LU85915A1 - Indole new 3-aminoalkyl-5-aminosulphonyl-alkyl indole derivs. - useful for treating migraine, and new intermediates - Google Patents

Abstract

Indole derivs. of formula (I), their pharmaceutically acceptable salts and solvates are new. R1=H, 1-6C alkyl or 3-6C alkenyl; R2=H, 1-3C alkyl, 3-6C alkenyl, Ph, phenyl (1-4C) alkyl or 5-7C cycloalkyl; R3 and R4=H, 1-3C alkyl or 2-propenyl, or together they are an aralkylidene gp. Alk=2-3C alkylene opt. substd. by 1 or 2 1-3C alkyl; A=2-5C alkylene, opt. substd. by 1 or 2 1-3C alkyl. Also new are intermediates (III) and salts and (IX) (X= leaving gp.).

Description

AT

4 The invention relates to new indole derivatives useful as medicaments and intermediates and methods for their preparation. The invention relates in particular to - compounds and pharmaceutical compositions useful in the treatment of migraine.

It is known that migraine pain is mainly of vascular origin and that it is caused by excessive dilation of the cranial vascular system. Known migraine treatments include the administration of compounds with vasoconstrictive properties such as ergotamine. However, ergotamine is a non-selective vasoconstrictor which contracts blood vessels throughout the body and has undesirable side effects which can be dangerous.

Migraine can also be treated by the administration of an analgesic generally in combination with an antiemetic, but these treatments are of limited value.

There is therefore a search for an effective and safe medicament for the treatment of migraine which can be used either prophylactically or to relieve established headaches, and a compound having selective vasoconstrictor activity fulfilling this role.

The Applicant has discovered a group of indole derivatives having a potent and selective vasoconstrictor activity.

The invention provides indoles corresponding to the general formula (I): "30 AlkNR-, R, R.R? Nso a / 34 nA" J H 35 in which /. · J -'- "" N.

Y] -f - (I)

• -V

2 R ^ represents a hydrogen atom or a C1_6 alkyl or C ^ _6 alkenyl radical; R2 represents a hydrogen atom or a C3_3 alkyl, C3_g alkenyl, phenyl, phenyl-alkyl or cycloalkyl radical; R ^ and R ^, which may be similar or different, represent a hydrogen atom or an alkyl radical in 2 or propenyl or R ^ and R ^ together form an aralkylidene radical; Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two C1-3 alkyl radicals; and ü A represents an alkylene chain containing two to five carbon atoms which may be unsubstituted or substituted by no more than two alkyl radicals en and their physiologically acceptable salts and solvates (eg their hydrates).

The invention covers all optical isomers of the compounds of general formula (I) and their mixtures, including their racemic mixtures.

According to general formula (I), the alkyl radicals of this formula may be straight or branched chain alkyl radicals containing 1 to 3 carbon atoms, or, in the case of R 1, 1 to 6 and preferably 1 to 3 carbon atoms. Examples of alkyl radicals include methyl, ethyl, propyl, and isopropyl. The alkenyl radicals preferably contain 3 or 4 carbon atoms and examples of these are the propenyl and butenyl radicals. It should be noted that when R. or R0 is an alkenyl radical, the -TV 1 double bond must be separated from the nitrogen atom by at least one methylene radical. Cycloalkyl radicals preferably contain 5 or 6 carbon atoms and examples are the cyclopentyl and / 7 cyclohexyl radicals. The alkyl fragments of the phenyl-alkyl radicals preferably contain 1 or 2 carbon atoms as is the case, for example, of the benzyl and phenethyl radicals. The aralkylidene radical is preferably an arylmethylidene radical such as benzylidene.

In the compounds of general formula (I), it is preferred that at least one of R 1 and R 2 represents a hydrogen.

A is preferably an unsubstituted alkylene chain containing 2 to 5 carbon atoms, in particular "2 or 3 carbon atoms. Alk is preferably an unsubstituted alkylene chain, in particular an unsubstituted alkylene chain containing 2 atoms of ç, carbon.

A preferred category of the compounds represented by the general formula (I) is that in which represents a hydrogen atom or an alkyl radical in and R 1 represents a hydrogen atom or an alkyl radical in or phenyl-alkyl in 20 Another preferred category of the compounds represented by the general formula (I) is that in which A represents the radical

Another preferred category of compounds is that in which, in the general formula (I) R ^ and R ^ which may be similar or different, each represents a hydrogen atom or an alkyl radical in

Cl-3 '

A preferred category of the compounds covered by the general formula (I) is that represented by the general formula (la):

* RlaR2aNS02 (CH2> n. (CH.,) NR R

z 2 \ ^ / (Ia) T j

35 H

/ 1 - 4 * in which * Rla represents a hydrogen atom or an alkyl radical; R2a represents a hydrogen atom or an alkyl radical or phenyl-alkyl C1-2; R ^ a and R ^ a which may be similar or different, each represent a hydrogen atom or a methyl or ethyl radical; and n represents 2 or 3, 10 and their physiologically acceptable salts and ------ their solvates (for example their hydrates).

A particularly preferred category of the compounds according to the invention is that represented by the general formula (Ib):

RlbHHS02 (CH2) 2 ^^ <CI! 2> 2 ™ 3b * 4b TYl

H

In which represents a hydrogen atom or a radical, alkyl; and R ^ and which may be similar or different, each represents a hydrogen atom or a methyl or ethyl radical; And their physiologically acceptable salts and their solvates (for example their hydrates).

In the compounds of formula (Ib), it is preferred that the total number of carbon atoms in and R ^ "30 does not exceed 2 and better than R ^ and R ^ j_ each represent a methyl radical.

* Preferred compounds according to the invention include: 3- [2- (ethylamino) ethyl] -N-methyl] -1H-indole-5-ethanesulfonamide.

/ 9? 5 N N-methyl-3- 2- (methylamino) ethyl -lH-indole-5-ethanesulfonamide; 3- (2-aminoethyl) -N-methyl-1H-indole-5-ethane-sulfonamide; 3- 2- (dimethylamino-ethyl-1H-indole-5-ethane-sulfonamide; 3- 2- (dimethylamino) ethyl -N-methyl-1H-indole-5-ethanesulfonamide; and physiologically acceptable salts and the solvates (e.g. hydrates) of these compounds.

Suitable physiologically acceptable salts of the indoles of general formula (I) include the acid addition salts-1 formed with organic or mineral acids, for example hydrochlorides, hydrobromides, sulfates, fumarates, maleates and succinates. Other salts may be useful in the preparation of the compounds of general formula (I), for example the adducts of creatininesulfate type and oxalates.

It should be noted that the invention covers the other physiologically acceptable equivalents of the compounds according to the invention, that is to say the physiologically acceptable compounds which are transformed in vivo into the parent compound. Examples of such equivalents include physiologically acceptable derivatives having a labile N-acyl radical, such as an N-acetyl derivative.

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

The compounds of the invention are useful in the treatment of pain resulting from dilation of the cranial vascular system, in particular migraine fj

/-""NOT

i.

6 "" and Horton's vascular headache.

In particular, the compounds of formula (Ib) previously defined, have proved to be very selective vasoconstrictors and extremely powerful action.

The compounds of general formula (Ib) are rapidly absorbed from the gastrointestinal tract and are suitable for oral or rectal administration. The compounds of formula (Ib) do not exhibit toxic or undesirable effects in rats at doses up to 6 mg / kg.

At the doses at which the compounds of formula (I) are effective in the treatment of migraine, the compounds have no noticeable effect on blood pressure and heart rate nor any noticeable bronchoconstrictor effect on the lungs.

The invention also provides a pharmaceutical composition suitable for use in medicine which comprises at least one compound of formula (I) or one of its physiologically acceptable salts or solvates (for example a hydrate) and which is presented for 20 administration by any suitable route.

These compositions can be prepared in a conventional manner by using one or more carriers or excipients suitable in pharmacy.

The compounds of the invention may therefore be presented for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Preferred are the compositions of the compounds of the invention suitable for oral administration.

For oral administration, the pharmaceutical compositions can be in the form, for example, of tablets or capsules prepared in the conventional manner with excipients suitable in pharmacy such as binders (for example pregelatinized corn starch, * 35 ^ polyvinylpyrrolidone or hydroxypropylmethyl-!; 7 cellulose); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (eg potato starch, sodium starch glycolate or croscarmellose); or wetting agents (for example sodium lauryl sulfate).

The tablets can be coated according to methods well known in the art. Liquid preparations for oral administration can be in the form, for example, of solutions, syrups or suspensions or can be presented in the form of a dry product to be taken up with water or another suitable vehicle; before use. These liquid preparations can be prepared in a conventional manner with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, cellulose derivatives, for example hydroxypropyl methylcellulose or hydrogenated edible fats); emulsifying agents (for example lecithin or gum arabic); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example methyl or propyl p-hydroxvbenzoates or sorbic acid). Liquid preparations can also contain conventional buffers, flavoring agents, colors and sweeteners as needed.

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

The compounds of the invention can be presented for parenteral administration by injection, for example by injection proper or infusion ----------------- 8 in the form of unit doses, by example in ampoules or multidose containers with addition of a preservative. The compositions can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and can contain preparation agents, such as suspending, stabilizing and / or dispersing agents and / or agents adjusting the tone of the solution. Otherwise the active ingredient may be in the form of a powder to be reconstituted before use with an appropriate vehicle, for example pyrogen-free sterile water.

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

For administration by inhalation, the compounds of the invention are sprayed in the form of an aerosol from pressurized packaging, using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra -fluoroethane, carbon dioxide or another suitable gas, or are administered with a nebulizer. In the case of a pressurized aerosol, the unit dose can be obtained by using a metering valve. Capsules or cartridges, for example of gelatin, intended for use in an inhaler or an insufflator, can be prepared to contain a powder mixture of a compound of the invention and a powder base suitable, such as lactose or starch.

A proposed dosage of the compounds of the invention for oral, parenteral, rectal or buccal administration to humans (for an average body weight of about 70 kg for example) in the treatment of migraine is 0.1 100 mg of active ingredient per unit dose /! 9 can be administered for example one to four times a day. It should be noted that the usual changes in dosage may be necessary depending on the age and weight of the patient as well as the severity of the condition to be treated.

For oral administration, a unit dose preferably contains 2 to 50 mg of active ingredient.

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

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

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

According to another aspect of the invention, it is possible to prepare the compounds of general formula (I) and their j! physiologically acceptable salts and their solvates (eg hydrates) according to the general methods set out below.

1 In the processes which follow, R ^, 1 ^ »R3» R ^, A

! and Alk are as defined by the general formula - (I) 1 unless otherwise indicated.

According to a general process (A), the compounds of general formula CD can be prepared by cyclization of compounds of general formula (XI): h1h2nso2a 5 (II)

NHN = CHCH2AlkQ

In which Q is the radical NR ^ R ^ or a corresponding protected derivative or is a labile group such as a halogen atom (for example chlorine or bromine) or an acyloxy radical which can be derived from a carboxylic acid - or sulfonic, such as an acetoxy, -chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy radical.

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

Particularly practical embodiments of the method are described below.

When Q is the radical NR ^ R ^ (or a protected derivative thereof), the process is desirably carried out in the presence of a polyphosphate ester in a reaction medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. The polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the process described in "Reagents for Organic Synthesis", (Fieser and Fieser, John Wiley and 35 Sons, 1967).

/ v f ,; bed ü r-d t. 9 | .

Otherwise, the cyclization can be carried out in an aqueous or non-aqueous reaction medium in the presence of an acid catalyst. When an aqueous medium is used, it may be an aqueous organic solvent such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (for example dioxane or tetrahydrofuran) as well as mixtures of such solvents, and the acid catalyst can, for example, be a mineral acid, such as concentrated hydrochloric acid or sulfuric acid or an organic acid such as acetic acid. In certain cases, the acid catalyst can also constitute the reaction solvent. In an anhydrous reaction medium which may comprise one or more alcohols or ethers (for example as described above), or esters (for example ethyl acetate), the acid catalyst is generally a Lewis acid, such as boron trifluoride, zinc chloride or magnesium chloride.

When Q is a leaving group, such as a chlorine or bromine atom, the reaction can be carried out in an aqueous organic solvent, such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (eg dioxane or tetrahydrofuran) in the absence of a catalyst consisting of a mineral acid, conveniently at a temperature. rature from 20 to 200 ° C, preferably from 50 to 125 ° C. This | process forms a compound of general formula (I) in | which and ^ 4 are both hydrogen atoms.

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

K

! i? ^ 35 '/ ri 12 r1r2nso2a ^^ / v ^^ ^ ΝΗΝΗ, (III) 5 or a salt (for example the hydrochloride) thereof, with a compound of formula (IV): OHCCH2AlkQ (IV) 10 (in which Q is as previously defined) or d1 a "salt or protected derivative thereof such as an acetal, for example a dialkylacetal or a cyclic acetal, for example formed with a suitable alkyl orthoformate or a diol or protected as a bisulfitic addition complex), using suitable conditions as described above, for the cyclization of a compound of general formula (II). (The Fischer-Indole Synthesis, B. Robinson, p 488 -Wiley 1982) In this embodiment, the compounds of general formula (II) can be formed as intermediates and can either be isolated before cyclization or react in situ to form the compounds desired of general formula (I).

The compounds of general formula (II) can, if desired, be isolated as intermediates by reaction of a compound of formula (III) or a corresponding protected salt or derivative thereof, with a compound of formula ( IV) or a corresponding protected salt or derivative, in a suitable solvent, such as an aqueous alcohol (for example methanol) or an aqueous ether (for example dioxane) at a temperature for example of 20 to 30 ° C.

If an acetal of a compound of formula (IV) is used, it may be necessary to carry out the reaction in the presence of an acid (eg acetic acid or hydrochloric acid).

L ~ 13

The compounds of formula (III) are new and constitute another aspect of the invention. The compounds of general formula (III) can be prepared according to - conventional methods for the preparation of a hydrazine, for example the reduction of the corresponding nitro compound, to form the amino derivative, by catalytic hydrogenation, then the reaction with nitrite of sodium in the presence of a mineral acid (eg hydrochloric acid) to form a diazonium salt which is then reduced, for example with stannous chloride, to the desired hydrazine of formula (III).

Another general process (B) for the preparation of the compounds of general formula (I) comprises the reaction of a compound of general formula (V). : 15

R-.R_NSO.5A AlkY

f Tj (v)

H

20 (in which Y is an easy-to-move group) or a corresponding protected derivative, with a compound of formula R ^ R ^ NH.

This displacement reaction can be conveniently carried out on the compounds of general formula (V) in which the substituent group Y is a halogen atom (for example chlorine, bromine or iodine); an OR 4 radical which is, for example, an acyloxy radical (which may be derived from a carboxylic or sulphonic acid) such as an acetoxy, chloroacetoxy, dichloro-acetoxy, trifluoroacetoxy or p-nitrobenzyloxy, p-toluenesulfonyloxy or methanesulfonyloxy radical; or a radical N + R'R "R" 'E, where R', R "and R" 'may be the same or different and each represents a radical / alkyl in and E represents an anion such as an ion / 7 | 14 * halide, for example a chloride, bromide or iodide ion;

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

The compounds of formula (V) where Y is an atom. halogen, can be prepared by reacting a hydrazine of formula (III) with an aldehyde (or a corresponding protected derivative) of formula (IV) where Q is a halogen atom, in an aqueous alcohol (for example 20 methanol) or an aqueous ether (for example dioxane) containing an acid (for example acetic or hydrochloric acid) - or by reaction of a compound of general formula (V) where Y is a hydroxy radical, with the trihalide appropriate phosphorus or with N-bromo-succinimide or triphenylphosphine in tetrahydro-furan. The intermediate alcohol, in which Y is a hydroxy radical, can also be used to prepare the compounds of formula IV) where Y is an OR5 radical, by acylation with the appropriate activated species (for example an anhydride or the chloride of sulfonyl) using conventional techniques. The intermediate alcohol can be prepared by cyclization of a compound of formula (II) in which Q is a hydroxy radical (or a corresponding protected derivative) under conditions

OC

standards.

/ 15

The compounds of formula (V) where Y represents an N + R'R "R" 'E radical can be prepared from the corresponding tertiary amine by reaction with an "alkylating agent, for example as described in 5 general process (E) below.

The compounds of general formula (I) can also be prepared according to another general process (C) comprising the reduction of a compound of general formula (VI): r1r2nso2a1 w J! (VI) N /

H

Where W is a radical which can be reduced to form the desired radical AlkN R ^ R ^ or to form a protected derivative of the radical AlkNR ^ R ^, and A "^ represents the radical A previously defined or a radical which can be reduced for form the radical A, or a corresponding protected salt or derivative.

The radicals A ^ which can be reduced to form the radical A required include the corresponding unsaturated radicals, such as C2-alkenyl radicals.

The necessary radicals Alk and NR ^ R ^ can be formed according to reduction stages carried out separately or simultaneously in any suitable manner.

The radicals which can be reduced to the radical Alk include the corresponding unsaturated radicals and the corresponding radicals containing one or more hydroxy radicals or carbonyl functions.

The radicals which can be reduced to the radical NR ^ R ^ include the nitro, azido, hydroxyimino, nitrile and amide radicals.

L

16

Examples of the radicals represented by the substituent radical W therefore include TNC> 2 (where T is an Alk radical or an alkenyl radical corresponding to the Alk radical); AlkN ^; AlkNR ^ COR ^; -COCONR3R4; 5 (CHR5) xCHRgCN; CHRgCOZ; (CHR5> xCRg = NOH; CH (OH) CHRgNR ^; COCHRgZ (where R ^ and Rg, which may be similar or different, each represents a hydrogen atom, or a C ^ _3 alkyl radical, Z is an azido radical or the radical NR- ^ R ^ or a corresponding protected derivative, 10 x is zero or 1 and R'4 is a hydrogen atom or a radical such as -CH2R'4 is the radical R'4, or R'4 is the OR radical where R is an alkyl or aralkyl radical).

Radicals that can be reduced to form the. radical NR ^ R ^ where R ^ and R4 are both. hydrogen includes the nitro, azido, hydroxyimino and nitrile radicals. The reduction of a nitrile radical produces the CH2NH2 radical and therefore provides a methylene radical of the Alk group.

A compound of general formula (I) where R4 is a hydrogen atom can also be prepared by reduction of a corresponding compound of general formula (I) where R4 is a benzyl radical, for example with- hydrogen in the presence of a catalyst, for example 10% palladium-on-carbon.

The required NR3R4 radical where R3 and / or R4 are other than hydrogen can be prepared by reduction of a nitrile (CHR5) xCHRgCN or an aldehyde (CHRg) xCHRgCH0 (where Rj-, Rg and x are as previously defined) in the presence of an amine R- ^ R ^ NH.

A particularly suitable process for preparing a compound of formula (I- where R, and / or R are other than hydrogen, is the reduction alkylation of the corresponding compound where R ^ and / or R ^ represent a hydrogen, with a suitable aldehyde or ketone (e.g. formaldehyde or acetone) in the presence

U

17 of an appropriate reducing agent. In certain cases (for example to introduce the radical R ^ when it represents a methyl), the aldehyde (for example formaldehyde) can be condensed with the primary amine and the intermediate thus formed can then be reduced with an appropriate reducing agent.

The radical NR ^ R ^ required where R ^ and / or R ^ are other than hydrogen, can also be prepared by reduction of a corresponding amide, for example AlkNR ^ COR '^ 10 (where R' £ is as above defined).

The reduction can be carried out according to conventional methods, for example by catalytic hydrogenation or by the use of a reducing agent, such as an alkali metal or alkaline earth metal borohydride or cyanoborohydride or a metal hydride. The reduction can conveniently be carried out in an organic reaction medium which may include one or more solvents.

Suitable solvents include alcohols, for example ethanol or propanol; cyclic ethers, for example dioxane or tetrahydrofuran; acyclic ether, for example diethyl ether; amides, for example dimethylformamide; and esters, for example ethyl acetate, and nitriles for example acetonitrile.

It should be noted that the choice of reducing agent and of the reaction conditions depends on the nature of the radicals W and A "* ·.

Suitable reducing agents which can be used in the above process for the reduction of the compounds of formula (VI) where W represents for example the radicals TNO2, AlkN3, (CHR ^ CHRgCN, (CHR5) xCR6 = NOH, CH (OH) CHRgNR ^ R ^ (where T, R ^ and Rg and x are as previously defined) comprise hydrogen in the presence of a metal catalyst, for example Raney nickel, or a noble metal catalyst, such as that platinum, / 18 platinum oxide, palladium or rhodium, which can for example be attached to a support consisting of carbon, Kieselguhr or alumina. In the case of Raney nickel, hydrazine can also be used as a source of hydrogen. This process can conveniently be carried out in a solvent, such as an alcohol, for example ethanol; an ether, for example dioxane or tetrahydrofuran; an amide, for example dimethylformamide; or an ester, for example ethyl acetate, at a temperature of -10 to + 50 ° C, preferably of -5 to + 30 ° C7 '-'

The reduction process can also be carried out on compounds of general formula (VI) where W represents for example the groups TNCC »CH (OH) CHRgNR ^ R ^ or COCHRg 15 (where T, Rg and Z are as previously defined) by the use of an alkali metal or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, this process being able to be practically carried out in an alcohol, such as propanol or l ethanol, or a nitrile, such as acetonitrile, and at a temperature of 10 to 100 ° C, preferably 50 to 100 ° C. In some cases, reduction using a borohydride can be carried out in the presence of cobaltous chloride.

The reduction of the compounds of general formula (VI) where W represents for example the radicals TK02, AlkN ^, AlkNR3COR ^, CHRgCOZ, (CHR5) xCRg = NOH, CH (OH) CHRgNR ^, -COCONR-jR ^ and COCHRgZ ( where R, R'4 / R5 / Rg / Z and x are as previously defined) can also be carried out by using diborane or a metal hydride such as lithium hydride and aluminum. This process . can be carried out in a solvent, for example an ether such as tetrahydrofuran and conveniently at a temperature of -10 to + 100 ° C, preferably from 50 to 100 ° C. 35 A particular embodiment of the method

V

19 a general (C) comprises the reduction of a compound of general formula (VI) where W is the radical CHR ^ CN, for example by catalytic reduction with hydrogen in the presence of a catalyst, such as palladium on carbon , 5 or rhodium-containing alumina, optionally in the presence of an amine HNR ^ R ^ or, to produce a compound where R ^ and R ^ are both hydrogen, by the use of aluminum hydride and lithium in l absence of an amine.

Suitable reducing agents which can be used in the reduction of the radical A1 include Ir'-hydrogen in the presence of a metal catalyst. The suitable metal catalysts and the process conditions are as described for the reduction of the radical W - The starting materials or the intermediate compounds of general formula (VI) can be prepared according to methods analogous to those described in the application for patent published GN n ° 2035310 and in "A Chemistry of Heterocyclic Compounds - Indoles Part II" chapter VI edited by WJ Houlihan (1972), Wiley Interscience, 20 New York.

A compound of general formula (VI) where W is the radical AlkNHCOR '^ can be prepared by acylation of the corresponding unsubstituted amine using conventional techniques.

The Fischer indolic cyclization process can be used to prepare a compound of general formula (VI) where W is the radical (CHR ^) ^ CHRgCN or CHR ^ CHRgN02 in a conventional manner. -

A compound of formula (VI) where A1 is an alkenyl radical containing 2 to 5 carbon atoms, can be prepared by reaction of a corresponding 5-halo indole of general formula (VII)

Hal _ W

„35 'WV) <VII> L ~ 20 Λ where W is as defined for the general formula (VI) and Hal is a halogen atom, for example bromine or iodine, with an appropriate alkene of formula (CI ^ ) pCH = CH2 (where p represents 0, 1, 2 or 3) in the presence of a catalyst, such as a palladium (II) salt, for example acetate, and a phosphine, for example triphenyl-phosphine or tri-o-tolylolphosphine, with a tertiary nitrogen base, such as triethylamine or tri-n-butylamine. The reaction can conveniently be carried out in a solvent, for example aceto-nitrile, methanol or dimethylformamide, and at a temperature of 75 to 160 ° C. Otherwise, the compounds of formula (VI) can be prepared by reaction of an indole-5-carbaldehyde of general formula (VIII) · 15

OHC (C H 2) q W

^ (VIII)

N H

Where W is as defined for the general formula (VI) and q is an integer from 1 to 4, with for example a suitable dialkyl phosphonate, under standard conditions.

The compounds of general formula (I) can be prepared by another general method (D) which comprises reacting an indole of general formula (IX): XS02A AlkNR3R4 30 \ IX) ^ N '

H

in which X represents a labile group, with an amine of general formula (X): / ....

35 21 R1 \ NH (X) / 5 R2

Examples of suitable labile groups X in the compound of general formula (IX) include a halogen atom (for example a fluorine, chlorine or bromine atom) or an OR ^ radical where R ^ represents a hydrocarbyl radical such than an aryl radical, for example, phenyl. The aryl radical may be unsubstituted or substituted by one or more substituents, such as halogen atoms; or nitro radicals; cyano; amino; alkyls, for example methyl; alkoxy, e.g. methoxy pie; acyl, for example acetyl, and alkoxycarbonyl, for example ethoxycarbonyl. The labile group represented by X is preferably a phenoxy group.

The reaction is conveniently carried out in the presence of a solvent and can be carried out in an aqueous or non-aqueous reaction medium.

The reaction medium can comprise one or more organic solvents such as ethers, for example dioxane or tetrahydrofuran; amides, for example Ν, Ν-dimethylformamide or N-methyl-25 pyrrolidone; alcohols, for example methanol or ethanol; esters, for example ethyl acetate; nitriles, for example acetonitrile; halogenated hydrocarbons, for example dichloromethane; and tertiary amines, for example triethylamine or pyridine, optionally in the presence of water. In some cases, the amine of formula (IX) can itself serve as a solvent.

If desired, aminolysis can be carried out in the presence of a base, such as a tertiary amine (eg triethylamine or pyridine); a f / ii v "'w1' 22 alcoholate (for example sodium tert-butoxide) or a hydride (for example sodium tert-butoxide) or a hydride (for example sodium hydride).

The reaction can conveniently be carried out at a temperature of from -20 ° C to + 150 ° C.

The compounds of general formula (IX) are new and constitute another aspect of the invention. They have a powerful and selective vasoconstrictive activity as described above for the compounds of general formula (I).

The starting materials of general formula (IX) where X represents a radical OR ^ can be prepared for example by reduction of a compound of general formula (XI)

n5 XS0 „A W

vJmJ (xi)

H

20 (where W is as defined for formula (VI)) or a corresponding protected salt or derivative.

The reduction can be carried out analogously to the general process (C) and examples of the appropriate groups W and details of the reaction conditions are given relative to the general process (C).

A compound of formula (IX) where X represents a halogen atom can be prepared for example by reacting the corresponding sulfonic acid derivative and a salt thereof with a halogenating agent, such as a halide or a phosphorus oxyhalide, in an inert organic solvent, for example phosphorus pentachloride in dichloromethane. One can prepare a sulfonic acid of formula (IX) where X is OH, par. example by acid or base catalyzed hydrolysis of an ester of formula (IX) (i.e. a /.

23 * compound where X represents the radical OR ^).

The compounds of general formula (XI) can be prepared according to methods analogous to those described in published British patent application No. 2035310-5 and in "A chemistry of Heterocyclic Compounds - Indoles

Part II ”Chapter VI edited by W.J. Hamilton (1972)

Wiley Interscience, New York, as well as in GB patent application No. 8315564 filed on par 10 According to another general process (E), it is possible to transform a compound of formula (I) according to the invention or a salt or derivative thereof protected corresponding to another compound of the invention according to conventional procedures. ques.

For example a compound of general formula (I) where one or more of R ^, R2, R ^ and R ^ are alkyl radicals, can be prepared from the corresponding compounds of formula (I) where one or more of R ^, R2 * R ^ and R ^ represent hydrogen atoms, by reaction with a suitable alkylating agent such as a compound of formula R ^ L where represents the radical, R2, R3 or R ^ desired and L represents a leaving group such as a halogen atom or a tosylate radical, or a sulphate. The alkylating agent can be, for example, an alkyl halide (for example methyl iodide or ethyl), an alkyl tosylate (for example methyl tosylate) or a dialkyl sulphate (for example dimethyl sulphate). 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 base. Suitable bases include, for example, alkali metal hydrides, such as sodium or potassium hydride, alkali metal amides, such as sodium amide, alkali metal carbonates, such as sodium carbonate and alkali metal alcoholates, such as methylate, ethylate or sodium or potassium tert-butoxide.

When an alkyl halide is used as the alkylating agent, the reaction can also be carried out in the presence of an acid scavenger, such as propylene or ethylene oxide. A catalyst such as tetrabutylammonium fluoride can also be used.

The reaction can conveniently be carried out at a temperature of from -20 ° C to + 100 ° C.

The compounds of formula (I) in which represents a C3-alkenyl radical R2 represents a C1-alkenyl radical, phenyl alkyl in or cycloalkyl in and / or one of R ^ and or both represent a propenyl radical, can be prepared in a similar manner by using an appropriate compound of formula

RxL or ^ χ ^ 25 ^ 4 * 20 According to another general process (F), it is possible to prepare a compound of general formula (I) according to the invention, or a salt thereof, by subjecting a protected derivative of general formula (I) or a salt thereof in a reaction to remove the protective group (s).

25 · Thus in an early stage of the reaction sequence for the preparation of a compound of general formula (I) or one of its salts, it may be necessary or desirable to protect one or more sensitive radicals of the molecule for avoid unwanted side reactions. For example, it may be necessary to protect the radical NR ^ ï ^, where R ^ and / or R ^ represent a hydrogen, by fixing a proton or with a radical easy to remove at the end of the reaction sequence. Such radicals can include, for example, aralkyl radicals, such as benzyl, diphenylmethyl / or triphenylmethyl: or acyl radicals such as N-benzyloxycarbonyl or tert-butoxycarbonyl or phthaloyl.

In some cases it may also be desirable to protect the nitrogen from the indole, for example with a. 5 aralkyl radical such as benzyl.

The subsequent cleavage of the protective group (s) can be carried out according to conventional procedures. It is thus possible to cleave an aralkyl radical, such as benzyl, by hydrogenolysis in the presence of a catalyst (for example, palladium on carbon) or of sodium and liquid ammonia; an acyl radical such as N-benzyloxycarbonyl can be eliminated by hydrolysis with, for example, hydrobromic acid in acetic acid or by reduction, for example by catalytic hydrogenation. Radiophthalic phthaloyl can be removed by hydrazinolysis (for example by treatment with hydrazine hydrate) or by treatment with a primary amine (for example methylamine).

Note that in some of the general methods 20 (A) to (E) previously described, it may be necessary or desirable to protect from sensitive radicals of the molecule as described above. Thus, a reaction stage comprising a deprotection of a protected derivative of general formula (I) or of a salt thereof, can be carried out after any of the methods (A) to (E) previously described.

Therefore, according to another aspect of the invention, the following reactions (G) in an appropriate framework can, if necessary and / or desirable, be carried out after any of the methods (A) to (E): (1) elimination of any protective group; and (2) converting a compound of general formula (I) or a salt thereof into a physiologically acceptable salt or a solvate (eg a hydrate) thereof.

i ~ \ 26

When it is desired to isolate a compound of the invention in the form of a physiologically acceptable salt, for example an acid addition salt, the free base of general formula (I) can be treated with an appropriate acid (for example succinic or hydrochloric acid) preferably in an equivalent amount in a suitable solvent (for example aqueous ethanol).

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

As they are used as the last main stage of the preparation sequence, the general methods indicated above for the preparation of the compounds of the invention can also be used to introduce the desired radicals into an intermediate stage. preparing the required compound. For example, the radical required in position 5 can be introduced either before or after the cyclization forming the indole nucleus.

It should therefore be noted that in these multi-stage processes, the order of the reactions must be chosen so that the reaction conditions have no effect on the radicals present in the molecule which is desired in the final product.

The invention is further illustrated by the following nonlimiting examples. All temperatures are in ° C. The "Hyflo" is a filtration aid. Reactivials are 4 ml thick-walled glass vials with a screw cap and a teflon-coated disc supplied by Pierce and Warriner (UK) Ltd. Chromatography is carried out either conventionally with silica gel (Merck, Kieselgel 60, Art. 7734) or by "flash" chromatography (WC Still, M. Kahn and A. Mitra, t 35 j. Org. Chem. 2923 , 4_3, 1978) on silica (Merck // fi 27 * 9385) and thin layer chromatography (TLC) on silica (Hacherly-Nagel, Polygram) unless otherwise indicated. The following abbreviations are assigned to the eluent used for chromatography and TLC.

- 5 (A) Methylene chloride-ethanol-ammonia (0.88) 50/8/1 (B) Methylene chloride-ethanol-ammonia (0.88) 100/8/1 (C) Methylene chloride-ethanol -ammonia (0.88) 10 60/8/1 (D) Methylene chloride-ethanol-ammonia (0.88) 25/8/1 (E) Methylene chloride-ethanol-ammonia (0.88) -200 / 8/1 (F) Methylene chloride-ethanol-ammonia (0.88). 750/10/1 (G) Methylene chloride-ethanol-ammonia (0.88) 40/10/1 (H) Ether-cyclohexane 1/1 20 (I) Methanol-chloroform 5/95 (J) Ether (K ) Methylene chloride-ether 1/1 (L) Methylene chloride-ethanol-ammonia (0.88) 75/8/1 25 (M) Isopropyl acetate (N) Ethyl acetate-ether 1/1 ( O) Methylene chloride-ethanol-ammonia (0.88) 83.5 / 15 / 1.5 (P) Acetic acid-ethyl acetate 1/99 20 (Q) Ethyl acetate-cyclohexane 1/1 ( R) Chloroform-methanol 50/1 (S) Chloroform-methanol 19/1 (T) Methylene chloride-ethanol-ammonia (0.88) 150/8/1 (U) Methylene chloride-ethanol-ammonia (0, 88) / /; a t s - i _ 28 89/10/1 (V) Petroleum ether (e.g. 6Û-80 ° C) -ethyl acetate 2/1 (W) Cyclohexane-ether 2/1.

The intermediates are subjected to a usual purity control by TLC, with detection in ultraviolet light and use of sprayed reagents such as potassium permanganate (KMnO 4). In addition, indole intermediates are detected by spraying aqueous ceric (Ce) sulfate and tryptamines by spraying an iodoplatinic acid (AIP) or ceric sulfate solution.

The proton nuclear magnetic resonance (NMR) spectra (½) are obtained either at 90 MHz using a Varian EM390 device or at 250 MHz using a Bruker AM or WM 250 device. S = singlet, d = doublet, t = triplet, q = quadruplet and m = multiplet.

Preparation .1 N-methyl-4-nitrobenzene-ethanesulfonamide hydrate 20 (4/1).

A solution of 6.5 g of 4-nitrobenzene-ethanesulfonyl chloride in 50 ml of methylene chloride is added dropwise over a period of 0.25 hours to a rapidly stirred ice-cold mixture of 4 ml of aqueous methylamine at 40% in 20 ml of methylene chloride. Additional 1 ml portions of 40% aqueous methylamine are added after stirring the suspension at 0 ° C for an additional hour and 0.5 hours respectively. The suspension is then stirred at 0 ° C for a further 0.5 hour before evaporating under reduced pressure to obtain a solid (about 7.0 g). This material is triturated with 100 ml of water and the solid is collected by filtration and then washed with 50 ml of petroleum ether (mp 60-80 ° C) and dried to obtain the title compound in the form of '' a powder (5.45 g). P.f. 126-129 ° C.

/ 29

Analysis found; C = 43.35; H = 4.9, N = 11.1%.

CaHl2N204S'025H2 ° requires C = 43.45; H = 5 / l; N = 11.3%.

Preparation- 2 4-amino-N-methylbenzene-ethanesulfonamide.

A solution of 7.9 g of the product of preparation 1 in 150 ml of ethanol and 10 ml of dimethylformamide is added to a previously reduced suspension of 10% palladium oxide on carbon (1.0 g, 50% aqueous paste) in 50 ml of ethanol and hydrogenated at atmospheric pressure. After 2 # 75 hours, a new portion (1.0 g) of catalyst is added and the hydrogenation is continued for a further 2 hours. A total of 2.14 1 of hydrogen is absorbed. The catalyst and the solvent are removed, respectively by filtration and by evaporation. 15 rotary ration, and the residual solid (8 g) was extracted with three 50 ml portions of boiling ethyl acetate. The combined hot extracts are filtered and evaluated | dry pore under reduced pressure to obtain a solid.

| This material is triturated with petroleum ether | 20 (m.p. 60-80 ° C) to obtain the title compound in the form of a powder (5.2 g) m.p. 101-105 ° C.

Preparation 3

4-hydrazino-N-methylbenzene-I ethanesulfonamide hydrochloride.

[25 1.0 g of the product of preparation 2 in I suspended in 6 ml of water is treated with 10 ml of concentrated hydrochloric acid which precipitates the hydrochloride.

! The mixture is then cooled to -5 ° C and treated with 0.38 g of sodium nitrite in 2 ml of water and 30 agitates for 50 minutes while maintaining the temperature below -5 ° C. The suspension was quickly filtered to remove unreacted starting material and the filtrate was slowly added to 5.0 g of stannous chloride in 10 ml of concentrated hydrochloric acid at 35 ° C. The solution is allowed to warm to 20 ° C in I / 30 Λ with vigorous stirring, the precipitate formed is collected and washed with 50 ml of ether to obtain the title compound (1.2 g; purity 66%) under form of a powder. CCM (A): Rf = 0.8 (AIP).

- 5 Preparation 4 4- [2- (3-cyanopropylidene) hydrazino] -N-methyl-benzene-ethanesulfonamide.

To a filtered solution of 0.6 g of the product of preparation 3 (having a purity of 66%) in 13 ml of water and 0.25 ml of 2N dilute hydrochloric acid, 0.23 g of 3-cyanopropanal-dimethylacetal and the solution obtained is stirred at room temperature for 24 hours. The precipitated solid is filtered off, washed with two 30 ml portions of water and 50 ml of diethyl ether and then dried to obtain the title compound in the form of a powder (0.3 g) m.p. 96-97 ° C.

Preparation 5 3- (cyanomethyl) -N-methyl-1H-indole-5-ethane-20 sulfonamide.

A suspension of 0.25 g of the product of preparation 4 in 2.5 g of polyphosphate ester and 5 ml of chloroform is heated at reflux for 5 minutes, then poured onto ice. The suspension obtained is stirred for 20 minutes and then extracted with four 10 ml portions of chloroform. The extracts are washed with 10 ml of 8% sodium bicarbonate and 10 ml of water, then dried, filtered and evaporated to give 0.35 g of an oil. This oil is chromatographed (J) to obtain the title compound (0.06 g) in the form of an oil. TLC (J): Rf = 0.5 (U.V.).

Example 1 3- (2-aminoethyl) -N-methyl-1K-indole-5-ethanesulfonamide hemisuccinate.

35 i 5 31

Process (I)

A solution of -1.019 g of the product of preparation ^ 3 in 25 ml of methanol and 5 ml of water is stirred at 50 ° C. and 0.117 g of 4-chlorobutanal-dimethyl acetal is added.

After 0.75 hours of stirring at 50 ° C, 0.117 g of 4-chlorobutanal-dimethylacetal is added and stirring is continued at 50 ° C for a further 0.75 hours. The pH of the solution is adjusted to 4 by the addition of 0.3 g of ammonium acetate and the mixture is brought to reflux for 5 hours. The solvent is removed by evaporation under reduced pressure and the residue is treated with 15 ml of a saturated aqueous potassium carbonate solution and extraction is carried out with four 50 ml portions of ethyl acetate. The extracts are dried (MgSO 4) and concentrated in the form of a - * -> gum (0.69 g). This material is chromatographed (B), (C) to obtain the free base of tryptamine in the form of a gum (0.072 g) which is taken up in 2 ml of hot isopropanol and which is treated with a hot solution of 0.0151 g succinic acid in 0.5 ml hot isopropanol. After adding approximately 1.0 ml of absolute alcohol to the boiling mixture, the solution is allowed to cool. The solid which crystallizes is collected by filtration, washed with ethyl ether and dried to obtain the title compound 25 in the form of a powder (0.046 g) m.p. 133-138 ° C.

Analysis found: C = 50.8; H = 6.1; N = 11.4 C13H19N3 ° 2S ’° '5C4H6 ° 4‘0'IC3H8 ° · 0” 75H2 ° requires: C = 51.1; H = 6.8; N = 11.7%.

NMR 6 (CD3SOCD3) 2.65 (3H, s, MeNHS02) 2.7-3.4 (8H, m, NHS02CH2CH2 and CH2CH2NH2), 6.8-7.5 (4H, m, aromatic).

Example 2 N-methyl-3- [2 ~ (methvlamino) ethyl] -1H-indole-5-ethanesulfonamide combined with succinic acid and water (6/4/3).

35 A solution of 0.45 g of the product of fi * sv 32 is hydrogenated preparation 5 in 25 ml of ethanolic methvlamine (25% w / V) on 0.8 g of 10% palladium oxide on carbon (paste 50% aqueous) previously reduced in 5 ml of ethanol. The catalyst is removed by filtration on "Hyflo" and the filtrate is concentrated to obtain 0.45 g of a gum which is dissolved in 5 ml of hot isopropanol and which is treated with a solution of 0.093 g of succinic acid in 0.5 ml of methanol. A thick gum precipitates. The reaction mixture is concentrated in vacuo (about 1 ml of solvent). The solvent is decanted and the residual gum is triturated with three 25 ml portions of diethyl ether to obtain a solid which is separated by filtration and dried to obtain the title compound in the form of a powder 15 (0 , 33 g) pf = 62-65 ° C.

Analysis found: C = 52.5; H = 6.8; N = 11.0.

<'14H21 ^ 3 ^> 2 ^ * ® ^' ^^ 2 ^ n ^ öessite: C = 52.3; H = 7.2; N = 10.9%.

The NMR spectrum agrees with that of Example 3. Example 3

N-methyl-3- [2- (methylamino) ethyl] -1H-indole-5-ethanesulfonamide hydrochloride.

In a similar manner to that of Example 2, 0.70 g of the product of Preparation 5 is hydrogenated, filtered and the filtrate is concentrated to obtain 0.7 g of a gum which is purified by flash chromatography (T, column diameter 3 cm). The gum obtained (0.3 g) is extracted with 20 ml of ethyl acetate, filtered and treated with an excess of hydrochloric acid in ether. The solid is collected by filtration, washed with 25 ml of ether and dried (15 h, 20 ° C., vacuum gun) to obtain the title compound in the form of a powder (0.24 g), m.p. 151-154 ° C.

Analysis found: C = 49.3; H = 6.6; N = 11.8.

35 C14H21N ^ 02S.HC1.0,5H20.0,07C4H802 requires: »33 * C = 49.3; H = 6.8; N = 12.1.

3 NMR 5 (CD3S0CD3) 2.50 (3H, s NHMe) 2.66 (3H, s SC> 2NHMe) 2.9-3.5 (8H, m ÇH2.CH2S02NH and CH2CH2NH) and 6.9-7, 5 (aromatic).

Example 4 3- (2-aminoethyl) -N- (phenylraethyl) -1H-indole-5-ethane-sulfonamide combined with creatinine, sulfuric acid and water (l / l / l / l).

(1) 4-nitro-N- (phenylmethyl) benzene-ethanesulfonamide.

9.83 ml of benzylamine in 10 ml of dichloromethane is added dropwise to a stirred ice solution of 7 g of 4-nitrobenzene-ethanesulfonyl chloride in 250 ml of dichloromethane. After 18 hours, the reaction mixture is washed with three 40 ml portions of water and three 25 ml portions of salt water, dried (Na2SO 4) and evaporated to dryness then the product is recrystallized from 50 ml of water. isopropanol to obtain the title compound as needles (6 g), mp 125-127 ° C.

(2) 4-amino-N- (phenylmethyl) benzene-ethanesulfonamide.

A suspension of 11 g of the product from stage (1) is hydrogenated in 120 ml of methanol over 2 g of 10% palladium oxide on carbon (50% aqueous paste) previously reduced at ordinary temperature and under pressure until the hydrogen fixation (1.99 1) ceases. The catalyst is filtered off and the filtrate is evaporated to dryness to obtain a solid which is purified by crystallization from methanol to obtain the title compound in the form of a solid (3.2 g) m.p. 109-llîaC.

30 CCM (E); Rf = 0.4 (CeIV).

(3) 4-hydrazino-N- (phenylmethyl) benzene-ethanesulfonamide hydrochloride.

A solution of 0.25 g of sodium nitrite in 1.9 ml of water is added to a cold suspension of 1 g 35 of the product of stage (2) in a mixture of 7.5 ml tt if 34 of acid concentrated hydrochloric acid and 4.5 ml of water while keeping the temperature below -5 ° C. This mixture is stirred at -5 ° C for 50 minutes and the remaining solid is filtered off. The ice-cold filtrate is then added slowly to a solution of 3.5 g of stannous chloride dihydrate in 7.5 ml of concentrated hydrochloric acid while keeping the temperature below 0 ° C. After the addition, the mixture is stirred at room temperature for 3 hours, the solid is collected 1 °, washed with three 50 ml portions of diethyl ether and dried to obtain the title compound as powder (0.46 g). TLC (B): Rf = 0.43 (AIP).

(4) 3- (2-aminoethyl) -N- (phenylmethyl-1H-indole-S-15 ethanesulfonamide combined with creatinine, sulfuric acid and water (l / l / l / l).

0.18 g of 4-chlorobutanal-dimethylacetal is added to a stirred solution of 0.45 g of the product of stage (3) in a mixture of 18 ml of ethanol and 4.5 ml of water and the mixture is heated. mixture at reflux for 2 hours. The cooled mixture is evaporated to dryness and the residue is chromatographed (A) twice to obtain the tryptamine in the form of an oil (70 mg) which is dissolved in a boiling mixture of 5.6 ml of ethanol and 0 , 7 ml of water and treated with 0.1 ml of an aqueous solution of creatinine and sulfuric acid (1/1, 2 M). Upon cooling, the title compound precipitates as a solid (96 mg) m.p. 217-220 ° C (softening at 210 ° C).

Analysis found: C = 47.0; H = 5.9; N = 14.2.

20 C ^ gl ^ ßN-jC ^ S.C ^ H ^ N ^ O. ^ SO ^ .I ^ O requires: C = 47.1; H = 5.8; N = 14.3%.

NMR (CD3SOCD3) 2.9-3.3 (8H, m, NHS02 CH2CH2 and CH2CH2NH2), 4.24 (2H, s, CH2NHSQ2), 6.85-7.5 (m, aromatic).

Example 5 3- [2- (Ethylamino) ethyl hemihydrate hemihydrate] - / lv

. I

35 * N-methyl-1H-indole-'5-ethanesulfonamide.

Process (I)

A 10% suspension of palladium oxide on hydrogen - 5 (0.8 g of a 50% aqueous paste) is hydrogenated beforehand for 20 minutes in 5 ml of ethanol.

0.40 g of the product of preparation 5 is added to 25 ml of ethanolic ethylamine and the suspension obtained is stirred for 2 hours at 20 ° C. The suspension is filtered through Hyflo and the filtrate is concentrated in vacuo to obtain 0.38 g of an oil which is chromatographed twice (B) to obtain 0.114 g of tryptamine as an oil. The oil is dissolved in 2 ml of absolute ethanol and 22.5 mg of succinic acid in ethanol are added. The crystals are collected by filtration to obtain 70 mg of the title compound, m.p. 148-150 ° C.

Analysis found: C = 54.5; H = 7.1; N = 10.9.

Cl5H23N3 ° 2S'0'5C4H6O4 * 0.5H2 ° requires c = 5i> 1 '· H = 7/2; N = 11.1%.

NMR (CD3SOCD3) 1.11 (3H, t, NHCH2Me), 2.64 (3H, s, MeNHS02), 2.78 (2H, q, NHCH2CH3), 2.85-3.4 (8H, m, NHS02CH2CH2, and CH2CH2NÎ0 6.9-7.5 (4H, m, aromatic).

Process (II) (1) N— [2— [5— [2 - [(Methylamino) sulfonyl] ethvl] -lH-indole-3-y1] ethyl1acetamide.

A solution of 0.3 g of the product of Example 1 in 15 ml of anhydrous tetrahydrofuran is treated with 0.084 ml of acetic anhydride and the mixture is stirred at room temperature for 1.5 hours. Then, the solution is evaporated to dryness twice and the residue is dissolved in 20 ml of ethyl acetate. This solution in ethyl acetate is washed with 20 ml of 8% aqueous sodium bicarbonate and then with 10 ml of water, dried and evaporated under reduced pressure to obtain 0.45 g of a gum. This material is chromatographed (A) to obtain the title compound as a gum 36 (0.389 g) TLC (A): Rf = 0.6.

(.2) 3- [2- (ethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hemisuccinate.

A solution of 0.3 g of the product of stage 5 (1) in 16 ml of anhydrous tetrahydrofuran (THF) is added to a stirred mixture of 0.353 g of lithium aluminum hydride in 20 ml of THF under an atmosphere of 'nitrogen. The suspension obtained is stirred for 2 hours at reflux and then allowed to stand overnight at room temperature before bringing to reflux for another hour. After cooling the reaction bath in ice, 10 ml of water are added and the mixture obtained is filtered on Hyflo. The filtrate is extracted with four 25 ml portions of ethyl acetate and the extracts are dried (MgSO 4) and then evaporated to give 0.187 g of a gum.

This material is chromatographed (A) to obtain the free base in the form of 0.12 g of a gum. A solution of 0.12 g of the free base in 2 ml of hot absolute alcohol is treated with a solution of 0.0229 g of succinic acid in 0.75 ml of methanol. The solution obtained is evaporated to dryness to obtain a foam which is triturated with anhydrous ether to obtain the "title compound in the form of a hygroscopic foam (0.068 g), mp 65-75 ° C, than the NMR and TLC (B; Rf = 0.25) are slow identical to the product of process (I).

Example 6 3- (3-aminopropyl) -N-methyl-1H-indole-5-ethane “sulfonamide combined with oxalic acid and ethanol (1 / 1.2 / 0.83).

(1) 3- [3- (1,3-'dihydro-1,3-dioxo-2H-isoindole-2-yl) propyl] -N-methyl-1H-indole-5-ethanesulfonamide.

Stirred at room temperature for 1.75 hours, a mixture of 2.5 g of the product of preparation 3 (having a purity of 68%) and 3.15 g of 2- (5.5-35 dimethoxypentyl) -lH-isoindole-1,3 (2H) -dione (having a tr \.

i (83% purity) in 200 ml of 10% aqueous acetic acid and then refluxed for 3 hours. The mixture is allowed to cool, it is extracted with three 100 ml portions of chloroform and the combined extracts are washed with 100 ml of 2N hydrochloric acid and 100 ml of 2N sodium carbonate, dried (Na2SO 4) and concentrated. under vacuum. By chromatography on a short column (F, column diameter: 15 cm), residual gum (4.33 g), 0.43 g of a solid is obtained. By crispe tallisation of this solid in 10 ml of a 1/1 mixture of chloroform and methanol, the title compound is obtained in the form of a solid (0.25 g), m.p. 169-169.5 ° C. TLC (F): Rf = 0.19 (CeIV).

(2) 3- (3-aminopropyl) -N-methyl-1H-indole-5-ethane- * 5 sulfonamide combined with oxalic acid and ethanol (1 / 1.2 / 0.38).

0.34 ml of hydrazine hydrate is added to a reflux suspension of 250 mg of the product of stage (1) in 10 ml of ethanol, the solution obtained is stirred for 4 hours and then allowed to cool. The suspension is concentrated in vacuo and the residual solid is partitioned between 25 ml of 2N sodium carbonate and three 25 ml portions of ethyl acetate. The combined organic extracts are then dried (Na ~ SO) and concentrated in vacuo. By flash column chromatography (G; column diameter: 1 cm) of the residue (110 mg), 98 mg of a gum are obtained which is dissolved in 3 ml of absolute ethanol at reflux and a solution of 30 is added. mg of oxalic acid in 0.5 ml of absolute ethanol. The suspension of gum is gently heated to obtain a solution and allowed to cool with stirring. The suspension obtained is filtered and the solid is washed with three 1 ml portions of absolute ethanol and dried under vacuum at 50 ° C. for 18 hours to obtain 35, the title compound in the form of a solid (118 mg) /! 5 38 m.p. 160-162 * C (softening at> 98 ° C).

“Analysis found: C = 49.2; H = 6.85; N = 9.6.

Cl4H2lN3 ° 2S * J ', ^ C2H204 * ^ / ^ (' 2H60 requires C = 49.1; H = 6.5; N = 9.5%.

5 N NMR (CD3SOCD3) 1.90 (2H, xn, CH2CH2CH2NH2), 2.62 (3H, d,

MeNHS02), 2.73 and 2.82 (4H, t and t, CH ^ CH2CH2NH2), 2.95-3.3 (4H, m, NHS02CH2CH2), 6.95-7.45 (4H, m, aromatic ).

Example 7

3- (2-Aminopropyl) -N-methyl-1H-10 indole-5-ethanesulfonamide hydrochloride.

(î) 4-nitropentanal.

A cold solution of 45 ml of acrolein and 120 ml of nitroethane in 750 ml of ether is added. tion of 15 drops of tri-n-butylphosphine in 60 ml of ether without allowing the temperature to exceed -8 ° C. The reaction is stirred for a further 30 minutes, 2 drops of methyl iodide are added and the ether is removed by evaporation in vacuo at 40 ° C. The residue is purified by column chromatography (H) to obtain 6.7 g of an oil which is distilled at 130-135 ° C (4 mbar) to obtain the title compound in the form of an oil ( 1.5 g).

TLC (H): Rf = 0.3 (KMn04).

(2) N-methyl-4- [2- (4-nitropentylidene) hydrazino] benzene-ethanesulfonamide.

To a filtered solution of 3.678 g of the product of preparation 3 (having a purity of 67%) in 20 ml of water, 1.5 g of 4-nitropentanal are added dropwise and the reaction is monitored by TLC. The reaction mixture is extracted with 200 ml of chloroform, dried (MgSO 4) and evaporated in vacuo to obtain 2.8 g of the title compound in the form of an oil which is used without further purification in the stage following.

TLC (I): Rf = 0.4 (CeIV).

(3) N-methyl-3- (2-nitropropyl) -1H-indole-5-ethane-35 sulfonamide.

/

/ V

* 39

A solution of 2.8 g of the product of stage (2), 28 g of polyphosphate ester and 50 ml of chloroform is heated at reflux for 5 minutes, then poured onto 100 g of ice. The suspension obtained is stirred for 5 minutes and extracted with three 100 ml portions of chloroform. The organic extract is washed with two 100 ml portions of an 8% solution of sodium bicarbonate and two 100 ml portions of water, dried (MgSO 4), filtered and evaporated to obtain 5.2 10 g of an oil. The oil is purified by flash chromatography (J. column diameter: 8 cm) to obtain 0.47 g of the title compound in the form of an oil.

TLC (J): Rf = 0.8 (KMn04, AIP).

Analysis found: C = 51.5, H = 5.6 ·; N = 12.7.

C14HigN304S requires C = 51.7; H = 5.9; N = 12.9.

(4) 3- (2-Aminopropyl) -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.43 g of the product of stage (3) is hydrogenated in 50 ml of ethanol on 0.4 g of 10% palladium oxide on charcoal previously reduced, for 75.5 hours at atmospheric pressure and at room temperature. The reaction mixture is filtered and evaporated under vacuum to obtain 0.27 g of an oil which is chromatographed (A; column diameter: 25 3 cm) to obtain tryptamine in the form of an oil (0, 23 g). A solution of the oil in 5 ml of ethanol is treated with acid, hydrochloric acid in ether (pH 3), the salt is filtered off and dried to obtain the title compound as solid 30 (0.2 g) pf 21-221 ° C.

Analysis found: C = 50, 4; H = 6.7; N = 12.2.

<'14H21N3 ^ 2 ^, HC ‘*' * ^, J '^ H20 n®cess ^ te c = 50.2; H = 6.7; N = 12.5.

NMR CCD3SOCD3) 1.19 (3H, d, CH-CH3), 2.64 (3H, d, S02NHCH3), 35 2.75-3.5 (7H, m, CH2CH (Me) NH2 and CH2CH2S02NH), 7 -7.55 (5H, m, i - 40 aromatic + NHSC ^) - Example 8 3- (2-aminoethyl) -N, N-dimethyl-1H-indole-5-etnane-sulfonamide combined with creatinine and sulfuric acid, 5 furic (1/1/1).

(1) 2- (1H-indole-5-yl) -N, N-dimethylethenesulfonamide.

A mixture of 7.7 g of 5-bromo-indole, 5.3 g of N, N-dimethylethenesulfonamide, 15 ml of triethylamine, 10 5 ml of acetonitrile, 0, is heated at 100 ° C. in an autoclave for 3 hours. 35 g of palladium (II) acetate and 0f “95 ~ g of tri-o-tolylphosphine. The cooled mixture obtained is subjected to a partition between 300 ml of 2N hydrochloric acid and two 150 ml portions of ethyl acetate. The combined extracts are dried. (Na2SO ^) and 15 evaporated in vacuo. The residue is purified by flash chromatography (V, 7 cm column) to obtain the title compound in the form of a crystalline solid (3.8 g) m.p. 148-150 ° C.

(2) N, N-dimethyl-1K-indole-5-ethanesulfonamide.

A solution of 3.8 g of the product of stage (1) in 400 ml of ethanol over 0.5 g of 10% palladium oxide on carbon (aqueous aqueous paste) is hydrogenated at ordinary temperature and pressure. 50%) for 2 hours. The catalyst is filtered off and replaced with a fresh amount (0.5 g; 50% aqueous paste) and the hydrogenation is continued for one hour. The catalyst is separated by filtration and evaporated! vacuum filtrate to obtain 2.8 g of a solid which is recrystallized from a mixture of ethyl acetate and hexane to obtain the title compound as a solid (2.0 g) pf 125-127 ° C.

- (3) 3- (dimethylamino) methyl -N, N-dimethyl-1H-indole-5-ethanesulfonamide.

A solution of 0.8 g of the product of stage (2) / L ~ I '41 ί in 40 ml of acetonitrile containing 0.6 g of Ν, Ν-dimethylmethyleneammonium chloride is stirred at room temperature for r 3 hours. . The solution obtained is subjected to a partition between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate. The organic extracts are dried (^ 250 ^) and evaporated in vacuo to obtain a solid. By trituration with ether, the title compound is obtained in the form of a solid (0.9 g) m.p. 156-159 ° C.

(4) 3- (cyanomethyl) -N, N-dimethyl-1H-indole-5-ethane-10 sulfonamide.

1.1 ml of iodomethane are added to a stirred solution of 2.7 g of the product of stage (3) in 30 ml of anhydrous dimethylsulfoxide and the solution obtained is stirred. naked at room temperature for 10 minutes. 2.7 g of potassium cyanide are added and the resulting mixture is stirred at room temperature overnight. The mixture is partitioned between 300 ml of 2N sodium carbonate and two 100 ml portions of ethyl acetate. The combined extracts are dried (^ 260 ^) and evaporated in vacuo to obtain an oil which is chromatographed by flash chromatography (J; I column of 5 cm) to obtain the title compound as a solid (1 , 3 g), pf 105-107 ° C.

(5) 3- (2-aminoethyl) -N, N-imethyl-1H-indole-5-! 25 ethanesulfonamide combined with creatinine and sulfuric acid I (1/1/1).

I Is hydrogenated at ordinary temperature and pressure I, a solution of 0.2 g of the product of stage (4) in 40 ml of ethanol containing 0.1 ml of concentrated hydrochloric acid, 0.2 g of '' 10% palladium oxide on carbon (50% aqueous paste) for 24 hours. The catalyst is filtered off and the filtrate is evaporated in vacuo to obtain an oil.

I The oil is subjected to a partition between 20 ml of acid j! - * 5 2N hydrochloric acid and 20 ml of ethyl acetate. It was alkalized the aqueous layer (Na2CO2) and extracted with two 20 ml portions of ethyl acetate. The combined extracts are dried (Na ^ O ^) and evaporated in vacuo to obtain tryptamine in the form of 0.05 g of an oil which is dissolved in a hot mixture of 9 ml of ethanol and 1 ml of water and 0.08 ml of a 1/1 solution of creatinine in sulfuric acid (2 M) is added. By filtration of the cooled mixture, the title compound is obtained in the form of a solid (0.05 g), m.p.

10 223-225 ° C (decomposition).

Analysis found: C = 39.9; H = 6.2; N = 15.85.

C14H21N302S * C4H7N30 * H2S03 * 2H20 requires c = 39.9 î H = 6.3; N = 15.5% N NMR (CD3SOCD3) 2.82 (6H, s, S02NMe2), 2-, 9-3.4 (8H, m, CH2 15 S02N and CH2CH2NH2), 7.0-7.55 ( 4H, m, aromatic).

Example 9 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide combined with creatinine, sulfuric acid and water (1/2 / 1.5 / 2).

A solution of 0.4 g of the product of preparation 5 in 25 ml of ethanolic dimethylamine (33% w / w) is hydrogenated at ordinary temperature and pressure over 0.7 g of 10% palladium oxide. on charcoal (50% aqueous paste) previously reduced, 25 for 3 hours. The catalyst is separated by filtration and the filtrate is concentrated under vacuum to obtain 0.35 g of an oil which is purified by flash chromatography (B, column diameter 8 cm). The oil obtained (0.25 g) is dissolved in 20 ml of hot ethanol and 2.5 ml of water and treated with 0.4 ml of a 1/1 aqueous solution of creatinine and acid sulfuric (2 M) and cooled to 5 ° C to precipitate the title compound as a solid (0.22 g), mp 193-197DC.

Analysis found: C = 38.2; H = 5.6; N = 17.0.

35 C15H93N3O2S.2C4H7N30.1,5H2SO4.2H2O requires C = 38.45;

H

43 H = 6.05; N = 17.5%.

The NMR characteristics agree with those of Example 10.

Example 10-5 3- [2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

Process (I)

A suspension of 14 g of 10% palladium oxide on hydrogen (coal paste 50% with water) in 100 ml of ethanol is hydrogenated beforehand for 20 minutes.

8 g of the product of preparation 5 are added to 400 ml of ethanolic dimethylamine (33% w / v) and the suspension obtained is stirred for 18 hours at 20 ° C. under a hydrogen atmosphere. The suspension is filtered through Hyflo and evaporated to obtain 8.4 g of an oil which is purified by flash chromatography (column diameter 8 cm) to obtain tryptamine in the form of an oil (6.0 g ). The oil is extracted with 2 liters of diethyl ether and 200 ml of ethyl acetate to leave 0.5 g of a residue which is discarded. The organic extracts are combined, evaporated in vacuo and dissolved in 300 ml of Analar ethyl acetate. Hydrochloric acid in ether is added dropwise with rapid stirring. The crystals obtained are collected by filtration, washed with 100 ml of ether and dried at 60 ° C for 16 hours to obtain 5.5 g of the title compound m.p. 137-139 ° C.

Analysis found: C = 51.8; H = 6.7; N = 11.9. C15H23N3 ° 2S * requires c = 52.1; H = 7.0; N = 12.15. ^ 30 NMR (CD3SOCD3) 2.65 (3H, d, MeNHS02), 2.84 (6H, s, NMe2), 3.0-3.45 (8H, m, CH2CH2NMe2 and NHS02CH2CH2), 7.0-7 , 6 (5H, m, aromatic + NHS02).

Process (ΓΙ) (1) 5- [2- R-methylamino) sulfonyl] ethyl] -1H- ^ 5 indole-3-acetic acid.

/ /! 'ί * 44

A solution of 0.3 g of the product of preparation 5 in 15 ml of ethanol and 15 ml of water containing -1.5 g of potassium hydroxide is heated at reflux for 18 hours, cooled and evaporate the ethanol in vacuo. The residue is partitioned between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo. The residue is purified by "flash" chromatography (M, column 3 cm in diameter) to obtain the title compound in the form of an oil which crystallizes on standing (0.1 g) m.p. 123-125 ° C.

(2) 3- (2-hydroxyethyl) -N-methyl-1H-indole-5-ethane-, sulfonamide.

A solution of 1.0 g of the product of stage (1) in 50 ml of anhydrous tetrahydrofuran (THF) containing 1.0 g of lithium aluminum hydride is heated at reflux under nitrogen for 6 hours. The mixture obtained is cooled and the excess reducing agent is decomposed by adding an excess of 10% aqueous THF. The mixture obtained is partitioned between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (N, column diameter 4 cm) to obtain the title compound as an oil (0.35 g).

IV

TLC (N): Rf = 0.4 (Ce).

(3) 3- [2- (dimethylamino) ethyl] -N-30 methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.44 g of triphenylphosphine in 3 ml of tetrahydrofuran (THF) is added in a single portion to a solution of 0.3 g of N-bromosuccin-imide (NBS) in 5 ml of THF to obtain a precipitate. A solution of 0.39 g of the product of stage (2) / 1445 Λ in 10 ml of THF is added and the mixture is stirred at room temperature for 18 hours. 20 ml of a solution of dimethylamine in ethanol (33% w / v) are added and the solution obtained is stirred at room temperature - 5 for 3 days then evaporated in vacuo and the residue is partitioned between 25 ml of 2N hydrochloric acid and two 25 ml portions of ethyl acetate. The aqueous layer is made alkaline (^ 2003) and extracted with two 25 ml portions of ethyl acetate. The combined extracts are dried (Na2S0ij) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (A, column diameter 4 cm) to obtain 0.08 g of the pure free base in the form of an oil. This oil is dissolved in 5 ml of absolute ethanol acidified with hydrochloric acid in ether and diluted with anhydrous ether to precipitate the title compound as a hygroscopic solid which is revealed by NMR and CCM (A, Rf = 0.4) be identical to the product of process (I).

Method (III) (1) 4- 2- [4- (dimethylamino) butylidene Ihvdrazino -N-methylbenzene-ethanesulfonamide.

0.87 g of 4,4-dimethoxy-N, N-dimethyl-butanamine is added to a solution of 2.0 g of the product of preparation 3 (having a purity of approximately 65%) in 40 ml of water, 2.2 ml of 2N hydrochloric acid is added and the mixture is stirred (pH ~ 1.5) at room temperature under nitrogen for 4 hours. 160 mg of acetal are added and stirring is continued at room temperature for one hour. The mixture is made alkaline with 20 ml of an 8% aqueous solution of sodium bicarbonate and extracted with three 70 ml portions of chloroform; the aqueous layer is saturated with sodium chloride and extracted again with three λ 35 portions of 120 ml of chloroform. The combined organic layers are dried (46 JMgSO 4) and evaporated to give 2.25 g of an oil. A 113 mg sample of the oil is purified by flash chromatography (U, column diameter 2 cm) to obtain the title compound as an oil (71 mg).

CCM (U): Rf = 0.4 (AIP).

(2) 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

2.1 g of the product from stage (1) 10 is refluxed with 10.5 g of polyphosphate ester in 40 ml of - chloroform with stirring under nitrogen for 8 minutes. The mixture is poured onto ice, stirred for 1.75 hours, basified with 100 ml of 2N sodium carbonate and extracted with three 250 ml portions of chloroform. The organic layers are dried (MgSO 4) and evaporated to obtain 1.96 g of an oil. By partial purification by flash chromatography (0, diameter of the column 3 cm), 0.726 g of an oil is obtained; further purification by chromatography with a short column provides the pure free base also as an oil (0.56 g). The oil is heated with 30 ml of Analar ethyl acetate and a portion (12 ml) of the solution is filtered which is acidified with hydrochloric acid in ether (to pH 2). The precit 25 is washed by decantation with anhydrous ether and dried under vacuum (60 ° C., 17 hours) to obtain the title compound in the form of a hygroscopic solid (129 mg) which is revealed by NMR and CCM (0, Rf = 0.25) be identical to the product of process (1).

Method (IV) (1) N, N ^ dimdthyl ^ 5- [2 - [(methylamino) sulfonyl] ethyl] -1H-indole-3-acetamide.

A mixture of 0.57 g of Ν, Ν'-carbonyl-diimidazole and 0.9 g of the product from stage (1) of process (II) in 25 ml / l is stirred at room temperature for 1 hour. / 3 / i * * 47 of freshly distilled tetrahydrofuran. The mixture is then cooled to 0 ° C and 2 ml of dimethylamine are added. After stirring (at 0 ° C) for 2 hours, the solvent is removed under reduced pressure. The residue (P) is chromatographed to obtain the title compound in the form of an oil (0.53 g).

TLC (P): Rf = 0.25 (CeIV).

(2) 2- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

10 A solution of 0.15 g of the product from stage ”(1) in 5 ml of freshly distilled tetrahydrofuran is added to a cold suspension (0 ° C) of 87 mg of lithium aluminum hydride in 10 ml of tetrahydrofuran freshly distilled under nitrogen and the mixture is heated to reflux for 2 hours. The cooled mixture is added to 15 ml of a saturated potassium carbonate solution and the organic phase is separated. The aqueous phase is extracted with 20 ml of ethanol and the combined organic phases are evaporated under reduced pressure to obtain an oil which is dissolved in 1 ml of absolute alcohol and 3 ml of an acid solution are added hydrochloric acid in ether. The solvent is removed by evaporation under reduced pressure and the residue is triturated with a 1/1 mixture of ethyl acetate and cyclohexane to obtain the title compound (0.1 g) m.p. 132-134 ° C, which is revealed by TLC (B, Rf = 0.1) and NMR to be identical to the product of process (I).

Method (V) (1) (E) -2 ^ (1H-indole-5-yl) -N-methylethenesulfonamide.

A mixture of 6.6 g of 5-bromoindole, 5.1 g of N-methylethene sulfonamide, 75 mg of palladium (II) acetate, 0, is heated at 100 ° C. in an autoclave for 3 hours. 2 g of tri-rO-tolyphosphine, 12 ml of triethylamine and 5 ml of acetonitrile. The reaction mixture is cooled and partitioned between 300 ml of 1 N hydrochloric acid 48 and two 150 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (Q, column diameter 5 7 cm) to obtain the title compound as a solid (2.3 g), mp 164-166 ° C.

CCM (Q): Rf = û, 25 (CeIV).

(2) N-methyl-1H-indole-5-ethanesulfonamide.

A solution of 2.3 g of the product of stage (1) is hydrogenated at ordinary temperature and pressure * 0. in a mixture of 30 ml of ethyl acetate and 15 ml of methanol on 0.2 g of 10% palladium oxide on charcoal (50% aqueous paste) for 4 hours until the fixation of hydrogen (240 ml) stops, the catalyst is filtered off and the filtrate is evaporated under vacuum to obtain an oil which is crystallized from ethyl acetate to obtain the title compound in the form of a solid ( 1.8 g) pf 122-124 ° C.

TLC (R): Rf = 0.4 (CeIV).

(3) N, N-dimethyl-5- [2 - [(methylamino) sulfonyl] eth1] - -oxo-1H-indole-3-acetamide.

0.3 ml of oxalyl chloride is added dropwise under nitrogen to a stirred solution of 0.7 g of the product of stage (2) in 30 ml of tetrahydrofuran and

2S

the solution obtained is stirred at room temperature for one hour. Dimethylamine gas is then bubbled through the solution for 10 minutes. The suspension obtained is subjected to a partition between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated under vacuum to obtain an oil which is purified by "flash" chromatography (S, column diameter 4 cm). The oil obtained is crystallized from a mixture of ethyl acetate and hexane to obtain 0.4 g of the title compound 49 in the form of a solid, m.p. 151-153 ° C.

(4) 3- [2- (dimethylamino) ethyll hydrochloride hemihydrate -N-methyl-1H-indole-5 ~ ethanesulfonamide.

A solution of 0.3 g of the product of stage (3) in 30 ml of tetrahydrofuran containing 0.3 g of lithium aluminum hydride is refluxed for 3 hours, cooled and decomposed. excess of reducing agent by addition of 10% aqueous THF.

The mixture obtained is partitioned between 100 ml of sodium carbonate (2 N) and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO 4) and evaporated under vacuum to obtain an oil which is purified by "flash" chromatography (A, column diameter 4 cm). The oil obtained (0.15 g) is dissolved in 5 ml of absolute ethanol, acidified with hydrochloric acid in ether and the salt is precipitated by adding an excess of anhydrous ether. The salt is separated by filtration and dried in vacuo to obtain the title compound as a solid (0.12 g) m.p.

86-92 ° C (softening at 62 ° C) which is revealed by NMR

and CCM (A, Rd = 0.4) be identical to the product of process (I).

Process (VI)

A solution of 0.4 g of the product of Example 1 in the form of the free base in 16 ml of n-propanol, cooled in an ice bath, is treated with 0.64 ml of aqueous formaldehyde (~ 40% solution ) and the suspension obtained is stirred for 0.75 hours under a nitrogen atmosphere. 0.54 g of sodium borohydride is added and the mixture obtained is stirred in an ice bath for 2 hours. The suspension is treated with about 6 ml of 2N hydrochloric acid and stirred for 10 minutes. The mixture obtained is evaporated to a small volume (keeping the temperature below 50 ° C), basified 35 with 20 ml of an 8% aqueous solution of bicarbonate 50 Λ sodium and extracted with five portions of 5 ml; ethyl acetate. The combined extracts are dried (MgSO 4) and evaporated to obtain 0.35 g of an oil which is chromatographed (B) to obtain tryptamine-5 in the form of an oil (0.48 g). We process a part

(0.140 g) of oil in 2 ml of absolute ethanol with an excess (.4 ml) of hydrochloric acid in ether and evaporated to dryness to leave a semi-solid which is triturated with l anhydrous ether to obtain the title compound 10 as a solid (0.1 g) mp 130-136 ° C ~ (softening at 128 ° C) which is revealed by NMR and TLC

(A, Rf = 0.3) be identical to the product of process (I).

Method (VII) To a solution of 146 mg of the product of Example 12 in 15 ml of anhydrous tetrahydrofuran at room temperature, 0.99 ml of a 1.0 M solution of tetrabutylammonium fluoride in THF. After stirring at room temperature for a period of 40 min, 100 μl of propylene oxide and then 1 ml of a 0.25 M solution of methyl iodide in THF are added and the mixture is kept for 40 minutes at room temperature then the reaction is stopped with 20 ml of a 10% aqueous solution of sodium thiosulfate and extracted with two 15 ml portions of ethyl acetate. The organic extracts are dried (Na2SO4) and concentrated in vacuo. TLC analysis (D) of the reaction mixture indicates the presence of the title compound (Rf = 0.50) which is identical to a sample prepared according to the method (I).

30 Example 11

3- 2- (Dimethylamino) ethyl -N-methyl-1H-indole-5-ethanesulfonamide oxalate.

A hot solution of 0.13 g of the product of Example 10 in the form of the free base is treated with 40 mg of oxalic acid in 2 ml of ethanol and the oxalate.

AT

51 immediately rushes. The solvent is evaporated off and the residual solid is crystallized from 10 ml of hot methanol to obtain the title compound in the form of a solid (80 mg), m.p. 198-199 ° C.

5 Analysis found: C = 50.9; H = 6.2; N = 10.4.

C15H23N3 ^ 2S ‘n®cessite C = 51.1; H = 6.3; N = 10.5%.

TLC: (L) Rf = 0.2 (AIP, Ce).

Example 12 3- [2- (Dimethylamino) ethyl] -1H-indole-5-ethanesulfonamide oxalate.

Heated in an autoclave at 110 ° C for 3 hours and then at 175 ° C for a further 2 hours, a mixture of 70 mg of the product of stage (5) of Example 18 in 15 ml of liquid ammonia. By cooling to room temperature, the ammonia is allowed to evaporate and the autoclave is recharged with 2 ml of pyridine and 15 ml of liquid ammonia. After 14 hours at 155 ° C, the autoclave is cooled to room temperature and the ammonia is allowed to evaporate. The mixture is concentrated in vacuo and the gum obtained is purified by "flash" chromatography to obtain the product in the form of 15.3 mg of a vitreous material which is taken up in 0.25 ml of ethanol, filtered and 4.6 mg of oxalic acid in 0.5 ml of ethanol is added to a solution. By concentration under vacuum, a solid is deposited, it is separated by filtration, washed with ether and dried under vacuum overnight to obtain 5 mg of the title compound.

30 CCM (A): Rf = 0.25 (AIP, KMn04).

NMR 6 (CD3SOCD3) 2.83 (6H, s, NMe2), 3.0-3.4 (9H, m, CH2CH2NMe2 and CH2CH2S02), 6.92 (2H, broad, S02NH2), 7.0-7, 6 (4H, m, aromatic).

Example 13 3- 3- [2- (dimethylamino) ethyl] -1H-indole-5-ethane-

L

* 52 *

Sulfonamide, o (JL) (E) -2- [3) (cyanomethyl) --lH-indole-5-ylj ethene-sulfonamide.

A solution of 428 mg of ethenesulfonamide, 940 mg of 5-bromo-3- (cyanomethyl) -1H-indole, 21 mg of palladium (II) acetate is treated in an autoclave at 130 ° C. for 48 hours. , 67 mg of tri-o-tolylphosphine and 1.1 ml I of anhydrous triethylamine in 15 ml of acetonitrile! anhydrous. After cooling to room temperature,! 10 the mixture is poured into 30 ml of water, and extracted with; “Three 30 ml portions of ethyl acetate. The 1 combined organic extracts are dried (MgSO 4) and concentrated i q j under vacuum. By "flash" chromatography (B) of the residue,; a powder is obtained. By recrystallization (hexane-dichloromethane) 550 mg of the title compound is obtained in the form of a powder, m.p. 176-178 ° C.

(2) 3- (cyanomethyl) -1H-indole-5-ethanesulfonamide.

Hydrogenated at ordinary temperature and pressure, a solution of 443.6 mg of the product of the product of stage (1) in 50 ml of absolute ethanol on 1.30 g of 10% palladium oxide on charcoal (50% aqueous paste) in 30 ml of absolute ethanol which has been previously reduced, for a period of 18 hours. The catalyst is separated by filtration on a buffer of \! 25 sand and celite, then washed thoroughly with 200 ml of ethanol. The combined filtrates are concentrated in vacuo and the residue is purified by chromatography; flash ÎB) to obtain a viscous oil which is solidified by trituration with diethyl ether; 30 to obtain the title compound in the form of an amorphous powder (260 mg), m.p. 109-111DC.

(3) 3- [2- (dimethylamino) ethyl] -1H-indole-5-ethane-sulfonamide.

A solution of 4.9 mg of the stage product is hydrogenated at ordinary temperature and pressure.

U

* 53 (2) in 5 ml of 33% ethanolic dimethylamine on 10 mg of 10% palladium oxide on charcoal (50% aqueous paste) previously reduced in 5 ml of absolute ethanol, for 14 hours. The mixture is filtered on a sand-celite pad and then washed with three 10 ml portions of ethanol and the combined filtrates are concentrated in vacuo. By flash chromatography (A) of the residue, 3.7 mg of the title compound are obtained which is revealed by TLC (A, Rf = 0.22) and NMR to be identical to the product of Example 12.

--------- Example 14

3- [2- (ethylmethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

(1) N-ethylmethyl-5- [2- [(methylamino) sulfonvl] ethyl] -15 1H-indole-3-acetamide.

A solution of 0.7 g of the product from stage (1) of (II) of Example 10 in 50 ml of anhydrous tetrahydrofuran (THF) containing 0.5 g of carbonyldiimidazole is stirred at ordinary temperature for one hour. 2 ml of N-methylamine is added and the solution is stirred at room temperature for 3 hours. The solution is partitioned between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are washed with 50 ml of 2N sodium carbonate, dried over Na2SO4 and evaporated in vacuo to give an oil. The oil is purified by "flash" chromatography, eluting with ethyl acetate to obtain the title compound in the form of an oil (0.2 g).

TLC: ethyl acetate, (CeIV): Rf = 0.2.

(2) 3- [2- (ethylmethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.2 g of the product of stage (1) in 50 ml of anhydrous THF 35 containing 0.2 g of lithium aluminum hydride is refluxed for 24 hours, and cooled. and the excess reducing agent is decomposed by adding 10% aqueous THF. The mixture obtained is partitioned between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate.

The combined extracts are dried (Na2SO4) and evaporated under vacuum to obtain an oil which is dissolved in 5 ml of ethanol, acidified with hydrochloric acid in ether and the salt is precipitated by addition of '' an excess (300 ml) of anhydrous ether. The salt is filtered off and dried in vacuo to give the title compound as a hygroscopic solid (0.08 g) m.p. 95-99 ° C.

Analysis found: C = 53.0; H = 7.6; N = 11.4 C ^ 3H2j-N302S .HCl requires C = 53.4; H = ’7.3; N = 11.7%. RM NMR (CD3SOCD3) 1.28 (3H, t, CH2CH3), 2.65 (3H, d, S02NHCH3), 2.81 (3H, s, CH2NCH3), 3.0-3.5 (m, CH2CH2S02 and CH2CH2NMe and NCH2CH3), 7.0-7.6 (5H, m, aromatic + SO2NH).

Example 15

N-methyl-3 [2- (2-propenylamino) ethyl] -20 lH-indole-5-ethanesulfonamide oxalate.

(1) 5- 2 - [(methylamino) sulfonyl ethyl) -N- (2-propenyl) -1H-indole-3-acetamide.

A solution of 0.7 g of the product from stage (1) of (II) of Example 10 in 50 ml of anhydrous tetrahyarofuran (THF) containing 0.5 g of carbonyldiimidazole is stirred at room temperature for one hour.

2 ml of allylamine are added and the solution is stirred at room temperature for 3 hours. The solution is partitioned between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate.

The combined extracts are dried (Na2SO 4) and evaporated in vacuo to obtain an oil. The oil is purified by "flash" chromatography eluting with ethyl acetate to obtain the title compound in the form of an oil (0.25 g) which crystallizes on standing.

55 m.p. 123-125 ° C.

(2) N-methyl-3- [2- (2-propenylamino) ethyl] -1H-indole-5-ethanesulfonamide oxalate.

A solution, 0.2 g of the product of stage (1) in 50 ml of THF is heated at reflux for 24 hours.

anhydrous containing 0.4 g of lithium aluminum hydride and the excess reducing agent is destroyed by adding 10% aqueous THF. The mixture obtained is partitioned between 50 ml of 10 5 N hydrochloric acid and 30 ml of ethyl acetate. The aqueous layer (Na2CO3) is made alkaline and extracted with two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO 4) and evaporated under vacuum to obtain 82 mg of an oil which is dissolved in 5 ml of ethanol, acidified with a solution of 25 mg of oxalic acid in 2 ml of methanol and the solution is evaporated in vacuo.

By trituration with anhydrous ether, the title compound is obtained in the form of a solid (80 mg) m.p. 105-108 ° C.

Analysis found: C = 49.7; H = 6.2; N = 9.6.

^ 16H23N3 ^ 2 ^ * * “2Η204‘ 1 '^ H2 ^ n®cessite c = 49.3; H = 6.4; N = 9.6%.

NMR (free base) 5 (CD3SOCD3) 2.65 (3H, s, S02NHMe) ', 3.0-3.4 (10H, m, CH2CH2SO2 and CH2CH2N and NCH2CH =), 5.17 25 (2H, m, -CH = CH2), 5.88 (1H, m, -CH = CH2), 7.0-7.5 (4H, m, aromatic).

Example 16 N-methyl-3- [2- [(phenylmethylidene) amino] ethyl] -1H-indole-5-ethanesulfonamide.

A solution of 1.0 g of the free base of the product of Example 1 in 10 ml of absolute ethanol containing 0 is stirred under nitrogen at reflux for 2 hours and then at room temperature for 48 hours. 04 g of freshly distilled benzaldehyde and 0.5 g of 3 A molecular sieve. The suspension is filtered on "Hyflo" and ή 56 the filtrate is evaporated under reduced pressure to obtain 0.036 g of a gum. By trituration with anhydrous ether, the title compound is obtained in the form of a powder (0.01 g) m.p. 146-148 ° C.

5 NMR 6 (CD3S0CD3 / CDC13) 2.72 (3H, d, S02NHMe) 3.08-3.32 (6H, m, CH2CH2S02 and CH2CH2N =), 6.3 (1H, q. Broad, SC ^ NH) 7.38-7.7 (6H, m, N = CH-Ph and indole-4) 8.18 (1H, s, N = CH).

Example 17 3- [2- (dimethylamino) ethyl} -N- (2-propenyl) -1H-indole-10 5-ethanesulfonamide.

~ Heated to 100®U "in a" Reactivial "for 36 hours, a solution of 30 mg of the product of stage (5) of Example 18 and 2 ml of * allylamine in anhydrous pyridine. reaction mixture v · 15 cooled and purified by "flash" chromatography (A) to obtain the title compound in the form of a viscous oil (3.4 mg).

CCM (1): Rf = 0.36 (AIP).

NMR (CD3SOCD3) 2.26 (6H, s, NMe2 ° 3.68 (2H, large t, 20 CH2CH = CH2) 5.17 (1H, dd, CH = CH2, proton E), 5.32 (1H, dd, CH = CH2, proton Z) 5.9 (1H, ddt, CH = CH2), 7.4 (2H, broad, SO2NH and indole-4).

Example 18 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-25 ethanesulfonamide.

(1) Phenyl 4-nitrobenzeneethanesulfonate. j To a solution of 14.4 g of 4-nitro- benzene-ethanesulfonyl chloride in 200 ml of benzene and 5 ml i | of tetrahydrofuran (THF), 5.5 g of phenol are added! 30 and 8.5 ml of triethylamine in 20 ml of THF while cooling with ice and the suspension obtained is stirred! at room temperature for one hour. We wash! t the mixture obtained with two 20 ml portions of acid

S

dilute hydrochloric acid, dry (MgSO ^) and concentrate! 35 into an oil which solidifies on standing. We wash the

U

57 d solid with 400 ml of ether and air dried for 1 hour to obtain 11.45 g of phenyl sulfonate.

A sample (400 mg) is recrystallized from 20 ml of ethanol to obtain the title compound in the form | - 5 of a solid (250 mg) m.p. 9-9-1 ° C.

j | (2) 4-Aminobenzeneethanesulfonate hydrochloride! phenyl.

ί To 2 g of 10% palladium oxide on charcoal J (in the form of a paste at 50% in water) in 50 ml j 10 of ethanol, which has been previously reduced, we add | "A suspension of 11 g of the product from stage (1) in 100 ml of ethanol and 200 ml of ethyl acetate and hydrogen is maintained at atmospheric pressure and temperature for 2 hours. The hydrogen fixation is 1.9 liters, the catalyst is filtered off (Hyflo), washed with an additional 250 ml of ethanol, the solvent is evaporated and the residual oil is dissolved in 200 ml of chloroform. Hydrochloric acid in ethanol is added to the solution (pH 1) and the title compound precipitates as a solid (3.1 g).

TLC, methylene chloride, Rf - 0.25 (Ce ^).

(3) 4) hydrochloride-phenobenzeneethane-sulfonate hydrochloride.

i To a suspension of 1 g of the product of stage (2) 25 in 10 ml of concentrated hydrochloric acid and 10 ml of water, 0.46 g of sodium nitrite is added in 2 ml i S of water to - 5 ° C (salted ice bath). 20 ml of water are added, the suspension obtained is filtered and the filtrate is added to a solution of 6.6 g of stannous chloride in 10 ml of concentrated hydrochloric acid at -5 ° C. The mixture is stirred at room temperature for 16 hours.

The solid obtained is filtered off, washed with 50 ml of ether and air dried for 30 minutes to obtain the title compound (0.51 g) contaminated with; 35 mineral matter. It is used in the next stage

: S

/ 58 * without further purification.

TLC (A): Rf = 0.75.

(.4) 4- [2- [4- (diinethylamino) butylidene] hydrazino] benzene phenyl ethanesulfonate.

5 A suspension of 0.5 g of the product from stage (3) and 0.5 g of 4,4-dimethoxy-N, N-dimethylbutanamine in 10 ml of water and 5 ml is stirred at room temperature for 2 hours. 2N hydrochloric acid (pH 1).

The solution obtained is saturated with potassium carbonate and extracted with four 20 ml portions of ethyl acetate. The extract is dried and evaporated to obtain the title compound as an oil (0.33 g) which is used in the next stage without further purification.

15 CCM (A): Rf = 0.5 (CeIV, AIP).

(5) 3- [2- (dimethylamino) ethyl] -1H-indole-5-ethane-sulfonate.de phenyl.

0.33 g of the product of stage (4) in 3.3 g of poly-20 phosphate ester and 8 ml of chloroform is heated at reflux for 10 minutes, poured onto 20 g of ice and neutralized with solid potassium carbonate. The aqueous layer is extracted with four 15 ml portions of chloroform, the extracts are combined, washed with 10 ml of salt water, dried and evaporated. The residue (B) is chromatographed to obtain the slightly impure product in the form of 0.1 g of an oil. A small sample (15 mg) is repurified by preparative layer chromatography (L, 20 x 20 cm; 2 mm) to obtain the pure title compound as an oil (7 mg).

: CCM (A): Rf = 0.5 (CeIV, AIP).

(6) 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethane-sulfonamide.

70 mg of the product of stage (5) are heated in 4 ml of a solution of pyridine saturated with methylamine in (59 a "Reactivial" for 1.5 hours. The mixture is concentrated and the residual oil is purified by column chromatography (B), to obtain the title compound in the form of an oil (7 mg) which is revealed by '5 NMR and TLC (B, Rf = 0.3) to be identical to the product of the process (I) from example 10.

The following examples illustrate pharmaceutical compositions according to the invention containing 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride as active ingredient. Other compounds of the invention can be presented very similarly.

TABLETS FOR ORAL ADMINISTRATION

They can be prepared by conventional methods such as direct compression or wet granulation.

DIRECT COMPRESSION

mg / Per 20 g mixing tablet 20 Active ingredient 2.24 0.488 g

B.P.X calcium hydrogen phosphate 95.26 19.052 g

Croscarmellose sodium USP 2.00 0.400 g

Magnesium stearate, B.P. 0.50 0.100 g

Weight of the tablet 100 mg 25 ± of quality suitable for direct compression.

The active ingredient is sieved before use. Calcium hydrogen phosphate, croscarmellose sodium and the active ingredient are weighed in a clean polythene sachet. The powders are mixed by vigorous stirring for 5 minutes. Weigh the magnesium stearate, add it to the mixture and then mix again for 2 minutes. The mixture is then compressed using a Manesty F3 tablet machine fitted with flat punches with 5.5 mm bevelled edges to produce tablets weighing 100 mg.

K

Λ 60

B WET GRANULATION

- mg / tablet

Active ingredient 2.24 u, Lactose B.P. 151.5 - 5 Starch B.P. 30.0

B.P. 15.0 pregelatinized corn starch

B.P. 1.5 magnesium stearate

Tablet weight 200.0

The active ingredient is screened through a suitable screen and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of purified water are added and the powders are granulated.

After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then shaped into tablets using punches 7 mm in diameter.

Tablets can be prepared at other concentrations by changing the ratio of the active ingredient to lactose or the weight of the tablets and using suitable punches.

The tablets can be coated with a film of suitable film-forming materials such as hydroxypropylmethylcellulose, according to conventional techniques. Otherwise the tablets can be coated.

25 CAPSULES

mg / capsule

Active ingredient 28.00

Starch 1500 * 174.00

B.P. magnesium stearate 1.00 - 30 Load weight 200.00 - i Form of starch suitable for direct compression.

The active ingredient is sieved and mixed with the excipients. The mixture is introduced into No. 2 hard gelatin capsules using an appropriate machine. You can also prepare other doses / // ^

i B

v t S v * 61 by modifying the weight of the load and, if necessary, by modifying the size of the capsule as appropriate.

SYRUP

5 mg / 5 ml dose

Active ingredient 28.00; Buffer): Aroma)

Colorant) 10 Preservative)

Thickener)

Sweetener)

Purified water for 5.00 ml

The active ingredient, buffer, flavor, color, preservative, thickener and sweetener are dissolved in a little water, the solution is adjusted to volume and mixed. The syrup thus prepared is clarified by filtration.

SUSPENSION

20 mg / 5 ml dose

Active ingredient 28.00

Aluminum monostearate 75.00 j Sweetener) j Flavor) qs 25 Color)? Fractionated coconut oil qs 5.00 ml

H

! The aluminum monostearate is dispersed in about 90% of the fractionated coconut oil. The suspension obtained is heated to 115 ° C. with stirring and then cooled again. The sweetening agent, flavor and color are added and the active ingredient is appropriately dispersed.

; VS

The suspension is brought to volume with the remainder of fractionated coconut oil and mixed.

: 35

HE

62

TABLETS FOR ORAL ADMINISTRATION

- rcg / coinpriinë> Active ingredient 2.24 v Lactose B.P. 94.56 5 Sucrose B.P. 86.7

Hydroxypropyl methylcellulose 15.0

B.P. 1.5 magnesium stearate

Weight of the tablet. 200.00

The active ingredient is screened with a suitable screen and mixed with lactose, sucrose and hydroxypropyl methylcellulose. Appropriate volumes of purified water are added and the powders are granulated.

After drying, the granules are shaped into tablets with appropriate punches.

15 SUPPOSITORIES FOR RECTAL ADMINISTRATION

Active ingredient 5.6 mg * Witepsol H15 per 1.0 g &

Brand of Adeps Solidus Ph. Eur.

A suspension of the active ingredient in molten Witepsol is prepared and molds for suppositories of 1 g are filled with an appropriate machine.

INJECTION FOR INTRAVENOUS ADMINISTRATION

mg / ml

Active ingredient 1.12 mg 25 Sodium chloride B.P. q.s.

B.P. q.s.p. 1.0 ml

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted using an acid or an alkali, in order to obtain optimal stability and / or to facilitate dissolution of the active ingredient. Alternatively, use suitable buffer salts.

The solution is prepared, clarified and filled with appropriate size vials which are sealed by melting the glass. The injection U is sterilized, it 63> ι

Ij I by heating in an autoclave using one of the J suitable cycles. Otherwise, the solution can be sterilized by filtration and packaged in ampoules! t sterile under aseptic conditions. The solutions can be conditioned in an inert atmosphere of nitrogen or another suitable gas.

FOR INHALATION INHALATION CARTRIDGES

mg / cartridge -1® Active ingredient (micronized) 16.8

Lactose B.P. q.s.p. 25.00

The active ingredient is micronized in a fine particle jet mill before mixing with the lactose for tablets in a powerful mixer. We ; „Fills the powder mixture with hard gelatin capsules # 3 in a suitable encapsulation machine.

The contents of the cartridges are administered using! j a powder inhaler such as Glaxo Rotahaler.

j DOSE PRESSURE AEROSOL

I 20 mg / dose per box Active ingredient (micronized) 0.560 134.4 mg l | Oleic acid B.P. 0.050 12 mg J Trichlorofluoromethane B.P. 22.25 5.34 g Ί 1 _ Dichlorodifluoromethane B.P. 60.90 14.62 g! y s

The active ingredient is micronized in a jet mill to form a fine powder. The acid is mixed; oleic with trichlorofluoromethane at a temperature of 10 to 15 ° C and the micronized drug is mixed: in this solution with a mixer with high shears; _ 30 ment. The suspension is introduced into aluminum V-cans for aerosol and is crimped onto the boxes with suitable metering valves delivering a dose of 85 mg I of suspension, then the boxes are filled with valves I with dichlorodifluoromethane under pressure. .

i 35

'L

64

TEST PROTOCOL

Determination of ECç.q values and rates; of concentration equipotent "The EC values ^ of the compounds according to the invention 5 and the concentration rates of these compounds with respect to 5-hydroxytryptamine are determined by the method described by W. Feniuk, P.P.A. Humphrey and A.D. Watts, in Br.J. Pharmacol., 1980, T3 191P-192P.

- ===: Toxicology 10 The compounds of Examples 1 and 3 were administered to Wistar rats, intraperitoneally, at a dose of 6 mg / kg, and that of Example 10 at doses - of 6 , 25,12.5 and 25 mg / kg Test results. c „Rate of omposes EC, -n (μM) concentration of example 50,. ,.

* eguipotent 1 0.89 1.2 2 0.075 0.9 4 0.12 1.3 20 5 0.315 1.65 9 0.31 4.7 12 0.17 3.3 14 1.0 3.7

The compounds of Examples 1,3 and 10 have no toxic effects when administered to rats at the doses described above.

'h

Claims (5)

1. New compounds of general formula (I): JÜ- R, R-NSO-A Alk ”F., R, 5 12 2 y 3 4 (J) \ N) H 10 in which '1T R ^ represents an atom hydrogen or C 1-6 alkyl or C 3-6 alkenyl; R2 represents a hydrogen atom or a radical C1-C6 alkyl, alkenyl in 3-6 'P ^ enyl., Phenyl-15 alkyl in C 1-4, or cycloalkyl in C, -_ 7; R ^ and R ^ which may be similar or different each represent a hydrogen atom or an alkyl radical in or 2-propenyl or R ^ and R ^ together form an aralkylidene radical; Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two alkyl radicals in A represents an alkylene chain containing 2 to 5 carbon atoms which may be unsubstituted or substituted by not more than two alkyl radicals en and their physiologically acceptable salts and their solvates. 2. New compounds of general formula (I) or their physiologically acceptable salts or their V * solvates according to claim 1 wherein one of R 1 and R 2 or both represent a hydrogen atom. 3. New compounds of general formula (I) or their physiologically acceptable salts or their products of solvation according to one of claims 1 or 2 where A and Alk represent unsubstituted alkylene chains. 4. New compounds of general formula (I) or their physiologically acceptable salts or solvates according to claim 3 wherein Alk represents an unsubstituted alkylene chain containing two carbon atoms. 5. New compounds of general formula (la): 10 "ιβ82 / 5 ¥ ®2 '„, (CH2 »2Nf! 3aR4a - / (la) L Jpi H 15 in which Rla rePr® has a hydrogen atom or a alkyl radical in; R2a represents a hydrogen atom or a radical in alkyl or phenyl-alkyl in '· R ^ a and R ^ a which can be similar or different each represent a hydrogen atom or a methyl or ethyl radical; and n represents 2 or 3, and their physiologically acceptable salts and their solvates. 6. New compounds corresponding to the general formula (Ib): * 30 RlbNHS02 (CH2> 2 / (CH2> 2KR3bR4b ι "I — i | (Ib) WA N / HU” * 9 67 in which ^ R ^ represents an atom of hydrogen or a C 3 -C 3 alkyl radical and v R ^ k and R ^ which may be similar or different each represents a hydrogen atom or a methyl or ethyl radical; and their physiologically acceptable salts and their products solvation. 7. Physiologically acceptable salts of a compound according to any one of claims 1 to 6, chosen from hydrochlorides, hydrobromides, "sulfates, fumarates, maleates and succinates. 8. A pharmaceutical composition comprising at least „a compound according to any one of claims 1 to 7, of general formula (I) or a physiologically acceptable salt or a corresponding solvate with a physiologically acceptable carrier. 9. Pharmaceutical composition according to claim 8 packaged for oral administration. 10. New compounds corresponding to the general formula (III): RiR2NS02A V ^ jl (ni) NHNH-, y in which, R2 and A are as defined for the general formula (I) of claim 1, and their w 30 salts. f- 11. New compounds corresponding to the general formula (IX): XSO A ÜU2A AlkNR3R4 35. jv îT ™, K / \ * 68 in which X represents a leaving group and A, Alk, ^ R ^ and R ^ are as defined for the general formula (I) in claim 1. 12. A process for the preparation of a compound of general formula (I) as defined in claim 1 or of a corresponding physiologically acceptable salt or solvate which comprises (A) the cyclization of a compound of general formula ( II): 10 | (II) ^ HN = CHCH2AlkÇ ^ in which Q is the radical NR ^ R ^ or a corresponding protected derivative or a labile group and R ^, R2, R ^, R ^, A and Alk are as defined for the general formula (I); or (B) the reaction of a compound of general formula (V): R1R2NS02A AlkY ^ (V), 5 'K' H in which Y is an easily displaced radical and R, R2, A and Alk are as defined for the general formula (I), or a corresponding protected derivative, with a compound of formula R ^ R ^ NH where R ^ and R ^ are as defined for the general formula (I); or (C) the reduction of a compound of general formula (VI): L '* Λ * 69 r1r2nso2a1 w I j {VI) i' V \ î! / 5 H in which W is a radical which can be reduced to form the radical AlkNR ^ R ^ or to form a protected derivative of the radical AlkNR ^ R ^, A "1 represents A or a radical which can be reduced to form the radical A and R ^, R2, R3, R ^ Alk and A .......: "are as defined for the general formula (I), or a corresponding protected salt or derivative thereof; or (D) the reaction of a compound of general formula (IX): t 15 XSO-A AlkXR RI il dx> kAJ H 20 in which X represents a labile group and, R ^, A and Alk are as defined for the general formula (I) with an amine of general formula (X): R1 \ NH (X) / K2 in which R ^ and R ^ are as defined for general formula (I); or (E) converting a compound of general formula, t (I) or a corresponding protected salt or derivative to another compound of general formula (I) or a corresponding protected salt or derivative; or 35 (F) the reaction of a protected derivative of formula L Λ. f ί * 70 general (I) to eliminate one or more protecting groups; and if necessary and / or if desired, complementary reaction of the compound thus obtained <in one or more stages comprising (G) (1) removing any protective group; and / or (2) converting a compound of general formula (I) or a salt thereof into a physiologically acceptable salt or a corresponding solvate. 10