CH652394A5 - INDOLIC DERIVATIVES, THEIR PREPARATION AND MEDICINES CONTAINING THEM. - Google Patents

Description

The present invention relates to heterocyclic compounds, processes for their preparation and pharmaceutical compositions containing them.

The invention provides an indole of general formula I:

(VII)

where W is a group capable of being reduced to give the required AlcNR4Rs group or one of its protected derivatives and where Rx, R2, R3, R4, Rs, R6, R7, Aie and n are as defined for the general formula (I ), or one of its protected salts or derivatives, the protective groups possibly present being removed and the compound being, if desired, isolated as such or as salts or solvating product, or else transformed into another salt or solvating product.

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

R1R2N (CIiR3) n

(IV)

NR? NH2

or one of its salts with a compound of general formula (V):

R6COCH2AlcQ (V)

or one of its protected salts or derivatives to obtain a compound of general formula (III):

R1R2N (CHR3 ^ n

(III)

NR7N = CRgCH2AlcQ

Rj, R2, R3, R4, R5, R6, R7 and n being as defined in the general formula (I) and Q being the group NR4RS or one of its protected derivatives or an leaving group, then the compound is cyclized of general formula (III), the protective groups possibly present being removed and the compound being, if desired, isolated as such or as salt or solvate or further transformed into another salt or solvate.

16. A method of preparing a compound of general formula (I) according to claim 1 wherein R4 and / or R5 are different from hydrogen, or one of its salts or solvates, characterized in that proceeds to the reducing alkylation with an aldehyde or a ketone and a reducing agent of a corresponding compound of general formula (I) according to claim 1, where R4 and / or Rs represent a hydrogen.

RlR2N <CHR3) n

AlcPïR. Rt 4 5

w

25 Rj represents a group CHO, COR8, C02Rs, CONR9R10, CSNRgRjo or SO2NR9R10, where

R8 represents an alkyl group substituted or not by 1 to 3 halogen, cycloalkyl, aryl or aralkyl atoms;

R9 represents a hydrogen atom or an alkyl group, and Rio represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group;

R2, R3, R4, R6 and R7, which may be the same or different, each represents a hydrogen atom or a Cà to Coy alkyl group;

R5 represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or aralkyl group or

R4 and R5 together form an aralkylidene group or R4 and R5 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated monocyclic ring; 40 n is 0 or 1, and

Aie represents an alkylene chain containing 2 or 3 carbon atoms which can be unsubstituted or substituted by at most two alkyl groups in Q to C3;

with the clarification that, when n is 0 and 45 i) R4 and R5 both represent alkyl groups, Ri does not represent the CHO or CORs group, and ii) Rx does not represent the SO2NH2 group;

their salts and solvates (for example hydrates).

The compounds according to the invention all include their so optical isomers and their racemic mixtures.

Referring to the general formula (I) the alkyl groups can be straight or branched chain alkyl groups and they preferably contain from 1 to 6 carbon atoms unless otherwise indicated. The alkyl groups represented by R 5 can be unsubstituted or substituted by 1 to 3 halogen atoms, for example fluorine. The cyloalkyl groups preferably contain from 5 to 7 carbon atoms. The term aryl, used as such or in the expression aralkyl, preferably represents a phenyl which may be unsubstituted or substituted by one or more alkyl groups, for example a methyl, halogen atoms, for example fluorine, or hydroxy or alkoxy groups, for example methoxy. The alkyl moiety of the aralkyl groups preferably contains from 1 to 4 carbon atoms. The aralkylidene group is preferably an arylmethylidene group. The alkenyl groups preferably contain from 65 3 to 6 carbon atoms.

Suitable physiologically acceptable salts of the indoles of general formula (I) include the acid addition salts formed with organic or inorganic acids, for example chlorines

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hydrates, hydrobromides, sulfates, fumarates and maleates. Other salts may be useful in the preparation of the compounds of formula (I), for example the creatinine sulfate adducts.

The compounds of the invention mimic the methysergide by contracting an isolated flap of the saphenous vein of a dog (E. Apperley et al., "Br. J. Pharmacol.", 1980, 68, 215-224) and, like the methysergide, have little effect on the blood pressure of the hypertensive rat with Doca. It is known that methylsergide is useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog; it has been hypothesized (P.R. Saxena, "Eur. J. Pharmacol", 1974, 27, 99-105) that this is the basis of its effectiveness. The compounds that the holder has experienced have a similar effect in anesthetized dogs and the compounds according to the invention are thus potentially useful for the treatment of migraine.

The invention therefore provides a pharmaceutical composition suitable for application in human medicine which comprises at least one compound of general formula I, one of its salts or solvates (for example hydrates) and formulated for administration according to n ' any suitable mode. These compositions can be formulated conventionally using one or more pharmaceutically acceptable carriers or excipients.

Thus, the compounds according to the invention can be formulated for the purposes of oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions can take, for example, the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (for example pregelatinized corn starch, polyvinylpyrrolidone or 'hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cell or calcium phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate), or wetting agents (for example sodium lauryl sulfate). The tablets can be coated by methods well known to those skilled in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product which can be reconstituted with water or other suitable vehicle before use. use. These liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example lecithin or acacia); non-aqueous vehicles (for example almond oil, oily esters or ethyl alcohol), and preservatives (for example methyl or propyl p-hydroxy benzoates or sorbic acid).

For buccal administration the composition can take the form of tablets or lozenges formulated in a conventional manner.

The compounds of the invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. The injectable formulations can be presented in the form of unit doses, for example in ampoules or in multidose containers, with the addition of a preservative. The compositions can take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents, such as suspending agents, stabilizing agents and / or dispersing agents. The active ingredient can also be in powder form for the purpose of reconstitution with an appropriate vehicle, for example sterile pyrogen-free water, before use.

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

For administration by inhalation, the compounds according to the invention are conveniently presented in the form of an aerosol in a pressurized package or a nebulizer, using a suitable propellant, for example dichlorodifiuoromethane, s trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve enabling a measured quantity to be supplied. Gelatin capsules and cartridges can be formulated, for example, for use in an inhaler or insufflator containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or the like. 'starch.

For oral, parenteral or oral administration to humans for the treatment of migraine, it is suggested for the compounds of the invention a dosage of 0.1 to 100 mg of active ingredient, pure unit dose which can be administered , for example 1 to 4 times a day.

The aerosol formulations are preferably arranged such that each metered or "puff" dose of aerosol contains from 20 to 1000 µg of the compound of the invention. The overall daily dose with an aerosol is in the range of 100 ng to 10 mg. The administration can be carried out several times a day, for example 2, 3, 4 or 8 times with, for example, 1, 2 or 3 doses each time. The overall daily dose and the measured dose supplied by capsules and cartridges in an inhaler or insufflator can be double that of aerosol formulations.

A preferred class of compounds represented by the general formula I is that where Aie represents an unsubstituted alkylene chain containing 2 carbon atoms. Another preferred class of compounds of general formula I is that where R4 and Rs each represents a hydrogen atom or a methyl or ethyl group and where R6 and R7 each represent a hydrogen atom. It is preferred that the total number of carbon atoms in R4 and R5 together does not exceed 2.

Another preferred class of compounds of general formula I is that where R3 represents a hydrogen atom. Another even more preferred class of compounds represented by the formula I is that in which R2 represents a hydrogen atom or a methyl group.

A preferred class of compounds according to the invention is represented by the general formula la:

40

RlaR2aNlCH2, n

CB.CHJR R,

2 2 4a 5a (Ia)

45 where

RIa represents a CHO, CONH2, CORgl or C02R8a group, where Rga is an alkyl group containing from 1 to 4 carbon atoms, for example a methyl, ethyl or isobutyl group, or a trifluoromethyl group;

50 Rj ,, represents a hydrogen atom or a methyl group;

n is 0 or 1, and

R, a and RSa, which may be similar or different, each represents a hydrogen atom or a methyl or ethyl group (with the precision that the total number of carbon atoms in R *, and RSa 55 together does not exceed not two and that when Rla represents a CHO group or a CORga group when n is 0, then Rta represents a hydrogen atom),

their salts and solvates (for example hydrates).

A class of compounds according to the invention which is particularly preferred is represented by the general formula Ib:

CH2CH2NR4bR5b

(Ib)

R, „represents a CHO, CONH2 or CO2R8b group where R8b is a methyl, ethyl or isobutyl group;

5

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Ra represents a hydrogen atom or a methyl group, and R ", and Rsb, which may be similar or different, each represents a hydrogen atom or a methyl or ethyl group (with the precision that the total number of atoms of carbon in R, b and Rsb together does not exceed two and that when R, b is the CHO group, R4b represents a hydrogen atom),

their salts and solvates (for example hydrates).

Another group of compounds according to the invention which is particularly preferred is represented by the general formula:

RlcR2cNC.H2

CH2CH2NR4CR5C

(the)

or

Rk represents a CHO group or a CORSc group where Rgc is an alkyl group containing from 1 to 3 carbon atoms, for example a methyl group;

R; t represents a hydrogen atom or a methyl group, and 20

R4c and R5c, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R *. and RSc together does not exceed two,

their salts and solvates (for example hydrates). 25

According to another aspect of the invention, the compounds of general formula I and their salts and solvates (for example hydrates) can be prepared, by following the general methods set out below. In the methods below, R15 R2, R3, R4, Rs, R6, R7, n and Aie are as defined for general formula I, unless otherwise indicated.

According to a general process, a compound of general formula I can be prepared by reacting a compound of general formula II:

R2NH {CHR3)

A1cNR4R5

(II)

or one of its protected derivatives, with an appropriate reagent which serves to introduce the group Rj.

Suitable reagents which serve to introduce the group R] include acids of the formula R, OH or the acylating agents which correspond to them, inorganic cyanates, suitable organic isocyanates or organic isothiocyanates.

Acylating agents which can be conveniently employed in the above process include acid halides (e.g. acid chlorides and sulfamoyl chlorides), alkyl esters (e.g. methyl ester or ester ethyl), activated 50 esters (eg 2- (1-methylpyridinyl) ester), symmetrical or mixed anhydrides, haloformates (eg ethyl chloroformate) or other derivatives of car- activated boxyîiques like those conventionally used in the synthesis of peptides. 55

The process can be carried out in a suitable aqueous or non-aqueous reaction medium, which is convenient to do at a temperature between -70 and + 150 ° C. Thus, the process can be carried out using an activated ester or an anhydride in a suitable reaction medium such as an amide (for example dimethylformamide), an ether (for example tetrahydrofuran), a nitrile (for example acetonitrile), a haloalkane (for example dichloromethane) or one of their mixtures, optionally in the presence of a base, such as pyridine or a tertiary amine such as triethylamine. The reaction is preferably carried out at a temperature between -5 and +25 C.

The reaction can be carried out using an alkyl ester in a suitable reaction medium such as an alcohol (for example

thanol), an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or a mixture thereof and conveniently at a temperature between 0 and 100 ° C. When the reagent is an inorganic cyanate, an inorganic isocyanate or an organic isothiocyanate, the reaction can be carried out in water, an alcohol (for example ethanol), an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or a mixture thereof, optionally in the presence of a base such as pyridine or a tertiary amine such as triethylamine and conveniently at a temperature between 0 and 100 ° C.

The acids of formula R, OH can themselves be used in the preparation of the compounds of formula I. It is desirable to conduct the reaction with such an acid in the presence of a coupling agent, for example carbonyldiimidazole or N, N'-dicyclo-hexylcarbodiimide. The reaction can be carried out in a suitable reaction medium such as a haloalkane (for example dichloromethane), a nitrile (for example acetonitrile), an amide (for example dimethylformamide) or an ether conveniently to a temperature between - 5 and + 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 (for example toluene or xylene), conveniently at a temperature between 50 and 120 ° C.

A compound of general formula I where R 1 represents - CHO can be prepared by heating a compound of general formula II in formic acid, preferably at reflux.

In a particular embodiment of this process, it is also possible to prepare a compound of formula I in which R [represents the group —CONRqR10 or - CSNR, R10 by reaction of a compound of formula II, or one of its protected derivatives , with phosgene or thiophosgene followed by an appropriate amine of formula RqRi0NH. It is convenient to carry out the reaction in an inorganic solvent, such as an aromatic hydrocarbon (eg toluene).

Certain compounds of general formula II where R2 is hydrogen can be prepared by reduction of a corresponding compound having a suitable reducible group as a substituent at position 5 such as - CN or CH., --C -

II

NOH

using, for example, lithium aluminum hydride.

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

RiR2N (CHR3) n

(III)

NR7N = CRgCH2AlcQ

where Q is the NR4RS group (or one of its protected derivatives) or an leaving group such as a halogen (for example chlorine), acetate, tosylate or mesylate.

Appropriate cyclization methods are mentioned in "A Chemistry of Heterocyclic Compounds-Indoles Part I", Chapter II, dir. pubi. W.J. Houlihan (1972) Wiley Interscience, New York. Particularly practical embodiments of the method are described below.

When Q is the NR4R5 group (or one of its protected derivatives), it is desirable to carry out the process in an aqueous reaction medium, such as an aqueous alcohol (for example methanol) in the presence of an acid catalyst. (In some cases the acid catalyst can also act as the reaction solvent.) Suitable acid catalysts include inorganic acids such as sulfuric acid or hydrochloric acid or organic carboxylic acids such as acetic acid. The cyclization can also be carried out in the presence of a Lewis acid such as zinc chloride in ethanol or boron trifluoride in acid

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acetic. It may be convenient to carry out the reaction at temperatures between 20 and 200 ° C, preferably 50 and 125 ° C.

When Q is an leaving group such as chlorine, the reaction can take place in an aqueous organic solvent, such as an aqueous alcohol (for example methanol, ethanol or isopropanol), in the absence of a mineral acid, conveniently at a temperature between 20 and 200 ° C, preferably between 50 and 125 ° C. This process results in the formation of a compound of formula I where R4 and Rs are both hydrogen atoms.

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

R ^ NCCHRj)

or one of its salts,

with a compound of formula V:

(IV)

NR? NH2

R6COCH2A1cQ

(V)

where Q is as defined above,

or one of its protected derivative salts (such as an acetal or ketal, for example formed with a suitable alkyl orthoformate), using the appropriate conditions as stated above.

The compounds of formula III can be isolated as an intermediate during the process for preparing compounds of general formula I in which a compound of formula IV, or one of its protected salts or derivatives, is reacted with a compound of formula V or one of its protected salts or derivatives, in a suitable solvent, such as an aqueous alcohol (for example methanol) and at a temperature of, for example, 20 to 30 ° C. If an acetal or a ketal of a compound of formula V, it may be necessary to conduct the reaction in the presence of an acid (for example acetic acid or hydrochloric acid).

As stated in the general methods below, the aminoalkyl substituent —AlcNR4Rs can be introduced at position 3 by various conventional techniques which may, for example, involve modification of a substituent at position 3 or the direct introduction of the aminoalkyl substituent in position 3.

Thus another general process for the preparation of compounds of general formula I involves reacting a compound of formula VI:

R1R2N (CHR3) iÎ-

(VI)

aqueous (eg methanol) containing an acid (eg acetic acid or hydrochloric acid) or by treating a compound of general formula VI where Y is a hydroxyl group with the appropriate phosphorus trihalide. The intermediate alcohol where Y is a hydroxyl group may also be used to prepare compounds of formula VI where Y is the OR group by acylation or sulfonylation with the appropriate activated species (e.g. an anhydride or sulfonyl chloride ) using conventional techniques. The intermediate alcohol can be prepared by cyclization of a compound of formula III where Q is a hydroxyl group (or one of its protected derivatives) using standard conditions.

The compounds of general formula I can also be prepared by another general process which involves reducing a compound of general formula VII:

RXR2M (CHR3) Ä

. w

•NOT

I.

(VII)

where Y is an easily displaceable group or one of its protected derivatives, with an amine of formula R4R5NH.

It may be convenient to carry out the displacement reaction on the compounds of general formula VI where the substituent group Y is a halogen atom (for example chlorine, bromine or iodine) or an OR group where OR is, for example, an acyloxy group, such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy or p-nitrobenzacetoxy or a sulfonate group (for example p-toluenesulfonate).

It is convenient to carry out the above reaction in an organic solvent (optionally in the presence of water), examples of which include alcohols, for example ethanol; ethers, for example tetrahydrofuran; esters, for example ethyl acetate; amides, for example N, N-dimethylformamide, and ketones, for example acetone, at a temperature between -10 and + 150 ° C, preferably between 20 and 50 ° C.

The compounds of formula VI where Y is a halogen atom can be prepared by reacting a hydrazine of general formula IV with an aldehyde or a ketone (or one of their protected derivatives) of general formula V where Q is an atom of halogen, in an alkanol

7

20 '

where W is a group capable of being reduced to give the desired group A1cNR4R5 or one of its protected derivatives,

or a salt or one of its protected derivatives.

The desired groups Aie and NR4R5 can be formed by steps

25 reduction which are carried out separately or together in any suitable manner.

The groups which can be reduced to group Aie include the corresponding unsaturated groups and the corresponding groups containing either a hydroxyl group or a carbonyl function.

The groups which can be reduced to NR4RS group where R4 and R5 are both hydrogens include the nitro groups,

azido, hydroxyimino and nitrile. Reduction of a nitrile group gives the CH2NH2 group and thus provides a methylene group of the Aie group.

The desired NR4H5 group can be prepared where R4 and / or Rs are different from hydrogen by reduction of a nitrile (CHRn) xCHR12CN or an aldehyde (CHR11), - CHR12CHO (where Ru and Rj2, which can be alike or different, each represents a hydrogen atom or a C1 to C3 alkyl group and

40 where x is 0 or 1) in the presence of an amine, R4R5NH. The group R4R5NH can also be prepared by reaction of the corresponding compound where R4 and / or R5 represent hydrogen with an appropriate aldehyde or ketone in the presence of an appropriate reducing agent. In some cases (for example for the introduction of

45 group Rs where R5 is benzyl) the aldehyde (for example benzaldehyde) can be condensed with the amine and then reduce the intermediate thus formed using an appropriate reducing agent.

As examples of groups represented by the substituent group W, there may be mentioned:

50 TN02 (where T represents Aie or an alkenyl group corresponding to the group Aie);

A1cN3;

(CHRu ^ CHR ^ CN;

COCHR12Z;

55 (CHRjjXCRI2 = NOH, or CH (0H) CHR12NR4Rs

(where Ru, R12 and x are as defined above and Z is an azido group N3 or the group NR4R5 or one of their protected derivatives).

It will be appreciated that the choice of reducing agent and reaction conditions depend on the nature of the group W and other groups already present on the molecule.

Suitable reducing agents which can be used in the above process include hydrogen in the presence of a catalyst.

65 metallic sor (except when R, is group CSNR9R10), an alkali metal boro-hydride or cyanoborohydride, for example sodium boro-hydride or cyanoborohydride (except when W contains a nitrile or hydroxyimino group) or a metallic hydride ,

7

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for example lithium aluminum hydride (where Rj is the group CSNRgRuo and one of the radicals R2, R9 and R10 is n hydrogen).

The metal catalyst can be, for example, Raney nickel or a noble metal catalyst, such as platinum, platinum oxide, palladium or rhodium, the support of which can be, for example, charcoal or kieselguhr. In the case of Raney nickel, hydrazine can also be used as the hydrogen source.

It may be convenient to carry out the reduction in the presence of hydrogen and a metal catalyst in a solvent such as an alcohol, for example ethanol, an ether, for example dioxane or tetrahydrofuran, or an ester, for example ethyl acetate, at a temperature between -10 and + 50 ° C, preferably - 5 and + 30 ° C. It may be convenient to carry out the reduction with borohydride or cyanoborohydride of alkali metal in an alcohol such as propanol or ethanol and at a temperature between 0 and 100 ° C. In some cases reduction with borohydride can be carried out in the presence of cobalt chloride. The reduction with metal hydride can be carried out using an ether, for example tetrahydrofuran, as solvent, and conveniently at a temperature between -10 and + 100 ° C.

The particular embodiments of this process include the reduction of a compound of formula VII where W is the group CHR12CN, CHRnCHR12N02, CH = CR12N02 or CHRnCR12 = NOH, for example, by catalytic reduction with hydrogen, for example of hydrogen in the presence of a catalyst such as palladium, optionally in the presence of a mineral acid such as hydrochloric acid or sulfuric acid.

A second embodiment of the process involves, for example, the reduction of a compound of formula VII where W is the group CHR12CN in the presence of an amine HNR4RS using hydrogen in the presence of a catalyst such as palladium , except that Rj cannot be - CSNR9R10.

According to a third embodiment, it is possible to reduce a compound of formula VII where W is the group COCHRl2Z, preferably by heating, by using for example sodium borohydride in propanol. When Z is an azido group, the process results in the formation of a compound of general formula I where R4 and Rs are both hydrogen atoms.

According to a fourth embodiment, it is possible to reduce a compound of formula VII where W is the group AlcN3 or CH (OH) CHR12NR4R5 by using for example hydrogen in the presence of a catalyst (for example palladium) or the borohydride sodium. These reducing agents are also suitable for the reducing alkylation of, for example, AlcNHR5 in the presence of an appropriate aldehyde or ketone.

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

The compounds of formula VII where W is the group (CHRu), CHR12CHO, should be prepared by oxidation (for example with Jones' reagent) of a compound of general formula VI where Y is a hydroxyl group. A compound of general formula VII can be prepared in which W is the group (CHRn), - CR12 = NOH by treatment of the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.

The intermediate compound of general formula VII where W is the group AlcN3 can be prepared from a compound of general formula VI where Y is a halogen atom using conventional methods.

Standardized reducing agents such as sodium borohydride can be used to prepare a compound of general formula VII where W is the group CH (OH) CHR12NR4Rs from the corresponding compound of formula VII where W is the group COCHR12NR4R5.

The following reactions can be carried out E in any suitable order, if necessary and / or if desired, after any of the methods described above:

i) transformation of a compound of general formula I or of one of its protected salts or derivatives into another compound of general formula I;

ii) removal of the protective group (s) possibly present), and iii) transformation of a compound of general formula I or of one of its salts into one of its salts or solvates (for example hydrates ).

Thus, a compound of formula I according to the invention can be transformed into another compound of the invention using conventional methods.

For example, one can prepare a compound of general formula I where R2, R4, R5 and / or R7 are alkyl groups from the corresponding compounds of formula I where one or more of the radicals R2, R4, R5 and R, represent a hydrogen, by reaction with a suitable alkylating agent such as an alkyl halide, an alkyl tosylate or a dialkyl sulfate. The alkylation reaction is conveniently 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 based. The basics appro-. required include, for example, alkali metal hydrides, for example sodium hydride, alkali metal amides, such as sodium amide, alkali metal carbonates, such as sodium carbonate or an alkali metal alkoxide such as sodium or potassium methoxide, ethoxide or t-butoxide.

A particularly suitable process for the preparation of a compound of formula I where R4 and / or R5 are different from hydrogen is the reducing alkylation of the corresponding compound where R4 and / or R5 represent hydrogen, with an appropriate aldehyde or ketone ^), (for example benzaldehyde or acetone) in the presence of an appropriate reducing agent. It is also possible to condense the aldehyde or the ketone with the primary amine and then reduce the intermediate thus formed using an appropriate reducing agent.

It will be appreciated that the choice of reducing agents and reaction conditions depends on the nature of the substituent groups already present on the compound of formula I to be alkylated. Suitable reducing agents which can be employed in this reaction include hydrogen in the presence of a metal catalyst, an alkali metal borohydride or cyanoborohydride (e.g. sodium borohydride or sodium cyanoborohydride) using the conditions described above or formic acid (using the carbonyl compound as the reaction solvent), at a temperature between 0 and 100 ° C, the most practical range being 0-50 ° C.

According to another embodiment, one can prepare a compound of general formula I where R5 is a hydrogen atom by reduction of a compound of general formula I corresponding where Rs is a benzyl group, for example with hydrogen in presence of a catalyst, for example 10% palladium on carbon.

It should be appreciated that in some of the above transformations it may be necessary or desirable to protect the sensitive groups possibly present in the molecule of the compound in question to avoid undesirable side reactions. Thus, during one of the reaction sequences described below, it may be necessary to protect the NR4R5 group, where R4 and / or R5 represent a hydrogen, with a group easily detachable at the end of the reaction sequence. These groups may include, for example, aralkyl groups, such as benzyl, diphenyl-methyl or triphenylmethyl; or acyl groups, such as N-benzyloxycarbonyl, t-butoxycarbonyl or phthaloyl.

In some cases, it may also be necessary to protect the indole nitrogen where R7 is hydrogen.

The subsequent cleavage of the protecting group can be carried out by conventional methods. So we can cleave an aralcoyl group like

5

10

15

20

25

30

35

40

45

50

55

60

65

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benzyl by hydrogenolysis in the presence of a catalyst (for example palladium on charcoal); an acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis with, for example, hydrobromic acid in acetic acid or by reduction, for example by catalytic hydrogenation. The phthaloyl group can be removed by hydrazinolysis (for example by treatment with hydrated hydrazine) or by treatment with a primary amine (for example methylamine).

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 done by treating the free base of general formula I with an appropriate acid, preferably with an amount equivalent or with creatinine sulfate in a suitable solvent (eg aqueous ethanol).

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

Besides their use as the last major step in the preparation sequence, the general methods indicated above for the preparation of the compounds of the invention can also be used for the introduction of the desired groups at an intermediate stage in the preparation of the required compound. . Thus, for example, the required group can be introduced in position 5 either before or after cyclization to form the indole nucleus. It should therefore be appreciated that in such multi-step processes, the reaction sequence should be chosen so that the reaction conditions do not affect groups present in the molecule and that one wishes to have in the final product.

The invention is clarified by the following examples. All temperatures are in degrees Celsius.

Preparation 1:

N- [3- (cyanomethyl) -1H-indol-5-yl] formamide

A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in methyl formate (20 ml) is stirred at room temperature for 24 h. The solid precipitate obtained is filtered off, washed with ether (2 x 20 ml) and dried under vacuum to give the title compound (0.41 g) in the form of a white microcrystalline solid. Mp 196-200 ° C (softening at 194 ° C).

Preparation 2:

5- (methylamino) -1H-indole-3-acetonitrile, Vt hydrated

A solution of 5-amino-1H-indole-3-acetonitrile (3.6 g) in triethyl orthoformate (80 ml) containing trifluoroacetic acid (3 drops) is refluxed for 24 h. The solvent is evaporated in vacuo and the residue is dissolved in absolute ethanol (50 ml), cooled to 0 ° C, treated with excess sodium borohydride (4.5 g) and then refluxed for 5 h.

The cooled solution is then poured into a mixture of 2N hydrochloric acid (400 ml) and ice, washed with ethyl acetate (2 x 100 ml) then the acid solution is made basic (Na2CO3) and extract with ethyl acetate (2 x 200 ml). These combined extracts are dried (Na2SO4), filtered, and the solvent is evaporated in vacuo, giving a brown oil. Column chromatography (silica gel 60, 250 g) eluting with ether gives the title compound as a tawny solid (1.5 g). Mp 120-122 ° C.

Preparation 3:

2- {2- [5- (aminomethyl) -1H-indol-3-yl] ethyl} -1H-iso-indole-1,3, (2H) -dione, hemisulfate, hydrated

Hydrogenated at ambient temperature and pressure on 10% palladium on charcoal (50% aqueous paste; 2.0 g) for 45 h a suspension of 3- [2- (1,3-dihydro-l , 3-dioxo-2H-iso-indol-2-yl) ethyl] -1H-indole-5-carbonitrile (4.7 g) in methanol (250 ml) and sulfuric acid (1.5 ml). The catalyst is removed by filtration, and the filtrate is evaporated to dryness, which gives an orange oil, which is dissolved in hot water (70 ml). Upon cooling, the title compound crystallizes as a creamy solid (3.8 g). Mp. 235-238 'C.

Preparation 4:

Phenylmethyl (2- [5- (aminomethyl) -1H-indol-3-ylJethyljcarbamate i) Phenylmethyl {2- [5- (hydroxymethyl) -H-indol-3-ylJethyljcarbamate

A solution of 3- {2 - [((phenylmetoxy) carbonyl) amino] ethyl} -lH-indole-5-carboxylic acid (9 g) and carbonyldi-imidazole is vigorously stirred under nitrogen at ambient temperature for 5 h. (5.2 g) in dry tetrahydrofuran (THF) (150 ml). A solution of lithium borohydride (1.6 g) in dry THF (70 ml) is added for 70 min, then the mixture is stirred for 18 h. Aqueous acetic acid (30%, 25 ml) is slowly added to the cooled mixture with ice and the solution is divided between brine (25%, 300 ml) and ethyl acetate (250 ml) . The organic layer is washed with sulfuric acid (0.4M, saturated with sodium chloride, 3 x 80 ml), brine (100 ml) and a solution of potassium carbonate (25%, 2 x 100 ml). The dried solution is evaporated in vacuo (MgSO 4), the residue is absorbed in dichloromethane (150 ml) and the insoluble material is filtered off. The filtrate is evaporated in vacuo to leave the alcohol (9 g) in the form of a colorless oil containing a certain amount (at about 45% M) of ethyl acetate. Thin layer chromatography (TLC) Si02 / Et20. Rf. 0.25.

ii) Phenylmethyl {2- [5-faminomethyl) -1 H-indol-3-ylJethyljcarbamate

Is poured for 2 min, maintaining its temperature at 25 ° C, a solution of diethylazodicarboxylate (1.48 g) in dry tetrahydrofuran (THF) (8 ml), in a stirred solution of phenyl-methyl- {2- [ 5- (hydroxymethyl) -1H-indol-3-yl] -ethyl} carbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4 h, the solvent is evaporated in vacuo and the residue is dissolved in a solution of hydrated hydrazine (15 ml) in ethanol (100 ml).

After 5 d the mixture is divided between sulfuric acid (0.5N, 500 ml) and ethyl acetate (2 x 300 ml). The aqueous layer is made basic with potassium carbonate and the product is extracted into ethyl acetate (200 ml). The dried extract (Na2SO4) is evaporated in vacuo to leave the crude amine (0.7 g) in the form of a brown oil which subsequently solidifies. Crystallization from ethyl acetate gives the title compound (0.15 g) as cream-colored crystals. Mp 123.5-126.5 ° C.

Example 1:

N - {[3- (2-aminoethyl) -1H-indol-5-ylJmethylJacetamide, compound with creatinine, sulfuric acid and water (IIIlll / l)

i) N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl)

ethylJ-1H-indol-5-ylJmethyljacetamide

A suspension, cooled with ice, of 2- {2- [5- (aminomethyl) -1 H-indol-3-yl] ethyl} -1 H-iso-indole-1,3 is treated dropwise (2H) -dione, hemisulfate, hydrated (1.01 g) in pyridine (40 ml) with acetic anhydride (0.6 ml). The mixture is stirred at room temperature for 1 h, water (15 ml) is added, and after having waited another 15 min the solution is acidified with 2N hydrochloric acid and extracted into acetate. ethyl (3 x 150 ml). The combined extract is washed with sodium carbonate (2N; 300 ml), dried (MgSO 4) and evaporated to dryness, which gives a yellow foam. Triturating with ethyl acetate (about 10 ml) this gives the title amide as a pale yellow crystalline solid (0.79 g). Mp 180-182 ° C.

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ii) N- [lj- (2-aminoethyl) -1H-indol-5-ylJmethyljacetamide, compound with creatinine, sulfuric acid and water (1/1/1/1)

A solution of N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl] -1H-indol-5 is heated at reflux for 4 h. -yl] methyl} a-ketamide (0.62 g) in ethanol (90 ml) and hydrated hydrazine (0.45 ml). After cooling, the solution is evaporated to dryness, and the white solid obtained is distributed between ethyl acetate (100 ml) and 2N sodium carbonate (100 ml). The aqueous phase is further extracted with ethyl acetate (3 x 100 ml), and the combined organic phase is dried (MgSO4) and evaporated to dryness, giving a yellow oil. This is dissolved in a hot mixture of ethanol (50 ml) and water (6 ml) and treated with an aqueous solution of creatinine and sulfuric acid (1/1, 2M, 0.85 ml) to give , after cooling, the title compound in the form of a white crystalline solid (0.48 g). Mp 233-235 ° C (dec.).

Analysis for C13H17N30 • C4H7N30 • H2S04 • H20 Calculated: C44.3 H 6.1 N18.2%

Found: C43.9 H 6.0 N 17.8%

Example 2:

Ethyl- [3- (2-aminoethyl) -lH-indol ~ 5-yl] carbamate, compound with Creatinine, sulfuric acid and water (2/2 / 2jl)

i) Ethyl- [3- (cyanomethyl) -1H-indol-5-yl] carbamate

A solution of 5-amino-1H-indole-3-acetonitrile (1.5 g) in dimethylformamide (35 ml) is treated with potassium carbonate (4.2 g) and ethyl chloroformate (0.9 ml) added dropwise for 20 min. After waiting a further 5 min, the reaction mixture is poured into water (150 ml), left to stand for 30 min and then extracted with ethyl acetate (3 x 130 ml). The combined ethyl acetate extracts are washed with water (2 x 150 ml), 8% sodium bicarbonate solution (2 x 150 ml) and water (2 x 100 ml) and dried (MgSO 4) and then the solvent is removed in vacuo under reduced pressure to give a brown oil. The oil is crystallized from ethyl acetate and cyclohexane to give the title compound (1.65 g) as a brown crystalline solid. Pf. 119-123: C.

ii) Ethyl- [3- (2-aminoethylj-1H-indol-5-ylJcarbamate, compound with creatinine, sulfuric acid and water (2/2/2/1 d

Ethyl- [3- (cyano-methyl) -1H-indol-5-yl] carbamate (1.5 g) is catalytically hydrogenated on 5% rhodium on alumina (0.5 g) in a mixture of ethanol (50 ml) and ammonia (0.6 ml) for 40 h to 40 then at 50 ° C for a further 8 h. The mixture is filtered through hyflo and evaporated to dry to give a brown oil, purified by column chromatography on 6 1 (25 g) using ethyl acetate / 2-propanol / water / ammonia (25/15/4/1) as eluent to give a brown oil (0.58 g) which is dissolved in ethanol and treated with an aqueous solution of creatinine and sulfuric acid (1/1, 2M, 1 ml) to give an off-white solid which is recrystallized from aqueous acetone to give the title compound as a colorless solid (0.65 g). Pf. 184.5-187.5J C.

Analysis for C13HI7N30, • C4H7N30 • H2S04-0,5H20:

Calculated: C 43.7 H 5.8 N 18.0%

Found: C43.4 H 5.9 N 17.65%

Example 3:

N- f [3-! 2-aminoethyl) -1H-indol-5-yl] methyl} formamide, compound with creatinine, sulfuric acid and water (l / l / l / I ji) Phenylmethyl- {2- [5- [( formy lamino imethyl] -I H-indoI-3-yl] -ethyl jcarbamate

A mixture of phenyl-methyl- {2- [5- (aminomethyl) -1 H-indol-3-yl] -ethyl Jcarbamate is heated at reflux for 9 h.

(0.25 g), ethyl formate (5 ml) and ethanol (1 ml). The solvent is evaporated in vacuo and the residue is evaporated with ethanol (2x5 ml) to give the title compound (0.27 g) as cream crystals. Pf. 114-1 ló2 C.

ii) N- {[3- (2-aminoethyl) -1H-indol-S-ylJmethyljformamide,

compound with creatinine, sulfuric acid and water (1/1/1/1)

A solution of phenylmethyl- {2- [5 - [(formylamino) methyl] -1H-indol-3-yl] ethyl} carbamate (0.34 g) in hydrogen is hydrogenated at ambient temperature and pressure (0.34 g) in ethanol ( 30 ml) on palladium oxide on charcoal (10%; 0.3 g pre-reduced) until the absorption of hydrogen ceases. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residual oil is dissolved in a hot mixture of ethanol (8 ml) and water (0.8 ml) and an aqueous solution of creatinine and sulfuric acid (1/1; 2M; 0) is added. , 8 ml). Filtration of the cooled solution gives the title compound as a white solid (0.33 g). Mp 197-200 ° C (foam).

Analysis for Ct2Hj 5N30 • C4H7N30 • H2S04 • H20:

Calculated: C 43.05 H 5.85 N 18.85%

Found: C43.2 H 5.8 N 19.0%

Example 4:

N-J3- f 2-aminoethyl) -1H-indol-5-ylJformamide, compound with Creatinine, sulfuric acid and water (1/1/1 / 1,3)

Hydrated hydrazine (30 ml) is slowly poured over 3 h into a mixture of N- [3- (cyanomethyl) -lH-indol-5-yl] formamide (1.0 g) and Raney nickel (2 g) in ethanol (100 ml) at reflux under nitrogen. The catalyst is removed by filtration and the filtrate is evaporated to give an oil (1.1 g) which is dissolved in a hot mixture of ethanol (60 ml) and water (30 ml) and the treated with a solution of creatinine sulfate (1.2 g) in water (4 ml). Dilution with ethanol (150 ml) precipitates the title compound as a white solid (1.4 g). Mp 175-183 ° C.

Analysis for C11H13N30-C4H7N30-H2S04- 1.3H20:

Calculated: C41, W H 5.7 N 19.2%

Found: C41.5 H 5.6 N 18.7%

Example 5:

N- [3- (2-aminoethyl) -1H-indol-5-yl] -N-methylformamide, compound with creatinine, sulfuric acid and water (8/10/9/16)

i) N- [3- (cyanomethyl) -1H-indol-5-ylJ-N-methylformamide

A solution of 5- (methylamino) -1H-indole-3-acetonitrile (0.2 g) in methyl formate (7 ml) is kept at room temperature for 36 h. The solvent is evaporated in vacuo and the residue is partitioned between ethyl acetate (10 ml) and 2N hydrochloric acid (10 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo which gives the title compound as a tawny solid (0.13 g). Mp 118-120 ° C.

ii) N- [3- (2-aminoethyl) -1H-indol-5-ylJ-N-methylformamide, compound with creatinine, sulfuric acid and water (8/10/9/16)

Following the process described in Example 4, the N- [3- (cyanomethyl) -1H-indol-5-yl] -N-methylformamide (1.2 g) in ethanol (150 ml) is reduced with Raney nickel (0.03 g) and hydrated hydrazine (23 ml) for 8 h. The title compound is obtained (1.4 g) in the form of a chamois solid. Mp 208-210 ° C after formation of creatinine sulfate.

Analysis for C12H15N30- 1.25C4H7N30- 1.125H2S04-2H20: Calculated: C40.4 H 6.0 N 18.7%

Found: C40.8 H 5.6 N 18.7%

Example 6:

Ethyl-J3- (2-aminoethyl) -1H-indol-5-yl] methylcarbamate, compound with creatinine, sulfuric acid and water (1/1/1/2)

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i) Ethyl- [3- (cyanomethyl) -1H-indol-5-yl] methylcarbamate

Ethyl chloroformate (0.21 ml) is poured dropwise into a stirred solution of 5- (methylamino) -1H-indole-3-acetonitrile (0.4 g) in dimethylformamide (15 ml). After 10 min the solution is diluted with water (30 ml), stirred for 30 min and extracted with ethyl acetate (2 x 100 ml). The combined extracts are washed with 10% brine (2 x 100 ml), 8% sodium bicarbonate (2 x 100 ml) and water (2 x 100 ml), dried (Na2SO4) and evaporated in vacuo to give the crude product as a brown oil. Trituration with ether gives a tawny solid (0.4 g). A sample is crystallized from ether to give the title compound as a white solid. Mp 104-106 ° C.

ii) Ethyl-13- (2-aminoethyl) -1H-indol-5-ylJmethylcarbamate, compound with Creatinine, sulfuric acid and water (ljljlj2)

A solution of ethyl- [3- (cyanomethyl) -1 H-indol-5-yl] methylcarbamate (0.2 g) in absolute ethanol (30 ml) containing hydrogen is hydrogenated at room temperature and at ambient pressure. concentrated hydrochloric acid (8 drops) on palladium on charcoal (10%, 0.4 g) until the absorption of hydrogen stops (8 h, 23 ml). The catalyst is removed by filtration, washed with absolute ethanol, and the filtrate is evaporated in vacuo to give a brown oil. The amine is dissolved in a hot solution of ethanol and water (8 / 1.18 ml) and treated with an aqueous solution of Creatinine and sulfuric acid (1/1, 2M, 0.38 ml) . Filtration of the cooled mixture gives the title compound as a white solid. Pf. 210-212 "C (dec.) (0.15 g).

Analysis for C, 4Hi9N302 • C4H7N30 • H2S04 ■ 2H20:

Calculated: C42.5 H 6.3 N 16.5%

Found: C42.7 H 5.9 N 16.7%

Example 7:

N- [3- (2-aminoethyl) -IH-indol-5-yl] urea, compound with creatinine, sulfuric acid and water (1/1/1/1)

i) N- [3- (cyanomethyl) -1H-indol-5-ylJurea

A solution of sodium cyanate (1.2 g) in water (10 ml) is poured into a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.5 g) in glacial acetic acid (5 ml) and water (10 ml). Continue to agitate until a brown gum precipitates (10 min). The aqueous layer is then removed by decantation, and extracted with ethyl acetate (2 x 100 ml). The combined extracts are washed with sodium carbonate solution (2N, 2 x 100 ml), dried (Na2SO4) and evaporated in vacuo to give the crude urea as an off-white solid (0, 3 g). The brown gum is purified by column chromatography (silica gel 60, 25 g) using ethyl acetate as eluent to give an additional amount of crude urea (0.1 g). Crude urea is then crystallized from isopropanol to give the title compound as a tawny solid (0.3 g). Mp 200-204 ° C.

ii) N- [3- (2-aminoethyl) -1H-indol-5-yl] urea, compound with creatinine, sulfuric acid and water (1/1/1/1)

Following the process of Example 4, the N- [3- (cyano-methyl) -1H-indol-5-yl] urea (0.2 g) in ethanol (30 ml) is reduced with nickel Raney (0.03 g) and hydrated hydrazine (6 ml) for 5 h. The title compound is obtained (0.15 g) in the form of a cream solid. Mp 208-212 ° C after formation of creatinine sulfate.

Analysis for Q iH14N4 • C4H7N30 • H2S04 • HzO:

Calculated: C40.3 H 5.6 N21.9%

Found: C40, W H 5.6 N 21.05%

TLC Silica - ethyl acetate / 2-propanol / water / ammonia at 0.88 (25/15/8/2). Rf. 0.44.

Example 8:

Methyl- [3- (2-aminoethyl) -1H-indol-5-yl] carbamate, compound with creatinine, sulfuric acid and water (ljl / lll)

i) Methyl-f3- (cyanomethyl) -1H-indol-5-yl] carbamate

Following the procedure of Example 6i, 5-amino-1H-indol-3-acetonitrile (0.8 g) in dimethylformamide (10 ml) is reacted with methyl chloroformate (0.5 ml) to give the title compound (0.44 g) as a white solid. Mp 146-148 ° C after column chromatography (silica gel 60, 100 g) eluting with ether.

ii) Methyl- [3- (2-aminoethyl) -1H-indol-5-ylJcarbamate, compound with creatinine, sulfuric acid and water (III-III)

Following the method of Example 6ii, methyl- [3- (cyanomethyl) -1H-indol-5-yl] carbamate (0.7 g) is hydrogenated in ethanol (100 ml) on palladium on carbon wood (10%, 1.0 g) for 24 h to give, after formation of creatinine sulfate, the title compound (0.5 g) as a white solid. Mp 197-200 ° C.

Analysis for Cj 2Hj SN302 - C4H7N30 - H2S04 - H20:

Calculated: C 41.55 H 5.7 N 18.2%

Found: C4I, 4 H 5.7 N18, 1%

Example 9:

N- {3- [2- (methylamino) ethylJ-1H-indol-5-yljformamide, compound with creatinine, sulfuric acid and water (III2jlll20)

A solution of N- [3- (cyanomethyl) -1H-indol-5-yl] formamide (0.3 g) is hydrogenated in absolute ethanol (30 ml) containing methylamine (33% in ethanol , 2 ml) at room temperature and pressure on palladium oxide on charcoal (10%, 0.5 g) for 24 h until the absorption of hydrogen stops (90 ml). The catalyst is filtered off, washed with absolute ethanol, and the filtrate is evaporated in vacuo to give a brown oil.

The amine is dissolved in a hot mixture of ethanol and water (8 / 1.18 ml) and an aqueous solution of creatinine and sulfuric acid (1/1, 2M, 0.6 ml) is added. Filtration of the cooled mixture gives the title compound as an off-white solid (0.35 g). Mp 205-207 ° C.

Analysis for C12H15N30- 1,2C4H7N30- I, 1H2S04-2H20: Calculated: C40.7 H 5.8 N 18.6%

Found: C40.6 H 5.5 N 18.8%

Example 10:

N - {[3- (2-aminoethyl) -1H-indol-5-yl] methyl} -N'-methylurea,

compound with creatinine, sulfuric acid and water (2d / 2d)

i) a N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl] -lH-indol-5-ylJmethylJ-N'-methylurea , hemihydrate

A suspension of 2- {2- [5- (aminomethyl) -1 H-indol-3-yl] ethyl} -1 H-iso-indole-1,3- (2H) -dione is cooled in a galcée bath. hemisulfate, hydrated (1.53 g) in pyridine (50 ml) and treated dropwise with methyl isocyanate (2.5 ml). The mixture is stirred at room temperature for 4 h, and water (15 ml) is added to the white suspension obtained. After 10 min the yellow solution is acidified with 2N hydrochloric acid, and extracted into ethyl acetate (3 x 100 ml). The combined organic extract is washed with a sodium carbonate solution (2N; 100 ml), dried (magnesium sulfate) and evaporated to dryness, which gives a pale yellow solid. After trituration with ether, this gives the pure title product in the form of a creamy crystalline solid (1.22 g). Pf. 210-212 "C. The following compounds are prepared analogously from 2- {2- [5- (amino-methyl) -1 H-indol-3-yl] ethyl} -1 H-iso -indole-1,3- (2H) -dione, hemisulfate, hemihydrate, and the appropriate isocyanate or isothiocyanate as detailed in Table I.

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Example 10: (continued)

ii) a N- {[3- (2-aminoethyl) -1 H-indol-5-yl] -methyl} -N'-methyl-urea, compound with creatinine, sulfuric acid and water (2/2 / 2/3)

Following the process described in Example III, a solution of N - {[3- [2- (1,3-dihydro-1,3, dioxo-2H-iso-indol-2-yl) is "deprotected" -ethyl] -lH-indol-5-yl] methyl} -N'-methylurea, hemihydrate (0.81 g)

in ethanol (80 ml) with hydrated hydrazine (0.8 ml) to give, after formation of creatinine sulfate, the title compound (0.32 g) as a white solid. Mp 205-207 ° C (dee.).

Analysis for CJ3H18N40- C4H7N30 -H2S04 • 1 ViHjO:

Calculated: C42, W H 6.2 N20.2%

65 Found: C42.5 H 5.9 N 20.0%

The following compounds are likewise prepared for "deprotection" of the appropriate starting product as it is described in detail in Table II.

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Example II:

i) a N- {[3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-ylj ethylJ-1H-indol-5-ylJmethyljbenzamide

Benzoyl chloride (0.9 ml) is added to a stirred suspension of 2- {2- [5- (aminomethyl) -1 H-indol-3-yl] -ethyl} -1 H-isoindole-1.3 - (2H) -dione, hydrated hemisulphate (1.0 g) in dry pyridine (40 ml). The mixture is stirred at room temperature for A h and then water (10 ml) is added. The solution obtained is stirred for XA h and acidified with 2N hydrochloric acid. The precipitated solid is filtered off, washed with water (30 ml) and dried (1.04 g). Recrystallization from aqueous dimethylformamide gives the title amide in the form of yellow crystals (0.77 g). Mp 227.5-229 ° C.

The following compounds are likewise prepared from 2- {2- [5- (aminomethyl) -1 H-indol-3-yl] ethyl} -1 H-iso-indole-1,3- (2H) - dione, hemisulfate hydrate and the appropriate chloro compound (R! - Cl) as described in detail in Table III.

ii) Following the process described in Example 10ii) a, the following compounds are likewise prepared by "deprotection" of the appropriate starting product as described in detail in Table IV.

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Example 12:

i) {3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl J-1H-indol-5-yljmethylurea A solution of 2- {2 is treated - [5- (amino-ethyl) -1H-indol-3-

yl] ethyl] -lH-iso-indole-l, 3- (2H) -dione, hemisulfate hydrate (1.01 g) in hot water (27 ml) with a solution of sodium cyanate (0.25 g ) in water (9 ml) and heated on a steam bath for 1 lA h. The reaction mixture is cooled and filtered to give the title urea as a white crystalline solid (0.82 g). Mp 230-232 ° C.

ii) By following the method as described in Example 10ii) a, we

"Unprotects" the above product as detailed in Table IV. 35

C Tables on next page) ->

Example 13:

N- [3- (2-aminoethyl) -1H-indol-5-yl] aetamide, compound with creatinine, sulfuric acid and water (2j3l2l5)

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i) N- [3- (cyanomethyl) -1H-indol-5-yl] acetamide

Acetyl chloride (0.21 ml) is poured dropwise into a stirred solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) and pyridine (0.24 ml) in dry acetonitrile (10 ml) at 0-2 ° C under nitrogen. When the addition is complete, the solution is stirred at 0 ° C for 45 min, poured into water (50 ml) and extracted with ethyl acetate (3 x 25 ml). The combined extracts are dried (MgSO4), filtered and evaporated under reduced pressure to give a brown solid (0.5 g) which is recrystallized from a mixture of ethanol and cyclohexane to give the composed of the title (0.43 g) in the form of off-white needles. Mp 171.5-175 ° C.

ii) N- [3- (2-aminoethyl) -1H-indol-5-ylJacetamide, compound with creatinine, sulfuric acid and water (21312) 5)

Following the process described in Example 4, the N- [3-55 (cyanomethyl) -1H-indol-5-yl] acetamide (0.3 g) in ethanol (15 ml) is reduced with nickel of Raney (0.06 g) and hydrazine hydrate (6.2 ml) for 6 h. The title compound is obtained in the form of a white crystalline solid. Mp 177-182 ° C (dec.).

Analysis for C12H15N30- 1.5C4H7N30-H2S04-2.5H20: 60 Calculated: C40.8 H 6.2 N 19.8%

Found: C40.6 H 5.7 N20, l%

Example 14:

N- [3- (2-aminoethyl) -1H-indol-5-yl] -2-methylpropanamide, compound with hydrochloric acid and water (4) 4/3)

ii) A solution of N- [3- (cyanomethyl) -1H-indol-5- is hydrogenated

65

yl] -2-methylpropanamide (0.4 g) in absolute ethanol (50 ml) containing concentrated hydrochloric acid (10 drops) at room temperature and pressure on palladium on charcoal (10% 1.5 g) for 16 h before replacing the catalyst (at 10%, 1 g). After waiting another 4 h, when the absorption of hydrogen (75 ml) has ceased, the catalyst is filtered off, washed with absolute ethanol, and the filtrate is evaporated in vacuo, which gives a solid brown. The crude hydrochloride is crystallized from a mixture of methanol and ethyl acetate, to give the title compound as a light brown solid (0.2 g). Pf. 274-276 = C.

Analysis for C14H19N30-0.75H20:

Calculated: C 56.95 H 7.3 N 14.2%

Found: C 56.7 H 7.4 N 13.7%

Example 15:

N- [3- (2-aminoethyl) -1H-indol-5-ylJtrifluoroacetamide, compound with creatinine, sulfuric acid and water (1/1/1/2)

ii) N- [3- (cyanomethyl) -1H-indol-5-yl] tri-fluoroacetamide (1.3 g) is hydrogenated in ethanol (50 ml) and ammonia (0.6 ml) at ambient temperature and pressure on rhodium-on-aluminia (0.5 g) for 48 h. The mixture is filtered through hyflo and evaporated to dryness under reduced pressure to give a brown oil. The brown oil is purified by column chromatography (silica gel 60, 25 g) using a mixture of ethyl acetate, 2-propanol, water and ammonia (25/15/4/1 ) as eluent. The solid obtained is dissolved in hot ethanol and treated with an aqueous solution of creatinine and sulfuric acid (1/1, 2M, 1 ml), then the solid obtained is recrystallized from aqueous acetone to give the title compound in the form of a pinkish solid. Pf. 186-215: C (dec.).

Analysis for C, 2H12F3N30 ■ C4H7N30 • H2S04-2H20:

Calculated: C37, W H 4.9 N 16.2%

Found: C 37.2 H 5.05 N 16.2%

The following compounds are prepared according to the method described in Example 13i from 5-amino-1H-indole-3-acetonitrile and the appropriate acid chloride or acid anhydride as described in detail in Table V.

(Table on next page)

Example 16:

N-f3- (2-aminoethylj-1 H-indol-5-ylJ-N'-methylthio-urea, compound with creatinine, sulfuric acid and water (1/1/1/1)

i) N- [3- (cyanomethyl) -1H-indol-5-yl] -N'-methylthio-urea, compound with ethanol (2/1)

Methyl isothiocyanate (0.40 ml) is added to a stirred solution of 5-amino-1H-indol-3-acetonitrile (1 g) in dry acetonitrile (20 ml). The solution is stirred at room temperature for 3 d. An additional amount of methyl isothiocyanate (0.05 ml) is added and the mixture is heated at 50 ° C for 5 h. The solution is evaporated in vacuo to give a viscous oil which solidifies when triturated with a mixture of ethanol and ether. The solid obtained is filtered off and dried in vacuo to give the title compound (1.17 g) as an off-white crystalline solid. Mp 103-110 ° C.

ii) N- [3- (2-aminoethyl) -1 H-indol-5-yl] -N'-methylthio-urea,

compound with creatinine, sulfuric acid and water (1/1/1/1)

Small amounts of lithium aluminum hydride (0.19 g) are added at 18-20 ° C to a stirred suspension of N- [3- (cyanomethyl) -1H-indol-5-yl] -N ' -methylthio-urea (0.4 g) in dry tetrahydrofuran (10 ml) under nitrogen. When the addition is complete, the yellow suspension is heated under reflux for 2 h. The suspension is cooled to room temperature and the excess lithium aluminum hydride is destroyed by carefully adding a mixture of ethanol and

Table III

Example No.

Starting material weight (g)

Ri - Cl

Amount of R] - Cl (ml)

Reaction time (h)

Product weight (g)

Molecular formula

Pf.

("vs)

ll (i) b

1.0

0-COC1

1.2

5

0.62

c2sh27n303

198 -198.5 '

ll (i) c

1.4

PhCH2COCl

4.8

6.25

0.85

C27H23N3O3- 'AH20

202.5-203.52

ll (i) d

1.14

EtOCOCl

0.5

1

0.92

c22h21n3o4- iah2o

158 - 9

11 (0 th

1.15

MeOCOCl

0.7

7

1.05

c2iH19n3o4

150 - 1

1 Recrystallized from ethyl acetate

2 Recrystallized from chloroform / ether

Table IV

Example product no.

Example number of the starting product

R.

Starting material weight (g)

EtOH volume (ml)

Volume n2h4-h2o

(ml)

Product weight (g)

Molecular formula

(ii) to ll (i)

PhCO -

0.51

60

0.3

0.24

c18hi9n3o-c4h4 <v

(ii) b

I l (i) b

<OC0-

0.61

30

0.35

0.35

c18h25n3o-c4h4o42

(ii) c

11 (0 c

PhCH2CO -

0.68

50

0.53

0.54

c19h21n3o • c4h7n3o • h2so4 • h2o

(ii) d

11 (0 d

Et02C -

0.49

60

0.32

0.50

c14h19n3o2-c4h7n3o-h2so4-% h2o

(ii) e ll (i) e

Me02C -

0.52

60

0.70

0.52

c13h17n3o2 • c4h7n3o • h2so4 ■ h2o

(Ü) f

12 (i)

H2NCO -

0.56

80

0.4

0.3

c12h16n4o • c4h7n3o • h2so4 • h2o

1 Transformed into a maleate salt with maleic acid in methanol / ether. Recrystallized from methanol / ethyl acetate

2 Transformed into a maleate salt with maleic acid in methanol / ether. Recrystallized from isopropanol / ethyl acetate

OJ

Table IV (continued)

Example product no.

Mp (° C)

Analysis

Find

Calculated

VS

H

NOT

VS

H

NOT

(ii) a

167-71

64.1

5.6

9.9

64.5

5.7

10.3

(ii) b

147-9

63.6

7.0

9.8

63.6

7.0

10.1

(ii) c

230-231.5

51.3

5.85

15.4

51.5

6.0

15.7

(ii) d

213-5 (dec.)

44.1

6.1

17.6

44.5

6.1

17.3

(ii) e

216-8 (dec.)

42.9

5.9

17.4

42.85

5.9

17.6

(ii) f

208-10 (Dec)

41.8

5.8

20.7

41.6

5.9

21.2

o \ m

W

vo

4to-

652,394

14

'—S

Cf-Î U

^ W

138-140 165-9

Molecular formula

O ©

z z, "

*

• -H M

W U

Recrystallization solvent

*

ethyl acetate / cyciohexane

* Purified by column chromatography on silica gel 60 (150 g) eluted with ethyl acetate

Product weight (g)

1.8

1.46

CH3CN volume (ml)

50 40

Volume of pyridine (ml)

CM

Reagent volume (ml)

1.8

2.45

Reagent

O

Ö £

0 R

U u

"<fc ö? * u

Starting material weight (g)

2.8 2.0

Example No.

<"" "" "-" "N

of water (1/1) (30 ml). The suspension obtained is filtered off and the filtrate is evaporated under reduced pressure to give a yellow semi-solid.

Ethanol (50 ml) and water (10 ml) are added and the solution is filtered to remove a small amount of insoluble matter. The filtrate is heated to reflux and treated with a hot solution of creatinine sulfate (0.6 g) in water (2 ml). After cooling,

the title compound is obtained in the form of a buff-colored solid. Pf. 226-229 C (dec.).

Analysis for C12H16N4S • C4H7N30 • H2S04 • H20:

Calculated: C40.2 H 5.7 N20.5%

Found: C40.3 H 5.5 N20, l%

Example 17:

N- [3- (2-aminoethyl) -1H-indol-5-yl] tiourea, fumarate, hemihydrate

i) Ethyl - {[[3- (cyanomethyl) -lH-indol-5-yl] amino] thiocarbonyl} -carbamate

Ethoxycarbonyl isothiocyanate (1.2 ml) is added dropwise to a stirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.7 g) in dry acetonitrile (50 ml ). After 10 min, the suspension obtained is diluted with water (40 ml) and stirred for 20 min.

The precipitate is separated by filtration, washed with dry acetonitrile, and dried in vacuo to give the title compound as a cream solid (1.5 g). Mp 201-202 ° C.

ii) N- [- (cyanomethyl) -lH-indoI-5-ylJ thio-urea

A solution of ethyl {[[3- (cyano-methyl) -lH-indoI-5-yl] -amino] thiocarbonyl} carbamate (0.5 g) in hydroxide is stirred at 40 ° C. for 2 h. 2N sodium (3 ml) and ethanol (10 ml). The precipitate obtained is filtered off, triturated with water (40 ml), washed with ethanol (approximately 30 ml) and dried in vacuo to give the title compound as a white solid (0.25 g), mp 212-214 ° C.

iii) N- [3-f 2-aminoethyl} -1H-indol-5-yIJthio-nrea, fumarate, hemihydrate

Lithium aluminum hydride (0.5 g) is added several times under nitrogen to a stirred suspension of N- [3- (cyanomethyl) -1H-indol-5-yl] thiourea (0 , 6 g) in THF (150 ml). When the addition is complete, aluminum chloride (1.74 g) is added, and the gray suspension obtained is stirred at reflux for 1 h.

The mixture is cooled in ice and the excess reagent is decomposed by carefully adding 10% water in THF. Brine (100 ml) and ethyl acetate (100 ml) are added, the insoluble material is filtered off, and the aqueous layer is extracted with ethyl acetate (100 ml).

The combined organic solutions are washed with brine (100 ml), dried (Na2SO4) and evaporated in vacuo to give a pale yellow oil. The oil is dissolved in a solution of fumaric acid (0.3 g) in methanol (5 ml) and the fumarate is precipitated by addition of ethyl acetate (250 ml). The salt is crystallized from isopropanol and recrystallized from a mixture of methanol and ethyl acetate to give the title compound as a cream solid (0.15 g). Mp 147-150 ° C.

Analysis for CnH, 4N4S • C4H404 • 0.5H20:

Calculated: C50, W H 5.3 N 15.6%

Found: C50, W H 5.4 N 15.8%

Example 18:

N- {l- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl} acetamide, compound with creatinine, sulfuric acid and water (1/1/1/2)

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

A suspension of 5-acetyl-1H-indole-3-ethanamine (1.0 g), phthalic anhydride (0.83 g) and sodium acetate (1.0 g) is heated at reflux for 3 h. in acetic acid (15 ml). After cooling, the title compound is deposited in the form of an off-white crystalline solid (1.5 g). Pf. 234-235: C.

ii) 2- [5- [1- [hydroxyimino Jethyl] -1 H-indol-3-yl} -1 H-iso-indole-1,3- (2H) -dione

A suspension of 2- [2- (5-acetyl-1H-indol-3-yl) ethyl] - is treated.

5

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15

20

25

30

35

40

45

50

55

60

65

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652,394

1H-iso-indole-1, 3- (2H) -dione (1.0 g) in ethanol (20 ml) with a solution of hydroxylamine acetate [produced from a solution of hydrochloride hydroxylamine (0.5 g) and sodium acetate (0.5 g) in water (5 ml) diluted with ethanol (75 ml) to deposit the sodium chloride]. The reaction mixture is heated at reflux for 2% h. After cooling the title compound separates by crystallization as a yellow solid (1.0 g). Mp 220-223 ° C.

iii) N- {l- [3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2H-isoindol-2-yl) ethyl] -lH-indol-5-yl ] ethyl} acetamide

A suspension of 2- {5- [1- (hydroxiimino) ethyl] -1H-indol-3-yl} -1H-iso-indole-1,3- (2H) -dione (0.8 g) is hydrogenated. methanol (150 ml) and concentrated sulfuric acid (0.8 ml) is hydrogenated on prereduced palladium on palladium on charcoal (0.8 g) at ambient temperature and pressure until l absorption of hydrogen stops (4 h, 120 ml). The catalyst is filtered off, washed with methanol, and dimethylformamide (10 ml) is added to the filtrate before the methanol is removed by evaporation under reduced pressure. The brown solution obtained is cooled in an ice bath and treated successively with pyridine (10 ml) and acetic anhydride (0.8 ml). The reaction mixture is allowed to warm to room temperature overnight, then partitioned between ethyl acetate (250 ml) and 2N dilute hydrochloric acid (500 ml). The organic phase is washed with water (5 x 100 ml), dried (Na2SO4) and evaporated to dryness to give a brown gum which is purified on a column of silica (silica gel 60 , 70 g) eluted with ethyl acetate to give the title compound as a yellow crystalline solid (0.45 g). Mp 224-226 ° C.

iv) N- {l- [3- (2-aminoethyl) -1H-indol-5-yl] -ethyl} acetamide, compound with creatinine, sulfuric acid and water (l / l / lß)

Following the process described in Example III, a solution of N- {l- [3- [2- (I, 3-dihydro-1,3, dioxo-2H-iso-indol-2-) is "deprotected" yl) ethyl] -1H-indol-5-yl] ethyl} acetamide (0.38 g) in ethanol (50 ml) with hydrated hydrazine (0.25 ml) to give, after formation of creatinine, the title compound in the form of a white crystalline solid (0.35 g). Mp 205-212 ° C (dec.).

Analysis for C14H19N30 • C4H7N30 • H2S04 • 2H20:

Calculated: C43.9 H 6.5 N 17.1%

Found: C43.4 H 6.15 N 17.65%

Example 19:

N- {[3- (2-aminoethyl) -1-methyl-1H-indol-5-ylJmethyljformamide, compound with creatinine, sulfuric acid and water (10! 12111110)

i) N- {f 3-f2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl J-1H-indol-5-yl] methyl jformamide

Formic acetic anhydride (5 ml) is added for 1 min to an ice-cold, stirred solution of 2- {2- [5- (aminoethyl) -1H-indol-3-yl] ethyl} -lH-iso-indol-l, 3- (2H) -dione, hemisulfate, hydrated (0.65 g) in dry pyridine (25 ml). After 10 min, the mixture is removed from the ice bath and stirred at room temperature for 1 hr.

The mixture is then cooled in ice and water (10 ml) is added. After 10 min, the mixture is slowly diluted with water to 400 ml, while scraping. Filtration gives pale yellow needles (0.53 g). Mp 174-176 ° C (partial melting at 145 ° C).

A sample (0.14 g) is recrystallized from ethyl acetate to give the title compound (0.11 g) as a yellow powder. Pf. 176-178 "C.

ii) N - '[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yljéthylJ-1-methyl-1H-indol-5-yl] methyl} formamide, hemihydrate

Sodium hydride in oil (80%, 0.045 g) is added under nitrogen to a stirred solution of N - {[3- [2- (1,3-dihydro-1,3-dioxo-

2H-iso-indol-2-yl) ethyl] -1H-indol-5-yl] methyl} formamide (0.5 g) in dimethylformamide (20 ml) and stirring is continued for 30 min. The solution is then treated with methyl iodide (0.2 ml). After 3 h, the solution is diluted with ethyl acetate (150 ml), washed with brine (10%, 3 x 50 ml), dried (sodium sulfate), filtered and evaporated to dryness, which gives a yellow solid which is crystallized from ethyl acetate to give the title compound (0.2 g) as an off-white solid . Mp 189-191 ° C.

iii) N - {[3- (2-aminoethyl) -1-methyl-1H-indol-5-ylJmethyljformamide, compound with creatinine, sulfuric acid and water (10/12/11/10)

A solution of N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl] -1-methyl is kept at room temperature for 2 h. -1H-indol-5-yl] methyl} formamide (0.3 g) in ethanolic methylamine (33%, 10 ml). The solvent is evaporated in vacuo and the residue is again evaporated with ethanol (3 x 50 ml). The residue is dissolved in a hot mixture of ethanol (50 ml) and water (1 ml) and an aqueous solution of creatinine and 2M sulfuric acid (1/1, 0.4 ml) is added. Filtration of the cooled mixture gives the title compound (0.26 g) as an off-white solid. Mp 204-208 ° C.

Analyze pova C13Hj7N30- 1,2C4H7N30- 1,1H2S04-H20:

Calculated: C43.4 H 6.1 N 19.8%

Found: C43.8 H 6.1 N 19.3%

Example 20:

N - {[3- (3-aminopropyl) -1H-indol-5-ylJmethyljformamide, compound with creatinine, sulfuric acid and water (1/1/1/2)

i) 2- {3- [5- (aminomethyl) -1H-indol-3-yl] propyl} -1H-iso-indol-1,3

(2H) -dione, sulfate

A suspension of 3- [3- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) pro-pyl] -1H-indol is stirred under a hydrogen atmosphere for 25 h. -5-carbonitrile (2.0 g) and palladium on carbon catalyst (50% aqueous paste, 0.85 g) in absolute methanol (100 ml) containing sulfuric acid (0.64 ml). The catalyst is filtered off and the filtrate is evaporated in vacuo. The yellow solid obtained is washed with ether (2 x 50 ml), crystallized from water (10 ml) and dried under vacuum to give the title compound as a green solid. pale yellow (1.77 g). Mp 176-178 ° C (dec.).

ii) N- {[3- [3- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) propylJ-1H-indol-5-ylJmethyljformamide

Following the process described in Example 19i, a solution of 2- {3- [5- (aminomethyl) -1H-indol-3-yl] propyl} -1H-iso-indol-1,3 ( 2H) -dione, sulfate (0.75 g) with formic-acetic anhydride (15 ml) in pyridine (27.5 ml) to give the title compound as a yellow solid (0, 49g). Mp 150-152 ° C after crystallization from ethyl acetate.

iii) N - {[3- (3-aminopropyl) -1H-indol-5-ylJmethyljformamide, compound with creatinine, sulfuric acid and water (1/1/1/2)

A solution of N - {[3- [3- (1,3-dihydro-1,3,3-dioxo-2H-iso-indol-2-yl) propyl] -lH- is stirred at ambient temperature for 2 V 2 h. indol-5yl] methyl} formamide (0.2 g) in ethanolic methylamine (33%, 5 ml), then evaporated to dryness under vacuum below 5 ° C. The off-white solid obtained is dissolved in cold ethanol (25 ml), filter, dilute with hot ethanol (25 ml) and water (10 ml) before treating with an aqueous solution of creatinine and 2M sulfuric acid (1 / 1.25 ml) to give, after recrystallization from aqueous acetone, the title compound in the form of an off-white solid (0.11 g). Mp 175-178 ° C.

Analysis for C13H17N30 ■ C4H7N30 ■ H2S04 • 2H20:

Calculated: C42.7 H 6.3 N 17.6%

Found: C 42.45 H 6.8 N 17.6%

5

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15

20

25

30

35

40

45

50

55

60

65

652,394

Example 21:

N - {[3- (2-aminoethyl) -1H-indol-5-ylJmethyljacetamide i) N - [(4-hydrazinophenyl) methylJacetamide hydrochloride

A solution of sodium nitrite (0.2 g) in water (2 ml) is added during 'A h to a stirred suspension of N - [(4-aminophenyl) methyl] acetamide hydrochloride (0.5 g) in water (1.5 ml) and concentrated hydrochloric acid (2 ml), keeping the temperature below 0 ° C. The solution is stirred while cooling with ice for 40 min then l Add, for 3 min, to an ice-cold, stirred solution, sodium acetate (2.3 g) and sodium sulfite (1.3 g) in water (14 ml). After 1 h, the ice bath is removed and the mixture is left to stand at room temperature overnight.

The mixture is acidified with concentrated hydrochloric acid and then heated to 85 ° C for 15 min. The solvent is evaporated in vacuo and the residue is again evaporated with ethanol (2 x 20 ml). The residue is extracted with ethanol (2 x 25 ml) and the filtered extracts are evaporated in vacuo to give a brown gum, which crystallizes when ethanol (about 3 ml) is added. Filtration gives a creamy crystalline solid (0.21 g), mp 205-210 ° C, which is recrystallized from ethanol to give the title compound as a beige crystalline solid (0 , 1 g). Mp 212-214 ° C.

ii) N- {[3- (2-aminoethylj-1H-indol-5-ylJmethylJacetamide

A solution of N - [(4-hydrazinophenyl) methyl] acetamide hydrochloride (0.05 g), 4-chlorobutanal-diethylacetal (0.05 ml) and sodium acetate (0, 02 g) in a mixture of methanol (1.5 ml), acetic acid (0.3 ml) and water (10 drops).

TLC on silica, ethyl acetate / 2-propanol / water / ammonia at 0.88 (25/15/8/2) shows that the title compound is the main basic product, Rf. 0.3.

Example 22:

N - {[3- [2- (methylamino) ethylJ-1H-indol-5-ylJ-methylJacetamide i) 5- hydrochloride (aminomethyl) -N-methyl-N- (phenylmethyl) -1H-indole-3-ethan -

amine

A solution of 3- {2- [methyl (phenylmethyl) amino] -ethyl} -1H-indole-5-carbonitrile (1.3 g) in dry tetrahydrofuran (100 ml) is treated with nitrogen hydride. lithium aluminum (1.0 g) and heated to reflux for 3 h. The excess lithium aluminum hydride is destroyed with wet tetrahydrofuran, the reaction mixture is diluted with ethyl acetate (200 ml), filtered and the filtrate is evaporated to dryness to give a pale yellow oil which slowly crystallizes to give the title compound as a creamy solid (1.2 g). Mp 84-85 ° C.

ii) N- {[3- [2- [methyl (phenylmethyl) amino JethylJ-1H-indol-5-ylJ-methyljacêtamidc, compound with creatinine, sulfuric acid and water (2/212/3)

A solution, cooled with ice, of 5- (aminomethyl) -N-methyl-N- (phenylmethyl) -1H-indole-3-ethanamine (1.3 g) in pyridine is treated dropwise. 5 ml) with acetic anhydride (0.9 ml) for 10 min. The solution is stirred at room temperature for 1 h and then evaporated to dryness to give a brown oil which is purified on a column of silica (silica gel 60, 50 g), which is eluted with ethyl acetate / methanol (5/1) to give the free base of the title compound as a pale brown oil (1.0 g). A sample of this oil (100 mg) is dissolved in a hot mixture of ethanol (8 ml) and water (1 ml) and treated with an aqueous solution of creatinine and 2M sulfuric acid (1/1, 0.15 ml). By cooling and scraping the title compound is deposited in the form of an off-white gummy solid. Mp 160-165 ° C (which begins to foam around 120 ° C).

iii) N- {[3- [2- (methylamino) ethylJ-1H-indol-5-ylJ-methyljacetamide hydrochloride

A solution of N - {[3- [2- [methyl (phenylmethyl) -amino] ethyl] -lH-indol-5-yl] methyl} acetamide (0.9 g) is hydrogenated in absolute ethanol (100 ml ) on palladium on charcoal (10%, 50% aqueous paste, 0.2 g) at ambient temperature and pressure until the absorption of hydrogen stops (4 h, 70 ml). The catalyst is filtered off, washed with ethanol and the filtrate is evaporated to a small volume and treated with ethereal hydrochloric acid and then with ether to deposit the title compound in the form of a white crystalline solid (0.24 g). Mp 240-242 ° C (darkens at 220 ° C) after recrystallization from ethanol.

Analysis for Cj 4H] 9N30 • HCl:

Calculated: C 59.7 H 7.15 N 14.9%

Found: C 59.6 H 7.1 N 14.75%

Example 23:

N- {[3- [2- (cy clopenty lamino) ethylJ-1H-indol-5-ylJmethyljformamide, compound with creatinine, sulfuric acid and water (4/6/5/6)

A solution of N - {[3- (2-aminoethyl) -1H-indol-5-yl] methyl} formamide (0.3 g) and cyclopentanone (1 ml) is hydrogenated in absolute ethanol (40 ml) at ambient temperature and pressure on 10% palladium oxide on carbon (50% aqueous paste; pre-stirred; 0.3 g) until absorption of hydrogen ceases.

The catalyst is filtered off, washed with ethanol (20 ml) and the filtrate is evaporated in vacuo. The residual pale yellow oil is divided between ethyl acetate (20 ml) and 2N hydrochloric acid (1 x 20 ml; 2 x 10 ml). The aqueous layer is made basic with solid sodium carbonate, saturated with sodium chloride and extracted with ethyl acetate (1 x 10 ml; 8 x 10 ml). The combined organic extracts are dried (Na2SO4) and evaporated to dryness.

The residual white gum (0.22 g) is dissolved in a hot mixture of acetone (15 ml) and water (2 ml) and an aqueous solution of creatinine and 2M sulfuric acid (1/1) is added. , 0.35 ml). After cooling and scraping the title compound crystallizes in the form of a pale yellow solid (0.25 g). Mp 196-198 ° C (shrinks to 40 190 ° C).

Analysis for C17H23N30 • 1.5C4H7N30 • 1.25H2S04 • 1.5H20: Calculated: C45.7 H 6.5 N 17.4%

Found: C45.4 H 6.7 N 17.2%

45

Example 24:

2-methylpropyl- [3- (2-aminoethyl) -lH-indol-5-ylJ-carbamate hydrochloride

50 i) 2-methylpropyl- [3- (cyanomethyl-1H-indol-5-yl] -carbamate, 'A hydrated

Isobutyl chloroformate (1.5 ml) is poured dropwise into a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry DMF (20 ml). After 10 min, the solution 55 is diluted with water (150 ml) and the mixture is stirred for 30 min. The solution obtained is extracted with ethyl acetate (2 x 100 ml) and the combined extracts are washed with brine (10%, 100 ml), water (100 ml), dried ( Na2SO4) and evaporated in vacuo to give the crude product as a brown oil. This is purified by column chromatography (silica gel 60.100 g) using ether as the eluent, to give the title compound as a colorless gum (1.08 g) which darkens to become a brown eraser when kept. This product cannot be crystallized from the usual organic solvents.

65

Analysis for Q sHj 7N302 • 0.25H20:

Calculated: C 65.3 H 6.4 N 15.2%

Found: C65.8 H 6.4 N 14.7%

16

5

10

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17

652,394

ii) 2-methylpropyl- [3- (2-aminoethyl j -lH-indol-5-vlJcarbamate) hydrochloride

A solution of 2-methylpropyl- [3- (cyanomethyl) -1 H-indol-5-yl] carbamate,% hydrate (0.5 g) is hydrogenated in absolute ethanol (30 ml) containing hydrochloric acid concentrate (8 drops) at ambient temperature and pressure on palladium on carbon (10%, 1 g) for 24 h before replacing the catalyst (10%, 0.5 g). After an additional 4 h when the absorption of hydrogen has ceased (90 ml), the catalyst is filtered off, washed with absolute ethanol, and the filtrate is evaporated in vacuo, which gives a pink solid. The crude hydrochloride is crystallized from a mixture of methanol and ethyl acetate, to give the title compound as a white solid (0.15 g). Mp 258-260 ° C.

Analysis for ClsH2iN302 • HCl:

Calculated: C 57.8 H 7.1 N 13.5%

Found: C 57.7 H 7.0 N 13.1%

Example 25:

N- {[3-f2- (phenylmethylidenamino) ethyl] -1H-indol-5-ylJmethylj-formamide, compound with toluene and water f 6/2/3)

A solution of N - {[3- (2-amino-ethyl) -1H-indol-5-yl] methyl} formamide (0.3 g) in absolute ethanol (1 ml) is poured dropwise into a stirred solution of benzaldehyde (0.15 g) in dry toluene (15 ml). The mixture is stirred for 5 min and then evaporated to dryness under reduced pressure. Toluene (15 ml) is added and the mixture is evaporated again to give the title compound as a dark brown oil (0.35 g).

Analysis for C19H19N30- '/ ï ^ Hg ■ 1 / 2H20:

Calculated: C 74.2 H 6.6 N 12.2%

Found: C 73.9 H 6.5 N 12.0%

-u (DMSO) 1.7 (1H, S) N = CHPh.

Example 26:

N- [3- (2-aminoethyl) -1H-indol-5-ylJ-N ', N'-dimethyl sulfamide i) N- [3- (cyanomethyl-H-indol-5-ylJ-N) maleate ', N'-dimethylsuljamide Dimethylsulfamoyl chloride is added dropwise

(1.2 ml) in a stirred solution of 5-amino-1H-indole-3-aceto-nitrile (1.7 g) in dry dimethylformamide (50 ml) containing triethylamine (2.8 ml). After 3 h, the suspension obtained is diluted with water (20 ml) and stirred for 30 min. The solution obtained is poured into water (100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic extracts are washed with water (100 ml) and brine (2 x 100 ml), dried (Na2SO4) and evaporated in vacuo to give a dark brown oil which is purified by chromatography on a column (silica gel 60, 100 g), eluting with ether / ethyl acetate (9/1) to give the title compound in the form of a white solid (0.75 g). Pf. 147-150 C.

ii) N- [3- (2-aminoethyl) -1H-indol-5-yl] -N ', N'-dimethyl sulfamide maleate

A solution of N- [3- (cyanomethyl) -1H-indol-5-yl] -N ', N'-dimethylsulfamide (0.3 g) is hydrogenated in absolute ethanol (50 ml) containing acid. concentrated hydrochloric acid (6 drops) at room temperature and pressure on palladium on charcoal (at 10%, 0.2 g) for 24 h before replacing the catalyst (at 10%, 0.5 g). After an additional 4 h, when the absorption of hydrogen has ceased (60 ml), the catalyst is removed by filtration, washed with ethanol, and the filtrate is evaporated in vacuo to give a brown oil. The oil is then distributed between ethyl acetate (2 x 20 ml) and 2N sodium carbonate (10 ml), the combined organic extracts are dried (Na2SO4) and evaporated in vacuo to give a tawny foam . The foam is dissolved in a solution of maleic acid (0.16 g) in methanol (4 ml) and the maleate is precipitated by addition of ethyl acetate (100 ml) and ether (150 ml). The salt is crystallized from a mixture of methanol and ethyl acetate to give the title compound (0.06 g) as a tawny solid. Mp 138-142 ° C.

Analysis for C12H18N402S -04 ^ 04:

Calculated: C 48.2 H 5.6 N14, l%

Found: C48.3 H 5.5 N 13.8%

Example 27:

N - {[3- (2-aminoethyl) -1H-indol-5-ylJmethyl} -N ', N'-dimethylsulf-amide, compound with creatinine, sulfuric acid and water (1/1/1 / 1)

i) N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethylJ-1H-indol-5-ylJmethyl} -N ', N' -dimethylsulfamide hemihydrate

A suspension, cooled with ice, of 2- {2- [5- (aminomethyl) -1H-indol-3-yl] ethyl} -1H-iso-indol-1,3 (2H) is treated dropwise ) -dione, hemisulfate, hydrated (2.0 g) in pyridine (40 ml) with dimethylsulfamoyl chloride (0.75 g) for 5 min. The solution is then allowed to warm to room temperature. After 16 h the orange solution is poured into water (100 ml) and extracted with ethyl acetate (3 x 70 ml). The combined organic extracts are washed with saturated copper sulfate (7 x 50 ml), 2N sodium carbonate (2 x 40 ml), dried and concentrated in vacuo to give an orange oil (1.3 g). Column chromatography (silica gel 60, 50 g) with chloroform as eluent gives the title compound (0.62 g) as a pale yellow solid. Mp 174-176 ° C.

ii) N- {[3- (2-aminoethyl) -1H-indol-5-ylJmethyl} -N ', N'-dimethyl-sulfonamide, compound with creatinine, sulfuric acid and water

(l / l / lID

A solution of N - {[3- [2- (1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl) ethyl] -1 H-indol- is heated at reflux for 2 h. 5-yl] methyl} -N ', N'-dimethylsulfamide, hemihydrate (0.45 g) and hydrated hydrazine (0.2 ml) in ethanol (20 ml). The filtrate is concentrated in vacuo to give a creamy solid which is divided between ethyl acetate (30 ml) and 2N sodium carbonate (25 ml) and the aqueous phase is reextracted with acetate. ethyl (1 x 25 ml; 2 x 15 ml). The combined organic extracts are washed with water (3 x 25 ml), dried and concentrated in vacuo to give the amine in the form of a pale yellow oil which gives, after formation of creatinine sulfate, the title compound (0.3 g) as a white crystalline solid. Mp 220-222 ° C.

Analysis for C13H20N4O2S • C4H7N03 • H2S04 • H20:

Calculated: C 38.9 H 6.0 N 18.7%

Found: C38.9 H 5.8 N 18.4%

Pharmaceutical examples Tablets:

They can be prepared by direct compression or wet granulation. The direct compression method is preferred but it may not be suitable for all cases since it depends on the dose and the physical characteristics of the active ingredient.

A. Direct compression mg / tablet

Active ingredient 10.0

Microcrystalline cellulose (British pharmacopoeia) 89.5

Magnesium stearate 0.5

100.0

The active ingredient is sieved through a 250 µm sieve, mixed with the excipients and compressed using 6.0 mm punches. Tablets of different strengths can be made by changing the compression weight and using suitable punches.

5

10

15

20

25

30

35

40

45

50

55

60

65

652,394

18

B. Wet granulation

Active ingredient Lactose (P.B.)

Starch (P.B.)

Pregelatinized corn starch (P.B.) Magnesium stearate (P.B.)

Compression weight mg / tablet 10.0 74.5 10.0 5 5.0 0.5 100.0

The active ingredient is sieved through a 250 µm sieve and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, granules are made, dried, sieved and mixed with magnesium stearate. The lubricated granules are compressed to give tablets as is said for the direct compression formulas.

The tablets may be coated with a film with materials suitable for film formation, for example methyl cellulose or hydroxypropyl methylcellulose using conventional techniques. Sugar tablets can also be coated.

mg / capsule 10.0 89.5 0.5 100.0

Capsules:

Active ingredient

* Starch 1500 Magnesium stearate (P.B.)

Weight when filled

* Form of directly compressible starch supplied by Coloron Ltd, Orpington, Kent (Great Britain).

The active ingredient is sieved through a 250 µm sieve and mixed with the other materials. The mixture is poured into No. 2 hard gelatin capsules using an appropriate filling machine. 'other doses by changing the weight when filled and if necessary by appropriately changing the size of the capsules.

Syrup: 35

mg / 5 ml dose 10.0 2750.0 500.0

Active ingredient Sucrose (P.B.) Glycerin (P.B.) Buffer

Dye flavoring agent

Preservative Distilled water q.s.

Suppositories:

Active ingredient 10.0 mg

* Witepsol H15 q.s.p. 1.0 g

* Adeps Solidus ph. Eur., Quality registered.

A suspension of the active ingredient in the material Witepsol H15 is prepared and poured using a suitable machine into suppository molds with a size of 1 g.

Injection for intravenous administration:

% w / v

Active ingredient 0.20

Injectable water (P.B.) q.s.p. 100.00

Sodium chloride can be added to adjust the effective osmotic pressure of the solution and the pH can be adjusted to that of maximum stability and / or to facilitate dissolution of the active ingredient using or diluted acid or alkali adding appropriate buffer salts.

The solution is prepared, clarified and poured into suitable size molds, sealed by melting the glass. The injection is sterilized by heating it in an autoclave using one of the acceptable cycles. The solution can also be sterilized by filtration and poured into sterile ampoules under aseptic conditions. The solution can be conditioned under an inert nitrogen atmosphere.

25 Inhalation cartridges:

5.0

The active ingredient, the buffer, the flavoring agent, the colorant and the preservative are dissolved in part of the water, and the glycerin is added. The rest of the water is heated to 80 ° C and the sucrose is dissolved and cooled. The two solutions are combined, adjusted to the necessary volume and mixed. The syrup obtained is clarified by filtration.

mg / cartridge

Active ingredient micronized 1.00

Lactose (P.B.) 39.0

The active ingredient is micronized in a micronizer to achieve a small particle size before mixing with normal grade lactose for tablets in a high energy blender. The powder mixture is distributed in No. 3 hard gelatin capsules on a suitable encapsulator. The contents of the cartridges are administered using a powder inhaler (for example a Rotahalar Glaxo).

Aerosol under pressure at quantified doses mg / quantified dose 0.500 0.050 22.25 60.90

per tube 120 mg 12 mg 5.34 g 14.62 g

45

Active ingredient micronized Oleic acid (P.B.)

Trichlorofluoromethane (P.B.)

Dichlorodifluoromethane (P.B.)

The active ingredient is micronized in a micronizer to have a small particle size range. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and the micronized drug is mixed in this solution with a mixer with high cutting power. The suspension is distributed quantitatively in aluminum aerosol tubes and appropriate dosing valves, providing a quantified dose of 85 mg of suspension are crimped onto the tubes and dichlorodifluoromethane is introduced by pressure into the tubes through the valves.

r

Claims (14)

652,394 1. Compound of general formula (I): A1cKR4R5 ^ Rj represents a CHO group, CORs CSNRgR10 OR SO2NR9R] 0, WHERE COtRrj CONRnR, Ra represents alkyl substituted or not substituted by 1 to 3 halogen, cycloalkyl, aryl or aralkyl atoms, R „represents a hydrogen atom or an alkyl group, and R, o represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group; R2, R3, R4, R6 and R7, which may be the same or different, each represents a hydrogen atom or a C1-C3 alkyl group; Rs represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or aralkyl group or R4 and R5 together form an aralkylidene group, or R4 and R5 together with the nitrogen atom to which they are attached form a 5- to 7-membered saturated monocyclic ring; n is 0 or 1, and Aie represents an alkylene chain containing 2 or 3 carbon atoms which may be unsubstituted or substituted by at most two C 1 -C 3 alkyl groups; with the clarification that, when n is 0 and i) R4 and Rs both represent alkyl groups, Ra does not represent the CHO or CORs group, and ii) R, does not represent the SO2NH2 group; their salts and solvates. 2. A compound according to claim 1, wherein Aie represents an unsubstituted alkylene chain containing two carbon atoms. 2 3 652,394 as such or as salts or solvate, or further transformed into another salt or solvate. 3. A compound according to claim 1, wherein R4 and R5, which may be similar or different, each represent a hydrogen atom or a methyl or ethyl group and where R6 and R, each represent a hydrogen atom. 4. A compound according to claim 1, wherein R3 represents a hydrogen atom. 5. A compound according to claim 1, wherein R2 represents a hydrogen atom or a methyl group. 6. Compound according to claim 1, corresponding to the general formula (la): RlaR2aN (C "2) B where R, a represents a CHO, CONH2, COR8 „or C02R8a group, where RSj is an alkyl group containing from 1 to 4 carbon atoms or a trifluoromethyl group; R1 represents a hydrogen atom or a methyl group; n is 0 or 1, and R ^ a and R; „which may be similar or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R4a and R5a together does not exceed two and that when Rla represents a CHO group or a COR8a group when n is 0, then R4a represents a hydrogen atom, their salts and solvates. 7. Compound according to claim 1 corresponding to the general formula (Ib): 'CH2CH2NR4bR5b (Ib) R, b represents a CHO, CONH2 or CO2R8b group where R5b is a methyl, ethyl or isobutyl group; Ra represents a hydrogen atom or a methyl group, and R4b and R5b, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R® and R5b together does not exceed two and that when R, b is the CHO group, Rib represents a hydrogen atom, 15 their salts and solvates. 8. Compound according to claim 1, corresponding to the general formula (le): RlcR2cNC.H2 GH2CH2NR4CR5C (IC) R, c represents a CHO group or a CORSc group where R8c is an alkyl group containing from 1 to 3 carbon atoms; R2c represents a hydrogen atom or a methyl group, and R, c and R5c, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R *. and R5c together does not exceed two, their salts and solvates. 9. Ethyl [3- (2-aminoethyl) -1H-indol-5-yl] carbamate, 2-methylpropyl [3- (2-aminoethyl) -1 H-indol-5-yl) carbamate, and 35 N - {[3- (2-aminoethyl) -1H-indol-5-yl] methyl} acetamide according to claim 1, their salts and solvates. 10. A compound according to claim 1, wherein the salt is a hydrochloride, hydrobromide, sulfate, fumarate or maleate. 11. Process for the preparation of a compound of general formula 40 (I) according to claim 1 or of one of its salts or solvates, characterized in that a compound of general formula (II) is reacted: R2NH (CHR3) CH2CH2NR4aR5a (la) aicnr4R5 (II) 50 R2, R3, R4, R5, R6, R7, n and Aie are as defined for general formula (I), or one of its protected derivatives, with an acid of formula R] OH or a corresponding acylating agent, the protective groups possibly present being removed and the compound being, if desired, isolated as such or as salt or solvate, or further transformed into another salt or solvate. 12. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its salts or solvates, characterized in that a compound of general formula (III) is cyclized: R1R2N (CHR3) ir 1 (ln) NR7N = CRgCH2AlcQ 65 where Q is the group NR4R5 or one of its protected derivatives or an leaving group and Rj, R2, R3, R4, R5, R6, R7, Aie and n are as defined for the general formula (I), the protecting groups possibly present being removed and the compound being, if desired, isolated 13. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its salts or solvates, characterized in that a compound of general formula (VI) is reacted: R1R2N (CHR3) ■ "tOcï Have there (VI) 17. Medicament, in particular useful in the treatment of migraine, consisting of the compounds of general formula (I) according to claim 1, or of a salt or solvate thereof. 18. Pharmaceutical composition, in particular useful in the treatment of migraine, characterized in that it contains, as active substance in meös, a compound of general formula (I) as defined in claim 1 or one of its salts or solvates. where Rj, R2, R3, R4, R5i R6, R7, Aie and n are as defined for the general formula (I) and where Y is an easily detachable group, or one of its protected derivatives, with a compound of formula R4RSNH , where R4 and R5 are as defined for general formula (I), the protective groups possibly present being removed and the compound being, if desired, isolated as such or as salt or solvate, or else transformed into another salt or solvate. 14. Process for the preparation of a compound of general formula (I) according to claim 1 or of one of its salts or solvates, characterized in that a compound of general formula (VII) is reduced: ^ ^ R1R2N (CHR3) v