention is N- [2- [3- [2- (methylamino) ethyl] -lH-indole-5-yl] ethyl] -methanesul-fonamide and its salts and solvates (for example hydrates ) physiologically acceptable.

The physiologically acceptable salts suitable for the indoles of general formula I include the acid addition salts formed with mineral or organic acids, for example hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, Oxalates, tartra-tes, citrates, fumarates , maleates, succinates and sulfonates, for example mesylates. Other salts may be useful for the preparation of the compounds of formula I, for example the adducts of creatininesulfate.

It should be noted that the invention extends to other physiologically acceptable equivalents of the compounds according to the invention, that is to say the physiologically acceptable compounds which are transformed in vivo into the parent compound. Examples of such equivalents include N-acylated derivatives having metabolic lability which are physiologically acceptable.

The compounds of the invention cause selective constriction of the carotid arterial bed in anesthetized dogs, while having a negligible effect on blood pressure. Their selective vasoconstrictor action has been demonstrated in vivo.

The compounds of the invention are useful for the treatment of pain resulting from dilation of the carotid vascular bed, in particular migraine and Horton vascular headache.

The invention also relates to a pharmaceutical composition suitable for use in human medicine which comprises at least one compound of formula I or a physiologically acceptable salt or solvate (for example hydrate) thereof and presented for administration according to a route. any suitable. These compositions can be presented in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.

Therefore, the compounds according to the invention can be presented for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions can be in the form, for example, of tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binders (for example pregelatinized corn starch, polyvinylpyrrolidone or hydroxypro-pylmethylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); wetting agents (for example sodium lauryl sulfate). The tablets can be coated according to methods well known in the art. Liquid preparations for oral administration can be, for example, in the form of solutions, syrups or suspensions or they can be presented in the form of a dry product intended to be reconstituted with water or another vehicle suitable before use. These liquid preparations can be prepared in a conventional manner with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example le-cithine or gum arabic); non-aqueous vehicles (for example almond oil, oily esters or ethyl alcohol); preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the compositions can be in the form of tablets or lozenges prepared in a conventional manner.

The compounds of the invention can be presented for parenteral administration by injection. The injectable compositions can be presented in unit administration forms,

for example ampoules, or in multidose containers with the addition of a preservative.

The compositions can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and can contain composition agents, such as suspending, stabilizing and / or dispersing agents. Otherwise, the active ingredient can be in the form of a powder intended to be reconstituted with an appropriate vehicle, for example sterile apyrogenic water, before use.

The compounds of the invention can also be presented in the form of rectal compositions, such as suppositories or enemas to keep containing, for example, conventional bases for suppository, such as cocoa butter or other glycerides.

For administration by inhalation, the compounds according to the invention are conveniently presented in the form of an aerosol delivered by pressurized containers with the use of an appropriate propellant, for example dichlorodifluoromethane, trichlorofluo-romethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas or using a nebulizer. In the case of a pressurized aerosol, the unit dose can be determined by means of a valve delivering a metered amount. Capsules or cartridges, for example in gelatin, for use in an inhaler or an insufflator may be presented to contain a mixed powder made of a compound of the invention and of 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 (having an average body weight of around 70 kg for example) for the treatment of migraine is 0.1 to 100 mg of the active ingredient per unit dose which can be administered for example 1 to 4 times a day. It should be noted that it may be necessary to modify, as usual, the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated.

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

The aerosol compositions are preferably designed so that each dose or "puff" delivered by a pressurized aerosol contains 0.2 to 2 mg of a compound of the invention and that each dose administered by capsules or cartridges in a inhaler or insufflator contains 0.2 to 20 mg. The overall daily dose by inhalation is in the range of 1 mg to 100 mg. The administration can be repeated several times a day, for example 2 to 8 times with each time taking 1, 2 or 3 doses.

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

The compounds of formula I and their physiologically acceptable salts or solvates (for example hydrates) can be prepared according to the general methods mentioned above. In the following processes, Rls R2, R3, R4, Rs, A and n are as defined for general formula I, unless otherwise indicated.

According to a general process (A), it is possible, to prepare a compound of general formula I, to react a compound of general formula II:

R2NH (CH2) n ^ /(CH2)2NR.,R5

or a salt thereof (for example an organic or mineral acid addition salt such as a hydrochloride addition compound,

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671017

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hydrobromide, maleate, sulfate or creatininesulfate) or an N-silylated derivative thereof or a protected derivative thereof with an agent introducing the group RjA.

Suitable agents for introducing the RjA group include acids of the general formula RjAOH or the corresponding acylating agents.

Acylating agents which can be used in practice in the above process include acid halides (e.g. carboxylic acid chlorides and sulfonyl chlorides), alkyl esters (e.g. methyl or ethyl ester), activated esters (for example 2- (1-methylpyridyl) ester), symmetrical anhydrides, mixed anhydrides or other activated derivatives of carboxylic acids such as those conventionally used in synthesis peptides.

The process can be carried out in a suitable aqueous or non-aqueous reaction medium, conveniently at a temperature of -70 to + 150 ° C. Therefore, the process using an acid halide, an activated ester or an anhydride can be carried out in an appropriate reaction medium such as an amide (for example N, N-dimethyl-formamide or hexamethylphosphoramide), an ether (for example tetrahydrofuran), an ester (for example ethyl acetate), a nitrile (for example acetonitrile), a haloalkane (for example dichloromethane) or their mixtures, optionally in the presence of an organic base, for example a tertiary amine such as triethylamine or pyridine, or a mineral base such as potassium carbonate or sodium bicarbonate. 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 (for example me-thanol), an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or their mixtures, and conveniently at a temperature of 0 to 100 ° C.

When A represents - CO—, carboxylic acids of formula R] COOH can also be used in the preparation of the compounds of formula I. The reaction is desirably carried out in the presence of a coupling agent, for example N , N'-carbo-nyldiimidazole or a carbodiimide such as N, N'-dicyclohexylcar-bodiimide. The reaction can be carried out in an appropriate reaction medium such as a haloalkane (for example dichloromethane), a nitrile (for example acetonitrile), an amide (for example dimethylformamide) or an ether (for example tetrahydrofuran) of conveniently at a temperature of - 50 to + 50 ° C, preferably of - 5 to + 30 ° C. The reaction can also be carried out in the absence of a coupling agent in an appropriate reaction medium, such as a hydrocarbon (for example toluene or xylene), conveniently at a temperature of 50 to 120 ° C.

To prepare a compound of general formula I in which RtA represents - CHO, it is possible to heat a compound of general formula II with ethyl formate, optionally in the presence of a solvent, for example ethanol.

The compounds of general formula II in which R2 is a hydrogen atom can be prepared for example by reduction of a corresponding compound having a suitable reducible group as a substituent in position 5, such as - (CH2) „_ iCN or a group corresponding cyanosubstituted alkenyl. The reduction can be carried out by catalytic hydrogenation or with a reducing agent such as lithium aluminum hydride.

Such nitriles can be prepared, for example, by cyclization of a suitable hydrazine in a manner analogous to the general process (B) described below. Alternatively, intermediates having a 5- (cyanoalkenyl) substituent can be prepared by reacting an appropriate indole-5-carboxaldehyde with a cyanoalkyl phosphonate.

The compounds of general formula II in which R2 is an alkyl group can be prepared for example by reduction of a corresponding nitrile in the presence of an amine R2NH2 or by reaction of a compound of formula II, in which R2 is a d atom hydrogen, with a suitable alkylating agent.

According to another general process (B), the compounds of formula I can be prepared by cyclization of a compound of general formula III:

Rj-A-RjNCCHj).

not \ // \

î fi (III)

• •

\ / \

nr3n = ch (ch2) 3q in which Q is the NR4RS group (or a protected derivative thereof) or a labile group or atom such as a halogen atom (for example chlorine or bromine) or a group acyloxy (for example an acyloxy carboxylic or sulfonic group, such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitro-benzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group).

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

Particularly practical embodiments of the method are described below.

When Q is the NR4RS group (or a protected derivative thereof), the process is desirably carried out in the presence of polyphosphate ester in a reaction medium which can comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or their mixtures. The polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform, according to the process described in "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sounds, 1967).

Otherwise, 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 can be an aqueous organic solvent such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (for example dioxane or tetrahydrofuran) as well as mixtures of such solvents. The acid catalyst can for example be a mineral acid such as hydrochloric acid or concentrated sulfuric acid or an organic acid such as acetic acid (in certain cases, the acid catalyst can also act as solvent for the reaction). In an anhydrous reaction medium which can comprise, for example, one or more ethers (such as those described above) or esters (such as ethyl acetate), the acid catalyst is generally a Lewis acid such as trifluoride. boron, zinc chloride or magnesium chloride.

When Q is an atom or labile group such as a chlorine or bromine atom, the reaction can be carried out in an aqueous organic solvent such as an aqueous alcohol (for example methanol, ethanol or isopropanol) by the absence of an acid catalyst, conveniently at a temperature of 20 to 200 ° C, preferably 50 to 125 ° C. This process causes the formation of a compound of formula I, in which R4 and Rs are both hydrogen atoms.

According to a particular embodiment of this process, the compounds of formula I can be directly prepared by reaction of a compound of general formula IV:

I II (IV)

• •

(in which T is a group - NR3NH2) or a salt thereof, with a compound of formula V:

OHC (CH2) 3Q (V)

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

The compounds of general formula III can, if desired,

be isolated as intermediates during the process of preparing the compounds of formula I, wherein a compound of formula IV or a protected salt or derivative thereof is reacted with a compound of formula V or a protected salt or derivative thereof ci, in water or in a suitable solvent, such as an aqueous alcohol (for example methanol), at a temperature for example of 20 to 30 ° C. If an acetal or a ketal of a compound of formula V, it may be necessary to carry out the reaction in the presence of an acid (for example acetic or hydrochloric acid).

The compounds of general formula IV can be prepared, for example, from the corresponding nitro compounds (i.e. those in which T is - NO2), according to conventional procedures.

Another general process (C) for preparing the compounds of general formula I comprises the reaction of a compound of general formula VI:

RrA-R2NBwA

rra-r2n (ch2)

not\ // \

/

(ch2) 2y

V V

r3

(VI)

(in which Y is an atom or group which is easy to move) or a protected derivative thereof with an amine of formula R4R5NH.

The displacement reaction can conveniently be carried out on the compounds of formula VI in which Y is a halogen atom (for example chlorine, bromine or iodine) or a group OR6 where OR6 is, for example , an acyloxy group which may be derived from a carboxylic or sulfonic acid, such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitro-benzyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group.

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

The compounds of general formula VI in which Y is a halogen atom can be prepared by reacting a hydrazine of general formula IV with an aldehyde or a ketone (or a protected derivative thereof) of formula V, in which Q is a halogen atom, in an aqueous alcohol (for example methanol) containing an acid (for example acetic or hydrochloric acid). The compounds of formula VI in which Y is the group OR6 can be prepared from the corresponding compound in which Y is a hydroxyl group, by acylation with the appropriate activated species (for example anhydride or sulfonyl chloride) using classical techniques. The intermediate alcohol can be prepared by cyclization of a compound of formula III, in which Q is a hydroxyl group (or a protected derivative thereof), under standard conditions.

The compounds of formula I can also be prepared according to another general process (D) comprising the reduction of a compound of general formula (VII):

\\ / \ / • n r3

(VII)

[in which W is a group which can be reduced to provide the group - (CH2) 2NR4R5 required or to provide a protected derivative of - (CH2) 2NR4R5, and B represents the group - (CH2) n— as io defined here or a group which can be reduced to - (CH2) n—] or a salt or protected derivative thereof.

The groups - (CH2) 2— and - NR4RS required in position 3 can be formed according to reduction stages which are carried out separately or together as appropriate.

Groups B which can be reduced to provide the required - (CH2) „- group include the corresponding unsaturated groups such as alkenyl or C2-C5 alkynyl groups.

Examples of the groups represented by the substituent W include

- (CH2) 2N02; —CH = CHN02; - (CH2) 2N3;

—CH2CN; —CH2CHO; -COCH2Z; -CH2CH = NOH; —CH (0H) CH2NR4Hs; - (CH2) 2NR4COR'5; -COCONR4H5 and —CH2COZ (where Z is an azydo group or the group —NR4R5 or a protected derivative thereof and R's is a hydrogen atom or a methyl or ethyl group or R'5 represents the group OR, where R7 is an alkyl or aralkyl group).

The groups which can be reduced to the fragment - (CH2) 2 - include the corresponding unsaturated group and the corresponding groups containing one or more hydroxyl groups or carbonyl functions.

The groups which can be reduced to the group - NR4RS where R4 and R5 are both hydrogen include the groups nitro, azido, hydroxyimino and nitriles.

In the latter case, the reduction provides the group - CH2NH2 and therefore a methylene group of the fragment - (CH2) 2 -.

A compound of general formula I in which Rs is a hydrogen atom can also be prepared by reduction of a corresponding compound, in which Rs is a benzyl group, for example with hydrogen in the presence of a catalyst such as 40 palletized coal at 10%.

The required —NR4R5 group in which R4 and / or R5 are other than hydrogen can be prepared by reduction of a nitrile —CH2CN or an aldehyde —CH2CHO in the presence of an amine R4R5NH.

45 A particularly suitable process for the preparation of a compound of formula I in which R4 and / or Rs are other than hydrogen is the alkylation by reduction of the corresponding compound in which R4 and / or Rs represent hydrogen with an aldehyde or an appropriate ketone (eg acetaldehyde or ac-50 tone) in the presence of an appropriate reducing agent. Reducing agents suitable for use in this process include hydrogen in the presence of a metal catalyst or an alkali metal borohydride or cyanoborohydride (e.g. sodium borohydride or cyanoborohydride) using the conditions described below 55 for the reduction of the compounds of formula VII. In certain cases (for example for the introduction of the R5 group where Rs is an ethyl), the aldehyde (for example acetaldehyde) can be condensed with the amine and the intermediate thus formed can then be reduced by using d 'an appropriate reducing agent.

60 The group - NR4RS required in which R4 and / or R5 are other than hydrogen can also be prepared by reduction of a corresponding amide group, for example of formula - (CH2) 2NR4COR'5 where R'5 is as above described.

It should be noted that the choice of reducing agent and the reaction conditions depend on the nature of the groups W, B and of the other groups already present on the molecule. It should also be noted that, when A represents —CO—, the group W must not contain an amide function.

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Suitable reducing agents which can be used in the above process for the reduction of the compounds of formula VII, where W represents for example the groups - (CH2) 2N02; -CN = CHN02, - (CH2) 2N3; -CH2CN; - CH2CH = NOHet —CH (OH) CH2NR4R5, include hydrogen in the presence of a metal catalyst, for example Raney nickel or a noble metal catalyst such as platinum, platinum oxide, palladium, l palladium oxide or rhodium, which can be carried for example on coal, kieselguhr or alumina. In the case of Raney nickel, hydrazine can also be used as a source of hydrogen. This process can, in practice, be carried out in a solvent such as an alcohol, for example ethanol, an ether, for example dioxane or tetrahydrofuran, an amide, for example dimethylformamide, or an ester, for example ethyl acetate, and at a temperature of -10 to + 50 ° C, preferably from -5 to + 30 ° C.

The reduction operation can also be carried out on compounds of formula VII, in which W represents for example the groups - (CH2) 2NO; -CH = CHN02; - (CH2) 2N3; —CH (OH) CH2NR4R5 or - COCH2Z (where Z is as previously defined), using an alkali metal or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, this operation can be carried out conveniently 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, reduction using a borohydride can be carried out in the presence of cobaltous chloride.

When A represents - SO 2 -, the reduction of the compounds of formula VII, in which W represents for example - (CH 2) 2 NO 2; —CH = CHN02; - (CH2) 2N3; - (CH2) 2NR4COR'5; —CH2CH = NOH; - CH (OH) CH2NR4R5; -COCONR4R5; - CH2COZ and - COCH2Z (where R's and Z are as previously defined), can also be carried out by the use of 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 from 50 to 100 ° C.

A particular embodiment of the general process (D) comprises the reduction of a compound of formula VII, in which W is the group - CH2CN, for example by catalytic reduction with hydrogen in the presence of a catalyst such as carbon palladium or rhodium alumina, optionally in the presence of an amine HNR4R5.

Suitable reducing agents which can be used in the reduction of group B include hydrogen in the presence of a metal catalyst. The conditions and the metal catalysts suitable for the reduction operation are those described for the reduction of group W.

The starting materials or the intermediate compounds of formula VII can be prepared according to methods analogous to those described in the published British patent application No. 2035310 and in "A Chemistry of Heterocyclic Compounds-Indoles Part II", chapter VI, edited by W J. Houlihan (1972) Wiley Interscience, New York.

The compounds of formula VII in which W is the group —CH2CHO can be prepared by oxidation (for example with Jones' reagent) of a compound of formula VI, in which Y is a hydroxyl group. To prepare a compound of formula VII, in which W is the group - CH2CH = NOH, it is possible to treat the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.

The intermediate compound of formula VII, in which W is the group - (CH2) 2N3, can be prepared from a compound of formula VI, in which Y is a halogen atom, using standard procedures.

Standard reducing agents such as sodium borohydride can be used to prepare a compound of formula VII, in which W is the group -CH (OH) CH2NR4R5, from the corresponding compound of formula VII, in which W is the group - COCH2NR4R5.

A compound of formula VII, in which W is the group - (CH2) 2NR4COR'5, can be prepared by acylation of the corresponding unsubstituted amine, using standard procedures.

The intermediate compounds of formula VII, in which B represents a C2-C5 alkenyl group, can be prepared by reaction of a compound of general formula VIII:

0HCCCH,) y »

î II II (VIII)

• • •

W / \ /

1 =

(in which W is as defined for general formula VII and n is 0 or an integer from 1 to 3) with, for example, an appropriate phosphonium salt, using standard conditions.

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

For example, a compound of general formula I, in which one or more of R3, R4 and / or R5 are alkyl groups, can be prepared from the corresponding compounds of formula I, in which one or more of R3, R4 and R5 represent hydrogen atoms, by reaction with an appropriate alkylating agent such as a compound of formula RXL (in which Rx represents the desired R3, R4 or Rs group and L represents a labile atom or group such as halogen atom or tosylate group) or sulfate (R5) 2SO4. The alkylating agent can therefore be, for example, an alkyl halide (for example metal or ethyl iodide), an alkyl tosylate (for example methyl tosylate) or a dialkyl sulfate (e.g. dimethyl sulfate).

The alkylation reaction can, conveniently, be carried out in an inert organic solvent such as an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or an aromatic hydrocarbon (for example 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 an alcoholate of alkali metal such as methyl-late, sodium or potassium ethylate or tert.-butoxide, or tetrabutylammonium 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 can conveniently be carried out at a temperature of -20 to 100 ° C.

Compounds of formula I, in which one or both of R3 and R4 represent propylene, may be prepared in a similar manner, using an appropriate compound of formula RXL or (R ^ SO ^

According to another general process (F) it is possible, to prepare a compound of general formula I according to the invention or a salt thereof, subjecting a protected derivative of general formula I or a salt thereof to a reaction for remove the protective group (s).

Thus, in an early stage of the reaction sequence for the preparation of a compound of general formula I or a salt thereof, it may be necessary or desirable to protect one or more sensitive groups in the molecule to avoid undesirable side reactions . For example, it may be necessary to protect the NR4R5 group, in which R4 and / or R5 represent hydrogen, by protonation or with an easily removed group at the end of the reaction sequence. These groups may include, for example

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for example, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, or acyl groups such as N-benzyloxycarbo-nyl or tert.-butoxycarbonyl or phthaloyl.

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

The subsequent cleavage of the protective group (s) can be carried out according to conventional procedures. Thus, an aralkyl group, such as benzyl, can be cleaved by hydrogenolysis in the presence of a catalyst (for example palladium on carbon) or sodium and 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 hydrogenation. The phthaloyl group can be eliminated by hy-drazinolysis (for example by treatment with hydrazine hydrate) or by treatment with a primary amine (for example methylamine).

It should be noted that in some of the general methods (A) to (E) described above, it may be necessary or desirable to protect the sensitive groups in the molecule as just described. Thus, a reaction stage comprising the deprotection of a protected derivative of general formula I or a salt thereof can be carried out after any of the methods (A) to (E) previously described.

Therefore, the following reactions in any suitable order can, if necessary and / or if desired, be carried out after any of the methods (A) to (E):

i) elimination of protective groups, and ii) conversion of a compound of general formula I or of a salt thereof into a physiologically acceptable salt or solvate (for example hydrate) thereof.

When it is desired to isolate a compound of the invention in the form of a salt, for example in the form of an acid addition salt, this can be carried out by treatment of the free base of general formula I with a suitable acid, preferably in an equivalent amount or with creatininesulfate in a suitable solvent (for example aqueous ethanol).

The starting materials or the intermediate compounds for the preparation of the compounds according to the invention can be prepared according to methods analogous to those described in the published British patent application No. 2035310.

As in the last main stage of the preparation sequence, the general methods indicated above for the preparation of the compounds of the invention can also be used to introduce the desired groups in an intermediate stage of the preparation of the required compound. Thus, for example, the group required in position 5 can be introduced before or after the cyclization to form the indole nucleus. It should therefore be noted that, in such multi-stage processes, the order of the reactions must be chosen so that the reaction conditions have no effect on the groups present in the molecule which must remain in the final product. .

The invention is further illustrated by the following examples in which all the temperatures are in degrees Celsius.

Chromatography is carried out either conventionally by the use of 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 by thin layer chromatography (TLC) on silica (Macherly-Nagel, Polygram) unless otherwise indicated. The following abbreviations define the eluents used for chromatography and TLC: (A) ethyl acetate / 2-propanol / water / 0.88 ammonia: 25/15/8/2; (B) CH2Cl2 / ethanol / ammonia 0.88: 89/10/1; (C) ethyl acetate; (D) CH2Cl2 / ethanol / ammonia 0.88: 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 / ammonia 0.88: 200/15/8/2; (J) ethyl acetate / 2-propanol / water / ammonia 0.88: 100/15/8/2; (K) ethyl acetate / 2-

propanol / water / ammonia 0.88: 50/15/8/2; (L) CH2Cl2 / ethanol / ammonia 0.88: 87/12 / 1.2; (M) CH2Cl2 / ethanol / ammonia 0.88: 95/5 / 0.5; (N) CH2Cl2 / ethanol / ammonia 0.88: 91/8 / 0.8.

The intermediates are subjected to an ordinary purity control by TLC with the use of ultraviolet light for detection and of sprayed reagents such as potassium permanganate (KMn04). In addition, indole intermediates are detected by spraying with aqueous ceric sulfate (Ce IV) and tryptami-nes by spraying with a solution of iodoplatinic acid (IPA) or ceric sulfate.

The proton nuclear magnetic resonance (1 H) (NMR) spectra are 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 = quadruplet.

Intermediate 1

4-hydrazinobenzene-acetonitrile hydrochloride

A solution of 4.0 g of sodium nitrite in 34 ml of water between -5 ° and -2 ° is added dropwise to a suspension of 7.6 g of 4-aminobenzene-acetonitrile in 80 ml of acid. concentrated hydrochloric acid and stirring is continued at -2 ° for 20 minutes. The mixture is filtered and the filtrate is added dropwise between 0 ° and 5 ° to a solution of 65 g of tin (II) chloride dihydrate in 130 ml of concentrated hydrochloric acid. The mixture is allowed to warm to room temperature overnight (17 hours), the precipitate is separated by filtration, washed with concentrated hydrochloric acid, cold absolute ethanol and anhydrous ether, and dry to obtain the title salt in the form of a powder (6.05 g), mp 207-210 ° (foam).

Intermediate 2

3- [2- (1,3-Dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -lH-indole-5-acetonitrile

A mixture of 3.15 g of intermediate 1 and 4.95 g of diethyl acetal of 4- (1,3-dihydro-1,3, dioxo-2H-iso-indole) is refluxed for 2 hours. 2-yl) butanal in 150 ml of aqueous acetic acid (25%), the mixture is cooled, the precipitate is separated by filtration and washed with water (2 x 20 ml) and then with ether (100 ml) . The crude product is triturated with ethyl acetate to obtain the title compound as a solid (3.2 g), m.p. 185-186 °.

Intermediate 3

2- [2- [5- (2-aminoethyl) -1H-indole-3-yl] ethyl] -1H-iso-indole sulfate 1,3-(2H) -dione

Hydrogenated on PdO on charcoal (50% aqueous paste, 0.96 g) at ordinary temperature and at 4.8 bar for 24 hours a suspension of 0.96 g of intermediate 2 in 100 ml of methanol containing 0 , 58 g of concentrated sulfuric acid. The catalyst is filtered off, washed with methanol and the filtrate is evaporated to dryness to obtain the title compound in the form of an oil (1.4 g).

Intermediate 4

2- [2- [5- (2-aminoethyl) -1H-indole-3-yl] ethyl J-1H-iso-indole-1,3- (2H) -dione hydrochloride

A solution of 1.5 g of intermediate 2 in 400 ml of methanol containing 0, is hydrogenated over PdO on charcoal (50% aqueous paste, 3.0 g) at ordinary temperature and under pressure for 24 hours. 6 ml concentrated hydrochloric acid. The catalyst is filtered off, washed with methanol and the filtrate is evaporated to dryness to obtain the title compound in the form of a foam (1.2 g), TLC (A): Rf = 0.6.

Intermediate 5

3- [2- (1,3-Dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-indole-5-carboxaldehyde, 'AH20

About 2 g of Raney nickel are added to a stirred solution

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4.98 g of 3- [2- (2,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -lH-indole-5-carbonitrile and 10.6 g d sodium hypophosphite in 100 ml of pyridine, 50 ml of water and 50 ml of acetic acid. The mixture is heated to approximately 50 ° for 6 hours by periodically adding Raney nickel (5 x approximately 2 g). After cooling, the mixture is filtered and the filtrate is diluted with 1250 ml of water and extracted with ethyl acetate (3 x 500 ml). The combined organic extracts are washed with hydrochloric acid (2N; 2 x 500 ml), dried (MgSO 4), evaporated in vacuo and an azeotropic distillation is carried out with toluene (2 x 100 ml) to obtain the title aldehyde as a solid (4.6 g). A sample (0.53 g) is purified by chromatography (C) to obtain the pure title aldehyde as a solid (0.49 g), m.p. 202-203 °.

Intermediate 6

(E) -3- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1 H-indole-5-yl] -2- propenenitrile

A solution of 1.6 ml of diethyl cyanomethylphos-phonate in 40 ml of tetrahydrofuran (THF) is added slowly

anhydrous to a stirred suspension of NaH (80%; 0.30 g) in 40 ml of THF under nitrogen. After 10 minutes, a solution of 1.70 g of intermediate 5 in 40 ml of THF is added to the clear solution obtained and the mixture is stirred at room temperature for 19 hours. The solution is then subjected to a partition between 200 ml of IN hydrochloric acid containing 50 g of NaCl and ethyl acetate (3 x 150 ml). The combined organic extracts are dried (MgSO4) and evaporated to dryness to obtain a solid (1.53 g) which is purified by chromatography (E) to obtain the title compound as a crystalline solid (1 , 13 g), pf 232-234 °.

Intermediate 7

4- [2- [4- (Dimethylamino) butylidene Jhydrazino Jbenzene-acetonitrile

9.45 g of 4,4-diethoxy-N, N-dimethylbutanamine are added to a stirred suspension of 9.2 g of intermediate 1 in 200 ml of deionized water at ordinary temperature under nitrogen, 22 ml are added 2N hydrochloric acid (pH 2) and stirring is continued at room temperature for 5 hours. The clear solution is made alkaline with 200 ml of 8% aqueous NaHCO3 and extracted with CHCl3 (3 x 200 ml). The organic layers are dried (MgSO4) and evaporated to obtain the title compound in the form of an oil (15.6 g). TLC (silica, B): Rf = 0.35.

Intermediate 8

5- (cyanomethyl) -N, N-dimethyl-1H-indole-3-ethanamine oxalate

15.4 g of intermediate 7 are heated under reflux with 108 g of polyphosphate ester in 200 ml of CHCl 3 with stirring under nitrogen for 8 minutes. The mixture is poured onto ice, 500 ml of 8% aqueous NaHCO3 are added and, after 20 minutes of stirring, the layers are separated and the aqueous layer is extracted with CHCl3 (3 x 400 ml). The aqueous layer is further basified to pH 9 with 200 ml of 2N Na2CO3, solid NaCl is added and the mixture is extracted with CHCl3 (3 x 400 ml). The combined organic layers are dried (MgSO 4) and evaporated to obtain an oil (40.2 g). The oil is partitioned between 200 ml of ethyl acetate and 2N hydrochloric acid (4 x 40 ml); the aqueous layers are basified (200 ml of 2N NaOH and 20 ml of 5N NaOH) and extracted with ethyl acetate (4 x 100 ml). The last organic layers are washed with salt water, dried (MgSO 4) and evaporated to obtain an oil (9.3 g) Purification by flash chromatography (B and D) provides a first crop (1.91 g ) in the form of an oil and a second crop (4.0 g) also in the form of an oil. The oil from the second crop is dissolved in 10 ml of hot methanol and 1.59 g of oxalic acid in hot methanol is added. By cooling the crystals deposit and, after cooling in ice, the crystals are separated by filtration, washed with methanol and dried to obtain the title compound (4.0 g), m.p. 183.5-187 °.

Intermediate 9

N3 Dioxalate, N3-dimethyl-1H-indole-3,5-diethanamine

3.17 g of intermediate 8 is subjected to a partition between 100 ml of 8% aqueous NaHCO 3 and CH 2 Cl 2 (3 × 80 ml), the organic layers are dried (MgSO 4) and evaporated to obtain the free base under as an oil (2.41 g). The oil is hydrogenated at 40 ° and 4.8 bar on 1.0 g of 5% rhodium-containing alumina in 200 ml of 7% w / w ethanolic ammonia for 15.5 hours. The catalyst is filtered off and the solvent is evaporated to obtain an oil (2.58 g). A portion (1.37 g) of the oil is dissolved in 6 ml of methanol and 1.12 g of oxalic acid is added in 2 ml of methanol. Addition of 80 ml of anhydrous ether provides a gum which is triturated with anhydrous ether to obtain the title compound as a solid (1.79 g), m.p. 160-170 ° (foam).

Intermediate 10

N3, N3-dimethyl-1H-indole-3,5-diethanamine dihydrochloride

2.40 g of intermediate 8 is hydrogenated at 3.8 bar on 10% palladium-on-carbon (50% aqueous paste; initially 1.2 g, then addition of 2.4 g after 25 hours and 1.2 g after 70 hours) in 240 ml of ethanol containing 2.4 ml of concentrated hydrochloric acid for 138 hours. The catalyst is filtered off and the solvent is evaporated to obtain a foam (2.81 g), a sample (about 0.7 g) of which is partitioned between 100 ml of saturated aqueous Na2CO3 and butanone (3 x 70 ml). The organic layers are washed with brine, dried (MgSO4) and evaporated to obtain an oil (0.57 g). A sample (169 mg) of the oil is purified by flash chromatography to obtain an oil (46 mg). TLC (A): Rf = 0.35.

Example 1

Composed of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] ethyl] methane-sulfonamide, Creatinine, sulfuric acid and water 35 (1: 1: 1: 1)

i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-indole-5-yl] ethyl] methanesulfonamide

A solution of 1.4 g of intermediate 3 in 10 ml of pyridine at 5 ° is treated with 0.46 ml of methanesulfonyl chloride. After 40 24 hours at room temperature, the mixture is poured onto 20 ml of concentrated hydrochloric acid and 100 g of ice. The solid obtained is collected and purified by chromatography (F) to obtain the title compound in the form of a foam (0.45 g). TLC (C): Rf = 0.2.

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ii) Composed of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] ethyl] metha-nesulfonamide, creatinine, sulfuric acid and water (1: 1 : 1: 1)

A solution of 0.29 g of the product from stage i) in 5 ml of ethanol and 2 ml of tetrahydrofuran is treated with 0.2 ml of hy-drazine hydrate and the mixture is heated at reflux for 3 hours. After cooling, the solution is evaporated to dryness and the solid obtained is partitioned between 50 ml of ethyl acetate and 10 ml of a saturated solution 55 of K2CO3. The aqueous layer is extracted with ethyl acetate (3 x 50 ml), the organic layer is dried (MgSO4) and evaporated to obtain an oil. This is dissolved in 20 ml of a hot mixture of ethanol and water (9/1) and treated with an aqueous solution of creatinine and sulfuric acid (1/1; 2M; 0.3 ml ). By cooling-60 ment, the title compound crystallizes (0.16 g), m.p. 209-210 °. NMR 8 (D20) comprises: 2.8-3.5 (14H, m, —CH2CH2NHSQ2Me and CH2CH2NH2 and creatinine N — Me); 7.2 (1H, dd, indole-6) and 7.5-7.7 (2H, m, indole-4 and indole-7).

65 Example 2

Composed of N- [2- [3- [2- (metliylamino) ethyl] -lH-indole-5-yl] ethyl] -methanesulfonamide, creatinine, sulfuric acid and water (2: 2 : 2: 1)

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i) N- [2- [3- [2 - [(methylsulfonyl) amino] ethyl] -1H-indole-5-yl] ethyl] -formamide, 'AH20

A solution of 0.98 g of the product of Example 1 in the form of the free base in 50 ml of ethyl formate and 50 ml of ethanol is brought to reflux for 48 hours. The solvent is evaporated in vacuo and the residue is partitioned between 25 ml of IN sulfuric acid and 50 ml of ethyl acetate. The aqueous layer is extracted with 25 ml of ethyl acetate and the combined organic extracts are washed with 25 ml of brine, dried over Na2SO4 and evaporated in vacuo to obtain an oil. Purification by column chromatography (C and F) provides a foam. By trituration with ethyl acetate, the title compound is obtained in the form of a solid (0.15 g), m.p. 89-91 °.

ii) Composed of N- [2- [3- [2- (methylamino) ethyl] -1H-indole-5-yl] ethyl] methanesulfonamide, creatinine, sulfuric acid and water (2: 2: 2: 1)

A solution of 0.6 g of the product from stage i) in 200 ml of tetrahydrofuran (THF) is added dropwise under nitrogen.

anhydrous to a stirred suspension of 0.7 g of LiAlH4 in 14 ml of anhydrous THF. The mixture is brought to reflux for 5 hours, cooled in ice and the excess reagent is decomposed by careful addition of 10% water in THF. 50 ml of salt water and 100 ml of ethyl acetate are added, the insoluble material is filtered off and the aqueous layer is extracted with 100 ml of ethyl acetate. The combined organic extracts are washed with 50 ml of salt water, dried (Na2SO4) and evaporated in vacuo to obtain an oil. The oil is dissolved in a hot mixture of 24 ml of ethanol and 3 ml of water and an aqueous solution of creatinine and sulfuric acid (1/1; 2M; 0.5 ml) is added. Filtration of the cooled mixture provides the title compound as a solid (0.37 g), m.p. 222-224 °.

NMR 5 (D20) comprises: 2.6-3.6 (17H, m, CH2CH2NHMe and CH2CH2NHSQ2Me and creatinine N — Me).

Example 3

Composed of N- [3- [3- (2-aminoethyl) -1H-indole-5-ylJpropyl] methanesulfonamide, creatinine, sulfuric acid and water (1: 1: 1: 1)

i) 2- [2- [5- (3-Aminopropyl) -1H-indole-3-yl] ethyl] -1H-iso-indole-1,3- (2H) -dione hemisulfate

A solution of 0.95 g of intermediate 6 in 550 ml of methanol and 1.0 ml of sulfuric acid is hydrogenated, at ordinary temperature and under pressure, over previously reduced palladium-on-carbon (10% aqueous paste). 50%; 2.08 g) for 0.5 hour until the fixation of hydrogen (201 ml) ceases. The catalyst is filtered off and the filtrate is evaporated in vacuo to obtain an oil (4.7 g). TLC (A): Rf = 0.3.

ii) N- [3- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-indole-5-yl] propyl] methanesulfonamide

A mixture of 4.7 g of the product from stage i), 1.0 ml of methanesulfonyl chloride, 300 ml of an 8% solution of NaHCO 3 and 250 ml of acetate is vigorously stirred at room temperature for 24 hours. ethyl by adding 1.0 ml of methanesulfonyl chloride after 17 hours. The mixture is separated (which contains an insoluble solid) and the aqueous phase is further extracted with ethyl acetate (2 x 200 ml). The combined organic extracts are washed with 200 ml of 2N hydrochloric acid, dried (MgSO4) and evaporated to give an oil (0.49 g) which is purified by chromatography on a silica column (H). When the appropriate fractions are allowed to stand, the title compound rapidly crystallizes as a solid (0.1 g), m.p. 165-167 °.

iii) Composed of N- [3- [3- (2-aminoethyl) -1H-indole-5-ylJpropyl] methanesulfonamide, creatinine, sulfuric acid and water (1: 1: 1: 1 )

A solution of 0.48 g of the product of stage ii) in 100 ml of ethanol is treated with 1.0 ml of hydrazine hydrate and the mixture is heated to

reflux for 1 hour 20 minutes. After cooling, the solution is evaporated in vacuo and subjected to azeotropic distillation with ethanol (2 x 50 ml) to obtain a solid which is subjected to partition between 100 ml of a 2N solution of Na2CO3 and ethyl acetate (3 x 100 ml). The combined organic extracts are dried (MgSO 4) and evaporated to dryness to obtain an oil which is dissolved in a hot mixture of 64 ml of ethanol and 8 ml of water, and an aqueous solution of creatinine and d sulfuric acid (1: 1; 2M; 0.56 ml). By cooling, the title salt crystallizes (0.43 g), m.p. 212-214 °.

NMR 5 (DMSO-d6) comprises: 2.6-3.2 (14H, m, CH2CH2CH2, NHS02Me, CH2CH2NH2 and creatinine N-Me); 6.8-7.5 (4H, m, aromatics) and 10.9 (1H, d, indole-1).

Example 4

Composed of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] ethyl] acet-amide, creatinine, sulfuric acid and water (10:12:11 : 20)

i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-indole-5-yl] ethyl] acetamide , 'AH20

A solution of 0.3 g of intermediate 4 in 10 ml of pyridine is cooled in an ice bath and treated dropwise with stirring with 0.3 ml of acetic anhydride. The solution is stirred at room temperature for 1 hour, diluted with 15 ml of water and stirred for 15 minutes. The solution obtained is poured into 50 ml of 2N hydrochloric acid and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with 50 ml of 2N hydrochloric acid, 50 ml of 2N Na2SO3, dried over Na2SO4 and evaporated in vacuo to give a foam which is purified by chromatography (C) to obtain the title compound under the form of a solid (0.125 g); m.p. 165-168 °.

ii) Composed of N- [2- [3- (2-aminoethyl) -H-indole-5-yl] ethyl] acet-amide, creatinine, sulfuric acid and water (10:12 : 11: 20)

A solution of 0.5 g of the product from stage i) in 100 ml of ethanol containing 1.0 ml of hydrazine hydrate is refluxed for 3 hours, evaporated in vacuo and evaporated with ethanol (2 x 20 ml). The solid obtained is partitioned between 100 ml of a 2N solution of Na2CO3 and ethyl acetate (2 x 100 ml). The combined organic extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is dissolved in a hot mixture of 16 ml of ethanol and 2 ml of water and treated with an aqueous creatinine solution and sulfuric acid (1/1; 2M; 0.5 ml). By cooling, the title salt crystallizes (0.3 g); m.p. 211-214 °.

NMR S (D20) includes 2.95 (3H, s, NHCOMe) and 2.7-3.6 (11H, m, CH2CH2NHCO, CH2CH2NH2 and creatinine N-Me).

Example 5

N- [2- [3- [2- (dimethylamino) ethyl] -lH-indole-5-yl] -ethyl] acetamide oxalate

0.4 g of intermediate 10 is added at room temperature to a stirred solution of 0.5 ml of triethylamine in 15 ml of anhydrous tetrahydrofuran under nitrogen and stirring is continued at room temperature for 5 minutes. The mixture is cooled to 0 °, 0.15 ml of acetic anhydride is added and stirring is continued for 4 hours between 0 ° and 10 °. The mixture is partitioned between 65 ml of a saturated Na2CO3 solution and butanone (3 x 50 ml); the organic layers are washed with brine, dried (MgSO4) and evaporated to obtain an oil (0.64 g). Purification by flash chromatography (B and D) provides an oil (139 mg) which is dissolved in 2 ml of methanol and combined with another sample (57 mg) which has been similarly prepared . 77 mg of oxalic acid in 0.5 ml of methanol are added. Addition of anhydrous ether forms a precipitate which is filtered off, washed with anhydrous ether and dried to obtain the title compound as a solid (205 mg) , pf 85-93 ° (foam).

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NMR 5 (DMSO) includes 1.81 (3H, s, NHCOMe); 2.7-3.0 (8H, m, NMe2 and CONHCH2CH2); 3.08 (2H, t, CH2CH2NMe2); 7.98 (1H, t, CONH) and 10.9 (1H, d, indole-1).

Example 6

N- [2- [3- [2- (dimethylamino) ethyl] -lH-indole-5-yl] ethyl] methane oxalate Sulfonamide

0.905 g of intermediate 10 is added to a stirred solution of 1.26 ml of triethylamine in 50 ml of anhydrous CH2Cl2 at room temperature under nitrogen and stirring is continued at room temperature for 5 minutes. 0.282 ml of methanesulfonyl chloride is added while cooling to 0 ° and the mixture is allowed to warm to room temperature with stirring for 5 hours. The mixture is poured into 60 ml of a 2N Na2CO3 solution and extracted with CH2Cl2 (3 x 50 ml); the organic layers are dried (MgSO 4) and evaporated to obtain a gum (0.85 g). Purification by short column chromatography (B, D, I, J and K) provides an oil (65 mg) which is dissolved in 1 ml of methanol. 25 mg of oxalic acid in 0.5 ml of methanol are added. The addition of anhydrous ether forms a precipitate which is washed with anhydrous ether and dried to obtain the title salt in the form of a solid (38 mg); m.p. 159-165 "(foam).

NMR 8 (DMSO) includes 2.9-3.0 (11H, m, NMe2 and Me-SO2NHCH2CH2); 3.0-3.4 <6H, m, CH2CH2NMe2 and S02NHCH2); 7.15 (1H, t, SO2NH) and 10.93 (1H, d, indole-1).

Example 7

N- [2- [3- [2-dimethylamino) ethylJ1 H-indole-5-yl] ethyl] -benzamide oxalate

0.53 ml of benzoyl chloride is added to a stirred solution of 0.95 g of intermediate 9 in the form of the free base and 0.7 ml of triethylamine in 40 ml of anhydrous CH2Cl2 at ordinary temperature under nitrogen and stirring is continued at room temperature for 1 hour 40 minutes. The mixture is washed with 20 ml of 8% aqueous NaHCO3 and water (2 x 20 ml), dried (MgSO4) and the solvent is evaporated. Combine the oil obtained (1.47 g) with another similarly prepared portion and purify by flash chromatography (B and L) to obtain a foam which is dissolved in 2 ml of methanol and a solution is added. 230 mg of oxalic acid in 1 ml of methanol. The addition of 80 ml of anhydrous ether forms a precipitate which is washed with anhydrous ether and dried to obtain the title salt in the form of a solid (0.873 g), m.p. 158-160 °.

NMR 8 (DMSO) comprises: 2.80 (6H, s, NMe2); 2.95 (2H, t, CONHCH2CH2); 3.06 (2H, m, CH2CH2NMe2); 3.55 (2H, q, CONHCH2CH2); 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 8

N- [2- [3- [2- (dimethylammo) ethyl] -lH-indole-5-yl] ethyl oxalate Benzene sulfonamide

0.61 ml of benzenesulfonyl chloride is added to a stirred solution of 0.98 g of intermediate 9 in the form of the free base and 0.72 ml of triethylamine in 400 ml of anhydrous CH2Cl2 at ordinary temperature under nitrogen and stirring is continued at room temperature for 1 hour 40 minutes. The mixture is washed with 20 ml of 8% aqueous NaHCO3 and water (2 x 20 ml), dried (MgSO4) and evaporated to obtain a foam (0.98 g). It is combined with a similarly prepared product and the combined samples are purified by chromatography (M and N). The foam obtained (0.607 g) is dissolved in 2 ml of methanol and 154 mg of oxalic acid in 1 ml of methanol are added. The addition of 80 ml of anhydrous ether forms a precipitate which is washed by decantation with anhydrous ether, which is separated by filtration and which is dried to obtain the title salt in the form of a solid. (0.702 g), mp about 80-90 ° (foam).

NMR 8 (DMSO) includes 2.7-2.85 (8H, m, NMe2 and SQ2NHCH2CH2); 2.95-3.1 (6H, m, SQ2NHCH2CH2 and CH2CH2NMe2); 7.37 (1H, br s, SO2NH); 7.55-7.7 (4H, m, Ph (m and p) and indole-4) and 10.9 (1H, s, indole-1).

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Example 9

i) Composed of N-f2-f3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-indole-5-yl] ethyl] benzamide and ethyl acetate (2: 1)

A solution of 1.72 ml of thionyl chloride in 20 ml of anhydrous tetrahydrofuran under nitrogen is added dropwise to a stirred and ice-cold solution of 1.41 g of benzoic acid in a mixture of 8.00 ml of triethylamine and 80 ml of anhydrous tetrahydrofuran. The solution is stirred in ice for 1 hour, 2.13 g of intermediate 4 is added and stirring is continued for 0.75 hour. The suspension obtained is subjected to a partition between 250 ml of 2N Na2CO3 and ethyl acetate (2 x 250 ml). The combined organic extracts are washed with water (2 x 250 ml) and 250 ml of 2N Na2CO3, dried (Na2SO4) and concentrated in 2 ° vacuum. The residual oil (3.1 g) is chromatographed (E). The required fractions are combined and concentrated in vacuo to obtain the title compound as a foam (0.92 g) m.p. 75-82 °.

ii) Composed of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] ethyl] benz-25 amide, creatinine, sulfuric acid and water (1: 1: 1: 1)

A solution of 0.90 ml of hydrazine hydrate and 0.67 g of the product from stage i) in 25 ml of ethanol is stirred at reflux for 3.5 hours and then allowed to cool. The suspension obtained is concentrated in vacuo and the residual solid is partitioned between 50 ml of 2N Na2CO3 and ethyl acetate (3 x 50 ml). The combined organic extracts are then dried (Na2SO4) and concentrated in vacuo. The residual gum (0.47 g) is dissolved in a hot mixture of 40 ml of ethanol and 5 ml of water and an aqueous solution of creatinine and sulfuric acid (1/1; 2M; 0.76) is added. ml). The solid which crystallizes on cooling is filtered off, washed successively with 27 ml of an 8/1 mixture of ethanol and water and 10 ml of ethanol and dried at 60 ° for 8 hours to obtain the title compound as a solid (0.60 g); m.p. 228-229.5 °.

NMR 8 (D20) comprises: 3.0-3.25 (9H, m, CONHCH2CH2, 40 CH2CH2NH2 and creatinine NMe); 3.68 (2H, t, CH2CH2NHC0) and 7.4-7.64 (7H, m, phenyl, indole-4 and indole-7).

Example 10

i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indole-2-yl) ethyl] -1H-45 indole-5-yl] ethylJenzenesulfonamide

A solution of 2.38 ml of benzenesulfonyl chloride in 25 ml of anhydrous dimethylformamide is added dropwise under nitrogen to a stirred ice-cold suspension of 2.0 g of intermediate 4 in a mixture of 3.0 ml of triethylamine, 50 ml of anhydrous tetrahydrofu-50 ranne and 25 ml of anhydrous dimethylformamide and stirring is continued for 2.75 hours. The suspension is allowed to stand at room temperature overnight and is partitioned between 500 ml 2N Na2CO3 and ethyl acetate (2 x 50 ml). The combined organic extracts are washed with water (2 x 5500 ml) and 500 ml of 2N Na2CO3, dried (Na2SO4) and concentrated in vacuo. The residual foam (2.41 g) is chromatographed (E). The required fractions are combined and concentrated in vacuo to obtain the title compound as a solid (0.73 g); m.p. 183-184 °.

60

ii) Composed of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] ethyl] benzenesulfonamide, creatinine, sulfuric acid and water (1: 1 : 1: 1)

A suspension of 0.60 g 65 of the product from stage i) and 0.75 ml of hydrazine hydrate in 30 ml of ethanol is stirred at reflux for 4.25 hours. The suspension obtained is evaporated under vacuum and the residual solid is partitioned between 25 ml of 2N Na2CO3 and ethyl acetate (3 x 25 ml). The organic extracts are then dried

11

671,017

combined (Na2SO4) and concentrated in vacuo. The residual gum (0.46 g) is dissolved in a hot mixture of 36 ml of ethanol and 4.5 ml of water and an aqueous solution of creatinine and sulfuric acid (1/1; 2M; 0) is added. , 68 ml). The solid which crystallizes on cooling is filtered off, washed with a mixture of ethanol and water (8/1; 2 x 5 ml) and ethanol (2 x 5 ml), then dried under vacuum at 60 ° for 6 hours to obtain the title compound as a solid (0.48 g); m.p. 216-217.5 °.

NMR 8 (DMSO) comprises: 2.78 (2H, t, SQ2NHCH2CH2); 2.85-3.2 (9H, m, SO2NHCH2, CH2CH2NH2 and creatinine N-Me); 7.2-7.4 (3H, m, indole-2, indole-7 and SQ2NH); 7.5-8.0 (6H, m-phenyl and indole-4) and 10.9 (1H, s, indole-1).

The following examples illustrate pharmaceutical formulations according to the invention, containing as active ingredient N- [2- [3- [2- [dimethylamino) ethyl] -1H-indole-5-yl] ethyl] methanesulfonamide. Other compounds of the invention can be formulated in a similar manner.

Tablets for oral administration

Direct compression 20

25

30

The active ingredient is sieved before use. Calcium hydrogen phosphate, croscarmellose sodium and the active ingredient are weighed in a clean polyethylene bag. The powders are mixed by vigorous stirring, then the magnesium stearate is weighed and added to the mixture which is still stirred. The mixture is then compressed using a Manesty F3 tablet machine equipped with 5.5 mm flat punches with beveled angles, in tablets, in order to achieve a compression weight of 100 mg.

The tablets can also be prepared by any conventional method, such as wet granulation.

Tablets with different strength can be prepared by changing the ratio of active ingredient to lactose or compression weight and using suitable punches.

The tablets can be film coated using materials suitable for film formation, such as hydroxypropyl cellulose, using standard techniques.

Alternatively, the tablets can be coated with sugar.

Injection for intravenous administration

mg / ml

Active ingredient Sodium chloride BP Water for injection BP

0.6 mg as needed 1.0 ml

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted, using an acid or a base, so as to obtain optimal stability and / or to facilitate the solution of the active ingredient. Alternatively, suitable buffer salts can be used.

The solution is prepared, clarified and filled in ampoules of appropriate size, sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the acceptable cycles.

Alternatively, the solution can be sterilized by filtration and filled in sterile ampoules under aseptic conditions. The solution can be stored under an inert atmosphere of nitrogen or other suitable gas.

mg / tablet

Active ingredient

2.4

Calcium hydrogen phosphate BP *

95.10

Croscarmellose sodium USP

2.0

Magnesium stearate BP

0.50

Compression weight

100 mg

* of a degree suitable for direct compression

R