BE1000072A4 - Indole derivatives useful as drugs and process and intermediates for their preparation. - Google Patents

Abstract

Indole derivatives useful as medicaments and process and intermediates for their preparation; indole derivatives correspond to formula (I) in which R1 is H, C1-6 alkyl, C3-7 cycloalkyl, phenyl or phenyl C1-4alkyl, R2 and R3 are independently H or C1-s alkyl, R4 and R5 are independently H, C1-7 alkyl or 2-propenyl, A is -CO- or -SO2-, n is 2 - 5 with the proviso that R1 is not H when A is -SO2, and their physiologically acceptable salts and solvates; these compounds with potent and selective vasoconstrictor activity are useful for the treatment of migraine; processes and intermediates for their preparation are also described.

Description

       

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



   Migraine pain is associated with excessive dilation of the cranial vascular system, and known treatments for migraine include the administration of compounds with vasoconstrictive properties, such as ergotamine. However, ergotamine is a non-selective vasoconstrictor that contracts blood vessels throughout the body and has undesirable and dangerous side effects. Migraine can also be treated by administering a pain reliever, usually in combination with an antiemetic, but these treatments are of limited value.
 EMI1.1
 



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



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



   The invention provides indole derivatives of
 EMI1.2
 general formula I
 EMI1.3
 

  <Desc / Clms Page number 2>

 in which: R1 represents a hydrogen atom, an alkyl group
 EMI2.1
 C, C - C - cycloalkyl or phenylalkyl (C.-C.) R2 a hydrogen atom or a Ca-C3 alkyl group; R-represents only in C1-C3; R4 and, which may be similar or different, each represents a hydrogen atom, a group
 EMI2.2
 alkyl A represents CO-ou'SO-- and n represents an integer from 2 to 5 that R1 does not represent hydrogen when A represents -SO2-1 and the physiologically acceptable salts and solvates (for example hydrates) thereof .



   The invention covers all the optical isomers of the compounds of formula I and their mixtures, including
 EMI2.3
 their
In general formula I, the alkyl groups can be straight chain or branched chain alkyl groups, such as methyl, ethyl or isopropyl groups. The cycloalkyl group can for example be a cyclopentyl or cyclohexyl group.



   The alkyl fragment of a phenylalkyl group (C-C.) Can be for example a methyl or ethyl fragment.



   In a category of compounds of formula I the group R may be a C1-C6 alkyl, phenyl or phenylalkyl (C1-C4) group.

  <Desc / Clms Page number 3>

 



   In general, the group R1 is preferably a methyl or phdnyl group.



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



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



   Another preferred category of compounds is that in which R4 and Rus, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group. It is preferred that the total number of carbon atoms in R4 and Re
 EMI3.1
 does not exceed 2.



  A particularly important compost according to the invention is N-- indole-5-yl] -ethyl] -n) and its physiologically acceptable salts and solvates (for example hydrates).



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



   It should be noted that the invention extends to the other physiologically acceptable equivalents of the compounds according to the invention, that is to say the compounds

  <Desc / Clms Page number 4>

 physiologically acceptable which are transformed in vivo into the parent compound. Examples of such equivalents include N-acylated metabolic labile ddrivds which are physiologically acceptable.



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



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



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



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



   For oral administration, the pharmaceutical compositions can be in the form, for example, of tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as

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 EMI5.1
 binders (eg pregelatinized corn starch, polyviylpyrrolidone or hydroxypropylmdthylcellulose)? fillers (for example lactose, microcrystalline cellulose or calcium phosphate) of lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch or sodium starch glycolate); or wetting agents (for example sodium lauryl sulfate).

   The tablets can be coated according to methods well known in the art. Liquid preparations for oral administration may for example be in the form of solutions, syrups or suspensions or they may be presented in the form of a dry product intended to be reconstituted with water or another suitable vehicle before the 'employment.



  These liquid preparations can be prepared in a conventional manner with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example lecithin or gum arabic); non-aqueous vehicles (eg almond oil, oily esters or ethyl alcohol); and preservatives (for example methyl or propyl p-hydroxybenzoates or sorbic acid).



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



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

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 example of ampoules or in 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 agents of compositions, such as suspending, stabilizing and / or dispersing agents. Otherwise the active ingredient can be in the form of a powder intended to be reconstituted with an appropriate vehicle, for example sterile pyrogen-free water, before use.



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



   For administration by inhalation, the compounds according to the invention are conveniently presented in the form of an aerosol delivered by pressure vessels with the use of an appropriate propellant, for example dichlorodifluoromdthane, trichlorofluoromethane, dichlorotdtrafluorodthane, carbon dioxide or other suitable gas or using a nebulizer. In the case of a pressurized aerosol, the unit dose can be determined thanks to a valve delivering a metered amount.

   Capsules or cartridges, for example in gelatin, for use in an inhaler or an insufflator may be presented to contain a mixed powder made of a compound of the invention and of a suitable powder base such as lactose or starch.

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   A proposed dosage of the compounds of the invention for oral, parenteral, oral or rectal administration to humans (having an average body weight of about 70 kg for example) for the treatment of migraine is 0.1 A 100 mg of the active ingredient per unit dose can be administered for example 1 to 4 times a day. It should be noted that it may be necessary to modify, as usual, the dosage according to the age and weight of the patient as well as the severity of the condition to be treated.



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



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



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



   According to another aspect of the invention, the compounds of formula I and their salts or solvates (by

  <Desc / Clms Page number 8>

 physiologically acceptable hydrates) can be prepared according to the aforementioned generous methods. In
 EMI8.1
 the following methods, RR, R, RR, and n are as defined for general formula I unless otherwise indicated.



   According to a general process (A), it is possible to prepare a compound of general formula I, to react a compound of general formula II
 EMI8.2
 or a salt thereof (for example an addition salt of organic or mineral acid such as an addition compound of the hydrochloride, hydrobromide, maleate, sulfate or crdatininesulfate type) or an N-silylated derivative thereof ci or a protected derivative thereof with an intro- agent
 EMI8.3
 combining the R1A group.



   Appropriate agents for introducing the R1A group include the acids of the general formula R1AOH or the corresponding acylating agents.



   Acylating agents which can be used in practice in the above process include acid halides (e.g. carboxylic acid chlorides and sulfonyl chlorides), alkyl esters (e.g. ester methyl or ethyl, active esters (for example the 2- methyl ester

  <Desc / Clms Page number 9>

   pyridylic)), symmetrical anhydrides, mixed anhydrides or other activated derivatives of carboxylic acids such as those conventionally used in the synthesis of peptides.



   The process can be carried out in an appropriate aqueous or non-aqueous reaction medium, conveniently at a temperature of -70 to + 1500C. Therefore, the process using an acid halide, an activated ester or a. anhydride can be produced in a suitable reaction medium such as an amide (for example N, N-dimethylformamide) or hexamethylphosphoramide, a dther (for example tetrahydrofuran), an ester (for example acetate ethyl), a nitrile (for example laceto-nitrile), a halogdnoalkane (for example dichloromethane) or their mixtures, optionally in the presence of an organic base, for example a tertiary amine such as triethylamine or pyridine, or a base mineral,

   such as potassium carbonate or sodium bicarbonate. The organic base can also serve as a reaction solvent. The reaction is preferably carried out at a temperature of - 5 to + 25OC.



   The reaction using an alkyl ester can be carried out in a suitable reaction medium such as an alcohol (for example methanol), an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or mixtures thereof and in a practical manner
 EMI9.1
 at a temperature of 0
When A represents -CO-, carboxylic acids of formula R1COOH can also be used in the preparation of the compounds of formula I. The reaction is desirably carried out in the presence of a coupling agent, for example N, N'- carbonyldiimidazole or a

  <Desc / Clms Page number 10>

 carbodiimide such as N, N'-dicyclohexylcarbodiimide.



  The reaction can be carried out in a suitable reaction medium such as a haloalkane (for example dichloromethane), a nitrile (for example acetonitrile), an amide (for example dimethylformamide) or an ether (for example tetrahydrofuran) of conveniently at a temperature of - 50 to + 50 "C, preferably of - 5 to + 30 C. The reaction can also be carried out in the absence of a coupling agent in an appropriate reaction medium, such as a hydrocarbon (e.g. tolubne or xylene), conveniently at a time
 EMI10.1
 temperature from 50 to 120oC.



   One can, to prepare a compound of general formula I in which R1A represented -CHO, heat a compound of general formula II with ethyl formate, optionally in the presence of a solvent, for example ethanol.



   The compounds of general formula 11 are new and also form part of the invention.



   The compounds of general formula II in which R2 is a hydrogen atom can be prepared for example by reduction of a corresponding compound having a suitable reducible group as a substituent at position 5, such as - (CH2) n-1 CN or a corresponding cyano-substituted alkenyl group. The reduction can be carried out by catalytic hydrogenation or with a reducing agent such as lithium aluminum hydride.



   Such nitriles are new and form part of the invention. These compounds can be prepared, for example, by cyclization of a suitable hydra zone in a manner analogous to the general process described below.

  <Desc / Clms Page number 11>

 



  Alternatively, intermediates having a 5- (cyanoalkenyl) substituent can be prepared by reaction of an indole-
 EMI11.1
 5-carboxaldehyde suitable with a cyanoalkyl phosphonate.



   The compounds of general formula II in which R2 is an alkyl group can be prepared for example by reduction of a corresponding nitrile in the presence of an amine R2NH2 or by drafting of a compound of formula 11, in which R2 is an atom hydrogen, with a suitable alkylating agent.



   According to another general process (B), the compounds of formula I can be prepared by cyclization of a compound of general formula III:
 EMI11.2
 wherein Q is the NR4R5 group (or a protected derivative thereof) or a labile group or atom such as a halogen atom (for example chlorine or bromine) or an acyloxy group (for example an acyloxy group carboxylic
 EMI11.3
 or sulfonic, such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group),
The reaction can conveniently be carried out in aqueous or non-aqueous reaction media and at temperatures of 20 to 200 ° C, preferably 50 to 125 ° C.

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   Particularly practical embodiments of the method are described below.



   When Q is the NR4RS group (or a protected ddrivd thereof), the process is desirably carried out in the presence of polyphosphate ester in an editorial medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane; dichloroethane, dichlorodifluoromethane or their mixtures.



  The polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the process described in "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sons , 1967).



   Otherwise, the cyclization can be carried out in an aqueous or non-aqueous reaction medium in the presence of an acid catalyst. When an aqueous medium is used, it can be an aqueous organic solvent such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (for example dioxane or tdtrahydrofuran) as well as mixtures of such solvents.

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

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   When Q is an atom or labile group such as a chlorine or bromine atom, the reaction can be carried out in an aqueous organic solvent such as an aqueous alcohol (for example ie methanol, ethanol or isopropanol) by the absence of an acid catalyst,
 EMI13.1
 conveniently at a temperature of 20 to 200 ° C, preferably 50 to 125 C. This process results in the formation of a compound of formula I in which R4 and RS are both hydrogen atoms.



   According to a particular embodiment of this process, the compounds of formula I can be directly prepared by reaction of a compound of general formula IV:
 EMI13.2
 (in which T is a group -NR3NH2)
 EMI13.3
 or a salt thereof, with a compound of formula V:
 EMI13.4
 (wherein Q is as defined above) or a protected salt or derivative thereof (such as an acetal or ketal, formed for example with an appropriate alkyl orthoformate or diol, or protected in the form of a complex

  <Desc / Clms Page number 14>

 bisulfitic addition) using the appropriate conditions described above for cyclization d. s compounds of general formula III.

   It will be noted that in this embodiment of the cyclization process (B), a compound of general formula III is formed as an intermediate which can be reacted in situ to form the desired compound of general formula I.



   The compounds of general formula III can, if desired, be isolated as intermediates during the process for the preparation of the compounds of formula I in which a compound of formula IV or a salt or protected derivative thereof is reacted with a compound of formula v or a salt or protected derivative thereof, in water or in a suitable solvent, such as an aqueous alcohol (for example methanol), at a temperature for example of 20 to 30 C. If one uses an acetal or ketal of a compound of formula V, it may be necessary to carry out the reaction in the presence of an acid (for example acetic or hydrochloric acid).



   The compounds of general formula IV can be prepared for example from the corresponding nitro compounds (that is to say those in which T is -NO 2), according to conventional procedures.



   Another general process (C) for preparing the compounds of general formula I comprises the reaction of a compound of general formula VI:
 EMI14.1
 

  <Desc / Clms Page number 15>

 (in which Y is an atom or group which is easy to move) or a protected derivative thereof with an amine of formula
 EMI15.1
 R.



   The displacement reaction can conveniently be carried out on the compounds of formula VI in which Y is a halogen atom (for example chlorine,
 EMI15.2
 bromine or iodine) or an ORe group where OR6 is for example an acyloxy group which can derive from a carboxylic or sulfonic acid, such as an acetoxy, chloroacetoxy, dichloroacdtoxy, trifluoroacetoxy, pnitrobenzyloxy, p-toluenesulfonyloxy group or methane-sulfonyloxy.



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



   The compounds of general formula VI in which Y is a halogen atom can be prepared by reaction of a hydrazine of general formula IV with an aldehyde or a ketone (or a protected derivative thereof) of formula V in which Q is a halogen atom, in an aqueous alcohol (for example methanol) containing an acid (for example acetic or hydrochloric acid). The compounds of formula VI in which Y is the group OR6 can be prepared

  <Desc / Clms Page number 16>

 from the corresponding compound in which Y is a hydroxyl group, by acylation with the appropriate activated species (eg anhydride or sulfonyl chloride) using conventional techniques.



  The intermediate alcohol can be prepared by cyclization of a compound of formula III in which Q is a hydroxyl group (or a protected derivative thereof) under standard conditions.



   The compounds of formula I can also be prepared according to another general process (D) comprising the reduction of a compound of general formula VII:
 EMI16.1
 without which W is a group which can be reduced for
 EMI16.2
 provide the group- <CH) NR, or to provide a dEivprotgde- (CH) NR. and B represents the
R- requiredgroup - (CH2) n-as defined here or a group which can be reduced to - (CH2) n- or a protected salt or derivative thereof.



   The groups - (CH2) 2-and -NR4R5 required in position 3 can be formed according to reduction stages which are carried out separately or together.
 EMI16.3
 appropriately.



   Groups B which can be reduced to provide the required group- (CHg) n- include groups

  <Desc / Clms Page number 17>

 corresponding unsaturated such as alkenyl or C-Cc alkynyl groups.



   Examples of the groups represented by
 EMI17.1
 the substituent W include- (CHL) N0 - (CHL); -CH Z - (OH) CH-NRR ;-( CH) NRCOR '; -CH = CHNO- CH2COZ (where Z is an azydo group or the group -NR4 Rc or a protected derivative thereof and RIS is a hydrogen atom or a methyl or ethyl group or R'5 represents the group OR7 where R7 is an alkyl or aralkyl group).



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



   Groups which can be reduced to the group -NR4R5 where R4 and R5 are both hydrogen include nitro, azido, hydroxyimino and nitriles.



   In the latter case, the reduction provides the -CH2NH2 group and therefore a methylene group of the fragment
 EMI17.2
 -) -.



   A compound of general formula I in which Rc is a hydrogen atom can also be prepared by reduction of a corresponding compound in which R5 is a benzyl group, for example with hydrogen in the presence of a catalyst such as
 EMI17.3
 coal coal
The group -NR4 Required in which R4 and / or R5 are other than hydrogen can be prepared by reduction of a nitrile -CH2CN or of an aldehyde -CH2CHO in the presence of an amine R $ 4R5NH.

   
 EMI17.4
 I

  <Desc / Clms Page number 18>

 
A particularly suitable process for the preparation of a compound of formula I in which R4 and / or R5 is other than hydrogen is alkylation by reduction of the corresponding compound in which R4 and / or Ru represent hydrogen with an aldehyde or an appropriate ketone (for example acetaldehyde or acetone) in the presence of an appropriate reducing agent.



  Reducing agents suitable for use in this process include hydrogen in the presence of a metal catalyst or an alkali metal borohydride or cyanoborohydride (e.g. sodium borohydride or cyanoborohydride) using the conditions described below for reduction of the compounds of formula VII.



  In certain cases (for example for the introduction of the group R5 where R5 is methyl), the aldehyde (for example acetaldehyde) can be condensed with the amine and the intermediate thus formed can then be reduced by using d 'an appropriate reducing agent.



   The required -NR4 Re group in which R4 and / or R are other than hydrogen can also be prepared by reduction of a corresponding amide group, for example of
 EMI18.1
 formula- <CH-) NRCOR'eoüR'est as previously described.



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



   Suitable reducing agents which can be used in the above process for the reduction of the compounds of formula VII where W represents for example

  <Desc / Clms Page number 19>

 
 EMI19.1
 the groups-) NO, -) N CN (CH-CH2CH = NOH and -CH (OH) CH2NR4 R5 comprise hydrogen in the presence of a metal catalyst for example Raney nickel or a noble metal catalyst such as platinum, platinum oxide, palladium, palladium oxide or rhodium, which can be carried, for example, on charcoal, 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 tdtrahydrofuran, an amide for example dimethylformamide or an ester, for example acetate d ethyl, and at a temperature of - 10 to + 50 "C, preferably due to 5 A + 30 C.



   The reduction operation can also be carried out on compounds of formula VII in which W represents for example the groups
 EMI19.2
 - (CH) NO) -N NRRg; -CH = CHNOor -COCH2Z (where Z is previously defined), using a borohydride or cyanoborohydride of alkali metal or alkaline earth metal, for example borohydride or sodium cyanoborohydride or calium, this operation.

   which can be carried out in a practical manner in an alcohol such as propanol or ethanol or a nitrile, such as acetonitrile and at a temperature of 10 h 100OC, preferably 50 h 100 C. In certain cases, the reduction using a borohydride can be carried out in the presence of cobaltous chloride.



   When A represents -SO2-, the reduction of the compounds of formula VII in which W represents

  <Desc / Clms Page number 20>

 
 EMI20.1
 for example- (CH) JMO? -CH = CHNO? - (CHM - <CH) NRCOR'g CH = NOH NR. -COCONR.Re; -CH-COZet-COCHZ (oüR'and Z are as previously ddf inis) can also be carried out by using a metal hydride such as lithium aluminum hydride. This process can be carried out in a solvent, for example an ether such as teterahydrofuran, and suitably at a temperature of - 10 to + 100oC, preferably from 50 to 100oC.



   A particular embodiment of the general process (D) comprises the reduction of a compound of formula VII in which W is the group -CH-CN, for example by catalytic reduction with hydrogen in the presence of a catalyst such as charcoal palladid or rhodium alumina, optionally in the presence of a
 EMI20.2
 amine HNR.



   Suitable reducing agents which can be used in the reduction of group B include hydrogen in the presence of a metal catalyst. The conditions and the metal catalysts suitable for the reduction operation are those described for the
 EMI20.3
 reduction of group W.



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



   The compounds of formula VII in which W is the group -CH2CHO can be prepared by oxidation (for example with Jenes' reagent) of a

  <Desc / Clms Page number 21>

 compound of formula VI in which Y is a hydroxyl group. One can, to prepare a compound of formula VII in which West the group -CH CH = NOH, treat the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.



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



   Standard reducing agents such as sodium borohydride can be used to prepare a compound of formula VII in which W is the group -CH (OH) CH @ NR4R5 from the corresponding compound of formula VII in which W is the group -COCH2NR4R5 .



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



   The intermediate compounds of formula VII in which B represents a C2-CS a1cenyl group can be prepared by reaction of a compound of general formula VIII:
 EMI21.1
 

  <Desc / Clms Page number 22>

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



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



   For example, one can prepare a compost of formula example, I in which one or more of R3 ′ R4 and / or R5 are alkyl groups from corresponding compounds of formula 1 in which one or more
 EMI22.1
 reaction with a compound agent x group R3'R4 or Rus and L represents an atom or labile group such as an atom of a toxylate group) or a sulfate (R) The alkylating agent x of R3'R4 and RS represent hydrogen atoms, so there can for example be an alkyl halide (for example metal or ethyl iodide) an alkyl tosylate (for example methyl tosylate) or a dialkyl sulfate (for example dimdethyl sulfate).



   The alkylation reaction can conveniently be carried out in an inert organic solvent such as an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or an aromatic hydrocarbon (preferably toluene) 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

  <Desc / Clms Page number 23>

 sodium amide, alkali metal carbonates such as sodium carbonate or an alkali metal alcoholate such as sodium or potassium methylate, ethylate or tert.-butoxide, or tetrabutylammonium fluoride.

   When an alkyl halide is used as the alkylating agent, the reaction can also be carried out in the presence of an acid-binding agent such as propylene or ethylene oxide.



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



   Compounds of formula I in which one or both of R3 and R4 represent propenyl can be similarly prepared using an appropriate compound of formula RxL or (Rx) 2SO4.



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



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



  These groups can for example include aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl; or acyl groups such as

  <Desc / Clms Page number 24>

 N-benzyloxycarbonyl or tert.-butoxycarbonyl or phthaloyl.



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



   The subsequent cleavage of the protective group (s) can be carried out according to conventional operating methods. Thus, an aralkyl group, such as benzyl, can be cleaved by hydrogenolysis in the presence of a
 EMI24.1
 catalyst (eg palladium carbon) or sodium and liquid ammonia; an acyl group such as N-benzyloxycarbonyl can be eliminated by hydrolysis with for example hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation. The phthaloyl group can be removed by hydrazinolysis (for example by treatment with hydrazine hydrate) or by treatment with a primary amine (for example methylamine).



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



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

  <Desc / Clms Page number 25>

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



   When it is desired to isolate a compound of the invention in the form of a salt, for example in the form of a
 EMI25.1
 acid addition salt, this can be carried out by treatment of the free base of general formula I with an appropriate acid, preferably in an equivalent amount, or with creatinine sulfate in an appropriate solvent (for example aqueous ethanol) .



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



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



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

  <Desc / Clms Page number 26>

 



   Chromatography is carried out either conventionally using silica gel (Merck, Kieselgel 60, Art. 7734) or by flash chromatography (WC Still, M. Kahn and A. Mitra, J. Org. Chem. 2933, 43, 1978) on silica (Merck 9385) and by thin layer chromatography (TLC) on silica (Macherly-Nagel, Polygram) unless otherwise indicated.

   The following abbreviations define the 4tuants used for chromatography and TLC: (A) ethyl acetate-2-propanol-water-0.88 ammonia; 25/15/8/2, (B) CH2Cl2ethanol-ammonia 0.88: 89/10/1, (C) ethylen acetate (D) CH2Cl2-ethanol-ammonia 0.88: 83/5/15/1 , 5, (E) ethyl acetate-cyclohexane: 1/1, (F) ethermethanol: 9/1, (G) ethyl acetate-methanol: 9/1, (H) ether, (I) acetate d 'ethyl-2-propanol-water- ammonia 0.88: 200/15/8/2, (J) ethyl acetate-
 EMI26.1
 Ethyl 2-propanol-water-ammonia-2-propanol-water-ammonia 0, (L) CH2C12-ethanol-ammonia:

   87/12/1, 2, (M) (N) Intermediaries are subjected to an ordinary purity control by TLC with the use of ultraviolet light for detection and of sprayed reagents such as potassium permanganate (KMnO.) . In addition, indole intermediates are detected by spraying with aqueous ceric sulfate (Ce IV) and tryptamines by spraying with a solution of iodoplatinic acid (IPA) or cric sulfate.



   The nu magnetic resonance spectra
 EMI26.2
 key proton (NMR) are obtained either at 90 MHz using a Varian EM 390 device, or at 250 MHz using a Bruker AM or WM 250 device: s = singlet, d = doublet, t = triplet, m = multiplet and q = quadruplet.

  <Desc / Clms Page number 27>

 



  INTERMEDIATE 1 4-Hydrazinobenzene-acetonitrile hydrochloride
A solution of 4.0 g of sodium nitrite in 34 ml of water between - 50 and - 20 is added dropwise to a suspension of 7.6 g of 4-aminobenzene-acetonitrile in 80 ml of concentrated hydrochloric acid and the stirring is continued at -20 for 20 minutes.



  The mixture is filtered and the filtrate is added dropwise between 00 and 50 to a solution of 65 g of tin (II) chloride dihydrate in 130 ml of concentrated hydrochloric acid. The mixture is allowed to warm to room temperature overnight (17 hours), the precipitate is separated by filtration, washed with concentrated hydrochloric acid, cold absolute ethanol and anhydrous ether and dried to obtain the title salt in the form of a powder (6.05 g), p. f. 207-2100 (foam).



  INTERMEDIATE 2 3- [2- (1,3-dihydrol-1,3-dioxo-2H-iso-indole-2-yl) -ethyl] - 1H-indole-5-acetonitrile
A mixture of 3.15 g of intermediate 1 and 4. 95% of diethyl acetal of 4- (1, 3-dihydro-1, 3-dioxo-2H-iso-indole-) is heated at reflux for 2 hours. 2yl) -butanal in 150 ml of aqueous acetic acid (25%), the mixture is cooled, the precipitate is separated by filtration and
 EMI27.1
 washed with water (2 x 20 ml) and then with ether (100 The crude product is triturated with acetate ml). of ethyl to obtain the title compound in the form of a solid (3 , 2 g), p. f. 185-186.

  <Desc / Clms Page number 28>

 
 EMI28.1
 



  3 2- 1H-iso-indole-1-sulfate, 3- Hydrogenate over PdO on charcoal (50% aqueous paste, 0.96 g) at ordinary temperature and for 24 hours a suspension of 0, intermediate 2 in 100 ml of methanol containing 0.58 g of concentrated sulfuric acid. The catalyst is filtered off, washed with methanol and the filtrate is evaporated to dryness to obtain the title compound in the form of an oil (1.4 g).



  INTERMEDIATE 4 2- [} - 6thylJ-1H-iso-indole-1 hydrochloride, Hydrogbne, on PdO on carbon (aqueous paste at 50 s, 3.0 g) at ordinary temperature and under pressure for 24 hours, a solution of 1, of the intermediate in 400 of methanol containing 0, concentrated hydrochloric acid. The catalyst is filtered off, washed with methanol and the filtrate is evaporated to obtain the title compound in the form of a foam (1.2 g), TLC (A): Rf 0.6.



  INTERMEDIATE 3- [2- (1, 1H-indole-5-carboxaldehyde, 1/4 H20 About 2 g of Raney nickel are added to a stirred solution of 4.98 g of 3-3dioxo-2H-iso-indole- 2-yl) -thyl] -iH-indole-S-carbonitrile and 10, sodium hypophosphite in 100ml

  <Desc / Clms Page number 29>

 of pyridine, 50 ml of water and 50 ml of acetic acid. The mixture is heated to about 50 ° C for 6 hours by periodically adding Raney nickel (5 x about 2 g). After cooling, the mixture is filtered and the filtrate is diluted with 1.250 ml of water and extracted with ethyl acetate (3 x 500 ml).

   The combined organic extracts are washed with hydrochloric acid (2N; 2 x 500 ml), dried (MgSO 4), evaporated in vacuo and azeotropic distillation is carried out with toluene (2 x 100 ml) to obtain the title aldehyde as a solid (4.6 g). A sample (0.53 g) is purified by chromatography (C) to obtain the pure title aldehyde in the form of a solid (0.49 g), p. f.



    202-2030.



  INTERMEDIATE 6
 EMI29.1
 
A solution of 1.6 ml of diethyl cyanomethylphosphonate in 40 ml of anhydrous tetrahydrofuran (THF) is slowly added to a stirred suspension.
 EMI29.2
 NaH (80%; 0, g) in 40 ml of THF under nitrogen.



   After 10 minutes, a solution of 1.70 g of Intermediate 5 in 40 ml of THF is added to the clear solution obtained and the mixture is stirred at ordinary temperature for 19 hours. The solution is then subjected to a partition between 200 ml of 1N hydrochloric acid containing 50 g of NaCl and ethyl acetate (3 x 150 ml). The combined organic extracts are dried (MgSO 4) and evaporated to dryness to obtain a solid (1.53 g) which is purified by chromatography (E) to obtain the title compound in the form of a crystalline solid (1 , 13 g), p. f. 232-2340.

  <Desc / Clms Page number 30>

 
 EMI30.1
 



  INTERMEDIATE 7 4-ss- acetonitril 9, of 4, dimethylbutanamine are added to a stirred suspension of 9.2 g of [4- (dimethylamino) -butylidene] -hydrazino] -benzene-intermediate 1 in 200 ml of deionized water at ordinary temperature under nitrogen, 22 ml of 2N hydrochloric acid (pH 2) are added and stirring is continued at ordinary temperature for 5 hours. The clear solution is made alkaline with
 EMI30.2
 200 ml of aqueous NaHCO .. A 8 and extracted with CECI% (3 x 200 ml). The organic layers are dried (MgSO4) and evaporated to obtain the title compound in the form of an oil (15.6 g). TLC (silica, B): Rf = 0.35.



  INTERMEDIATE 8 Oxalate of 5- (cyanomethyl) -N, N-dimethyl-1H-indole-3dthanamine
15.4 g of intermediate 7 are heated under reflux with 108 g of polyphosphate ester in 200 ml of CHCl 3 with stirring under nitrogen for 8 minutes. The mixture is poured onto ice, 500 ml of 8% aqueous NaHCO3 are added and, after 20 minutes of stirring, the layers are separated and the aqueous layer is extracted with CHCl3 (3 x 400 ml).

   The aqueous layer is further basified to pH 9 with 200 ml of 2N Na2CO3, solid NaCl is added and the mixture is extracted with CHIC1- (3 x 400 ml). The combined organic layers are dried (MgSO4) and evaporated to obtain an oil (40.2 g).
 EMI30.3
 The oil is subjected to a partition between 200 ml of ethyl acetate and 2N hydrochloric acid (4 x 40 ml); the aqueous layers are made alkaline (200 ml of 2N NaOH

  <Desc / Clms Page number 31>

 and 20 ml of 5N NaOH) and Qn extracted with ethyl acetate (4 x 100 ml). The last organic layers are washed with soda water, dried (MgSO4) and evaporated to obtain an oil (9.3 g).

   Purification by flash chromatography (B and D) provide a first crop (1.91 g) as an oil and a second crop (4.0 g) also as an oil. The oil from the second crop is dissolved in 10 ml of hot methanol and 1.59 g of oxalic acid are added in hot methanol.

   By cooling, crystals deposit and after cooling in ice, the crystals are separated by filtration, washed with methanol and dried to obtain the compound of
 EMI31.1
 titre (4, INTERMEDIATE 9 N3 Dioxalate, N "-dimethyl-1H-indole-3, 5-diethanamine 3, of intermediate 8 are subjected to a partition between 100 ml of 8% aqueous NaHCO 3 and CH 2 Cl 2 (3 x 80 ml), the organic layers are dried (MgSO 4) and evaporated to obtain the free base in the form of an oil (2.41 g). The oil is hydrogenated at 400 and 4.8 bars over 1.0 g of 5% rhodium-containing alumina in 200 ml of 7% w / w ethanolic ammonia for 15.5 h The catalyst is separated by filtration and the solvent is evaporated to obtain an oil (2.58 g).

   A portion (t, 37 g) of the oil is dissolved in 6 ml of methanol and 1.12 g of oxalic acid in 2 ml of methanol are added. The addition of 80 ml of anhydrous ether provides a gum which is triturated with anhydrous ether to obtain the title compound as a solid (1.79 g), e.g. f. 160-170Q (foam).

  <Desc / Clms Page number 32>

 



  INTERMEDIATE 10 Dichlorhydratede N3, N3-dimethyl-1H-indole-3,5-di-dthanamine
 EMI32.1
 Hydrogen 2, intermediate 8 b 3, 8 on 10% palladid carbon (aqueous paste
40 to 50%; initially 1, 2 g, then addition of 2, 4 9 after 25 hours and 1.2 g after 70 hours) in 240 ml of ethanol containing 2, 4 ml of concentrated hydrochloric acid for 138 hours. The catalyst is separated by filtration and the solvent is evaporated to obtain a foam (2.81 g) of which a sample is submitted (approximately 0.7 g). Ai is partitioned between 100 ml of saturated aqueous Na2CO3 and butanone (3 x 70 ml).

   The organic layers are washed with salt water, dried (MgSO) and evaporated to obtain an oil (0.57 g).



  A sample (169 mg) of the oil is purified by flash chromatography to obtain an oil (46 mg).



  CCM (A): Rf = 0.35.



  EXAMPLE 1
 EMI32.2
 Composed of 3-methane-sulfonamide of creatinine, acid and water (1 (i) ethyl) A solution of 1, diaire 3 is treated in 10 ml of pyridine h 5 ml of methanesulfonyl chloride. hours at room temperature, the mixture is poured onto 20 ml of concentrated hydrochloric acid and 100 g of ice.

   The solid obtained is collected and purified by chromatography.

  <Desc / Clms Page number 33>

 written (F) to obtain the title compound in the form of a foam (0.45 g). CCM (C): Rf = 0.2.
 EMI33.1
 (ii) N-ss-ethylj-methanesulfonamide of crdatinine, sulfuric acid and water 1: 1)
A solution of 0.29 g of the product of stage (i) in 5 ml of ethanol and 2 ml of tetrahydrofuran is treated with 0.2 ml of hydrazine hydrate and the mixture is heated at reflux for 3 hours. After cooling, the solution is evaporated to dryness and the solid obtained is partitioned between 50 ml of ethyl acetate and 10 ml of a saturated solution of K2CO3.

   The aqueous layer is extracted with ethyl acetate (3 x 50 ml), the organic layer is dried (MgSO4) and evaporated to obtain an oil. This is dissolved in 20 ml of a hot mixture of ethanol and water (9/1) and treated with an aqueous solution of creatinine and sulfuric acid
 EMI33.2
 (1/1 2 M of the crystallized title (0.16 g), p.



  NMR <$ (DO) includes and CHCHNH and creatinine N-Me); 7, 2 (1H, and i7, 5-7, 7 (2H, m, indole-4 and indole-7).



  EXAMPLE 2
 EMI33.3
 Composite of N- ethyT] -methanesulfonamide, creatinine, sulfuric acid and water (i) N-C2- 5-yl-ethyl] -formamide, 1/4 H20 Refluxed for 48 hours a solution of 0.98 g of the product of Example 1 in the form of the free base in 50 ml of ethyl formate and 50 ml of ethanol. The solvent is evaporated in vacuo and the residue is subjected

  <Desc / Clms Page number 34>

 to a partition between 25 ml of sulfuric acid t N and 50 tnl of acetate of thyl. The aqueous layer is extracted with 25 ml of ethyl acetate and the organic extracts are washed.
 EMI34.1
 ques combined with 25 ml of salt water, dried on MaSO. and evaporated under vacuum to obtain an oil. Purification by column chromatography (C and F) provides a foam.

   By trituration with ethyl acetate, the title compound is obtained in the form of a solid (0.15 g), e.g. f. 89-91D.
 EMI34.2
 



  (ii) indole-5-yl] -6thyL] -n) creatinine, sulfuric acid and water (2: 2: 2: 1)
A solution of 0.6 g of the product of stage (i) in 200 ml of anhydrous tetrahydrofuran (THF) is added dropwise under nitrogen to a stirred suspension of 0.7 g of LiAlH. in 15 ml of anhydrous THF. The mixture is brought to reflux for 5 hours, cooled in ice and the excess reagent is decomposed by addition
 EMI34.3
 conserved water at 10% in THF. 50 ml of salt water are added and 100 the insoluble material is filtered off and the aqueous layer is extracted with 100 ml of ethyl acetate.

   The combined organic extracts are washed with 50 ml of salt water, dried (NaSOj and evaporated in vacuo to obtain an oil. The oil is dissolved in a hot mixture of
 EMI34.4
 24 ml of ethanol and 3 ml of water and an aqueous solution of creatinine and sulfuric acid (1/1; 2 M; 0.5 ml) is added. Filtration of the cooled mixture provides the title compound as a solid (0.37 g), e.g. f.222-224.
 EMI34.5
 



  RMNS CHNHMe and CHCH, and creatinine N-Me). '

  <Desc / Clms Page number 35>

 (D20) includes: 2, 6-3, 6 (17H, m, CHEXEMPLE 3 composed of N- [3- [3- (3- (2-aminoethyl) -1H-indole-5-yl] -propyl] -
 EMI35.1
 mdthanesulfonamide, creatinine, sulfuric acid and (1) 2-yl] -ethyl] -1H-iso-indole-1, 3- (2H) -dione hemisulfate
IleauOn hydrogen At ordinary temperature and under pressure, a solution of 0.95 g of intermediate 6 in 550 ml of methanol and 1.0 ml of sulfuric acid on 10% palladium on carbon previously reduced (paste
 EMI35.2
 aqueous the empty catalyst N-D-ss-D ' <
A mixture of 4.7 g of the product from stage (i), 1.0 ml of methanesulfonyl chloride is stirred vigorously at room temperature for 24 hours.

   
 EMI35.3
 300 ml of an 8% solution of NaHCO 3 and 250 ml of ethyl acetate by adding 1.0 ml of methanesulfonyl chloride after 17 hours. The mixture is separated (which contains an insoluble solid) and the aqueous phase is further extracted with ethyl acetate (2 x 200 ml).



  The combined organic extracts are washed with 200 ml of 2N hydrochloric acid, dried (MgSO 4) and evaporated to obtain an oil (0.49 g) which is purified by chromatography on a silica column (H). When the appropriate fractions are allowed to stand, the title compound crystallizes quickly as a
 EMI35.4
 solid (0, 1

  <Desc / Clms Page number 36>

    g), p. f. 165-167 ". (Iii) N- [3- [3- (2-aminoethyl) -1H-indole-5-yl] propyl] -methanesulfonamide, creatinine, sulfuric acid and water (1: 1: 1: 1)
A solution of 0.48 g of the product of stage (ii) in 100 ml of methanol is treated with 1.0 ml of hydrazine hydrate and the mixture is refluxed for 1 hour
 EMI36.1
 20 minutes.

   After cooling, the solution is evaporated in vacuo and subjected to azeotropic distillation with ethanol (2 x 50 ml) to obtain a solid which is subjected to partitioning between 100 ml of a 2 N solution of Na2CO3 and ethyl acetate (3 # 100 ml). The combined organic extracts are dried (MgSO 4) and evaporated to dryness to obtain an oil which is dissolved in a hot mixture of 64 ml of ethanol and 8 ml of water and an aqueous solution of creatinine and d sulfuric acid (1: 1 2 K: 0.56 ml). By cooling, the title salt crystallizes (0.43 g), p. f. 212-2140.
 EMI36.2
 



  NMR MHSOMe, CHCH, and crdatinine N-Me); (4H, and 10, EXAMPLE 4 Compound of 2-ss-acetamide, creatinine, sulfuric acid and water (10 (i) N- [2- -1] - -acetamide,
A solution of 0.3 g of intermediate 4 in 10 ml of pyridine is cooled in an ice bath and treated dropwise with stirring with 0.3 ml of acetic anhydride. The solution is stirred at room temperature for 1 hour, diluted with 15 ml of water and stirred for 15 minutes. We pour the solution

  <Desc / Clms Page number 37>

 obtained in 50 ml of 2N hydrochloric acid and extracted
 EMI37.1
 with ethyl acetate (2 x 50 ml).

   The combined extracts are washed with 50 ml of 2N hydrochloric acid, 50 ml of 2H Na2CO3, dried over Na2SO4 and evaporated in vacuo to obtain a foam which is purified by chromatography (C) to obtain the compound of titer as a solid (0.125 g); m.p. 165-168.



  (ii) Compound of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] - ethyl-acetamide, creatinine, sulfuric acid
 EMI37.2
 and water (10: 12: 11: 20) A solution of 0.5 g of the product of stage (. i) in 100 ml of methanol containing 1.0 ml of hydrate is refluxed for 3 hours hydrazine, evaporated in vacuo and evaporated with ethanol (2 x 20 ml). The solid obtained is subjected to a partition
 EMI37.3
 between 100 ml of a 2 N solution of Na2CO3 and ethyl acetate (2 x 100 ml).

   The combined organic extracts are dried (Na2SO4) and evaporated under vacuum to obtain an oil which is dissolved in a hot mixture of 16 ml of ethanol and 2 ml of water and treated with an aqueous creatinine solution and sulfuric acid (1/1? 2 M; 0.5 ml). By cooling, the title salt crystallizes (0.3 g); p. f. 211-2140.



  NMR # (D2 O) includes 2.95 (3H, s, NHCOMe); and 2, 7-3, 6 (11H, m, CH2 CH2 NHCO, CH2 CH2 NH2 and crdatinine N-Me).



  EXAMPLE 5
 EMI37.4
 N - /] - \) - -5-Yl] -ethyl] -acetamide oxalate
0.4 g of intermediate 10 is added at room temperature to a stirred solution of 0.5 ml of triethylamine in 15 ml of anhydrous tetrahydrofuran under nitrogen and stirring is continued at temperature

  <Desc / Clms Page number 38>

 ordinary for 5 minutes. The mixture is cooled to 0, 0.15 ml of ascetic anhydride is added and stirring is continued for 4 hours between 00 and 100. The mixture is subjected to a partition between 65 ml of a solution.
 EMI38.1
 saturated tion of butanone (3 x 50 ml) 2 3 the organic layers are washed with soda water, dried (MgSO.) and evaporated to obtain an oil (0.64 g).

   Purification by flash chromatography (B and D) provides an oil (139 mg) which is dissolved in 2 ml of methanol and which is combined with another
 EMI38.2
 sample (57 mg) that was prepared in a similar fashion. 77 mg of oxalic acid in 0.1 ml of methanol are added. The addition forms a preci-
5pité which is separated by filtration, washed with anhydrous ether and dried to obtain the title compound as a solid (205 mg), p. f. 85-930 (foam).
 EMI38.3
 



  NMR 6 (DMSO) includes 1, (BH, 7.98 (1H, t, CONH) and 10.9 (1H, d, indole-1).



  EXAMPLE 6
 EMI38.4
 N- 5-yl [-ethyl] -methanesulfonamide [2-D- [2- (dlmethylamino) -ethyl] -lH-indole-oxalate 0.905 g of intermediate 10 is added to a stirred solution of 1, 26 ml of triethylamine in 50 ml of anhydrous CH2Cl2 4 at room temperature under nitrogen and stirring is continued at room temperature for 5 minutes. 0.282 ml of methanesulfonyl chloride is added while cooling to 0 "and the mixture is allowed to warm to room temperature with stirring for 5 hours.

   The mixture is poured into 60 ml of a 2 N solution of Na 2 CO 3 and extracted with

  <Desc / Clms Page number 39>

   CH2C12 (3 x 50 ml); the organic layers are dried (MgSO4) and evaporated to obtain a gum (0.85 g) '.



  Purification by chromatography on a short column (B, D, I, J and K) provides an oil (65 mg) which is dissolved in 1 ml of methanol. 25 mg of oxalic acid in 0.5 ml of methanol are added. The addition of anhydrous ether forms a precipitate which is washed with anhydrous ether and dried to obtain the title salt in the form of a solid (38 mg); p. f. 159-165Q (foam).



  NMR 6 (DMSO) includes 2, 9-3, 0 (11H, m, NMe2 and
 EMI39.1
 ); and SO 7, 15 and 10,
MeSO2NHCH: CHEXEMPLE 7 N- [2- [3- [2- (dimethylamino) -ethyl] -1H-indole-5-yl] -ethyl] -benzamide oxalate
0.53 ml of benzoyl chloride is added to a stirred solution of 0.95 g of intermediate 9 in the form of the free base and 0.7 ml of triethylamine in 40 ml of anhydrous CH2Cl2 at ordinary temperature under nitrogen and stirring is continued at room temperature for 1 hour 40 minutes. We wash the mixture,
 EMI39.2
 with 20 ml of 8% lacquered NaHCO3 and water, it is dried (MgSO4) and the solvent is evaporated.

   Combine the oil obtained (1.47 g) with another portion prepared in a similar manner and purify by flash chromatography (B and L) to obtain a foam which is dissolved in 2 ml of methanol and a solution is added. 230 mg of oxalic acid in 1 ml of methanol. The addition of 80 ml of anhydrous ether forms a precipitate which is washed with anhydrous ether and dried to obtain the title salt in the form of a solid (0.873 g), p. f. 158-160.

  <Desc / Clms Page number 40>

 
 EMI40.1
 



  I NMR 2); 2, CONHCHCH2) CONHCHt) and indole-4); 8, 63 and 10, EXAMPLE 8 of N- [2- [3 0-1 H-indoleOxalate (DMSO5-yl] -ethyl] -benzenesulfonamide
0.61 ml of benzbnesulfonyl chloride is added to a stirred solution of 0.98 g of intermediate 9 in the form of the free base and 0.72 ml of triethylamine in 40 ml of anhydrous CH-Cl at ordinary temperature under nitrogen and stirring is continued at room temperature for 1 hour 40 minutes.



  The mixture is washed with 20 ml of 8% aqueous NaHCO3 and water (2 # 20 ml), dried (MgSO.) And evaporated to obtain a foam (0.98 g). It is combined with a similarly prepared product and the combined samples are purified by chromatography (M and N).



  The foam obtained (0.657 g) is dissolved in 2 ml of methanol and 154 mg of oxalic acid in 1 ml of methanol are added. The addition of 80 ml of anhydrous ether forms a precipitate which is washed by decantation with anhydrous ether, which is separated by filtration and which is dried to obtain the title salt in the form of a solid ( 0.702 g), mp about 80-90 (foam).
 EMI40.2
 



  NMR S and SONHCHCH);



  2.95-3.1 (6H, m, SO2NHCH2, CH2 and CH2 CH2 NMe2); 7.37 (1H, br s, SO2 NH); 7.55-7.7 (4H, m, Ph (m and p) and indole-4) and 10.9 (1H, s, indole-1).

  <Desc / Clms Page number 41>

 
 EMI41.1
 



  EXAMPLE 9 (i) indole-2-Yl) -benzamide and ethyl acetate (2/1)
A solution of 1.72 ml of thionyl chloride in 20 ml of anhydrous tdtrahydro-furan under nitrogen is added dropwise to a stirred and ice-cold solution of 1.41 g of benzolic acid in a mixture of 8.00 ml. of triethylamine and 80 ml of anhydrous tdtrahydrofuran. The solution is stirred in ice for 1 hour, 2.13 g of intermediate 4 are added and stirring is continued for 0.75 hour.

   The suspension obtained is subjected to a partition between 250 ml of 2N Na2CO3 and ethyl acetate (2 x 250 ml). The combined organic extracts are washed with water (2 x 250 ml) and 250 ml of 2N Na2CO3, dried (Na, SO.) And concentrated in vacuo. Chromatography (E) residual oil (3.1 g). The required fractions are combined and concentrated in vacuo to obtain the title compound as a foam (0.92 g) p. f. 75-820.
 EMI41.2
 



  (N - [) ethy-Q-benzamide, creatinine, sulfuric acid and water (1
A solution of 0.90 ml of hydrazine hydrate and 0.67 g of the product of stage (i) in 25 ml of ethanol is stirred at reflux for 3.5 hours, then allowed to cool. The suspension obtained is concentrated in vacuo
 EMI41.3
 and the residual solid is partitioned between 50 ml of 2N Na2CO3 and ethyl acetate (3 x 50 ml). The combined organic extracts are then dried (Na. ,, SO) and concentrated in vacuo. The residual gum (0.47 g) is dissolved in a hot mixture of 40 ml of ethanol and

  <Desc / Clms Page number 42>

 5 ml of water and an aqueous solution of creatinine and sulfuric acid (1/1; 2 M; 0.76 ml) is added.



  We separate. by filtration the solid which crystallizes on cooling, washed successively with 27 ml of an 8/1 mixture of ethanol and water and 10 ml of ethanol and dried at 600 for 8 hours to obtain the title compound under form of a solid (0.60 g); m.p. 228-229.5.
 EMI42.1
 



  NMR D20): 3.25 (9H, CH2CH2NH2 and creatinine NMe) and 7, indole-4 and indole-7).



  EXAMPLE 10 <i yl) -dthyq-1] -ben yl> -6thy w includes A solution of 1.38 ml of benzenesulfonyl chloride in 25 ml of anhydrous dimethylformamide is added dropwise under nitrogen to a stirred ice-cold suspension of 2.0 g of intermediate 4 in a mixture of 3.0 ml of triethylamine, 50 ml of anhydrous tetrahydrofuran and 25 ml of anhydrous dimdthylformamide and stirring is continued for 2.75 hours. The suspension is allowed to stand at room temperature overnight and is partitioned between 500 ml 2N Na2CO3 and ethyl acetate (2 x 50 ml). The combined organic extracts are washed with water (2 x 500 ml) and 500 ml of 2N Na2CO3, dried (Na2SO4) and concentrated in vacuo.

   The residual foam (2.41 g) is chromatographed (E). The required fractions are combined and concentrated in vacuo to obtain the title compound as a solid (0.73 g); p. f.183-184.

  <Desc / Clms Page number 43>

 



   (ii) Compound of N- [2- [3- (2-aminoethyl) -1H-indole-5-yl] -
 EMI43.1
 ethyfl-benzenesulfonamide, creatinine, dthyll-benzbnesulfonamide acid, crdatininer, sulfuric acid and water (1: 1: 1: 1)
A suspension of 0.60 g of the product from stage (i) and 0.75 ml of hydrazine hydrate in 30 ml of ethanol is stirred at reflux for 4.25 hours. The suspension obtained is evaporated under vacuum and the residual solid is subjected to a partition between 2S ml of 2N Na2CO and 13 x 25 ml ethyl acetate). The combined organic extracts are then dried (NaSO.) And concentrated in vacuo. The residual gum (0.46 g) is dissolved in, a hot mixture of 36 ml of ethanol and 4.5 ml of water and an aqueous solution of creatinine and sulfuric acid is added. d / 1? 2 M; 0.68 ml).

   The solid which is crystallized by filtration is separated by filtration, washed with a mixture of ethanol and water (8/1; 2 x 5 ml) and ethanol (2 x 5 ml) then dried under vacuum at 60 for 6 hours to obtain the title compound as a solid (0.48 g); m.p. 216-217.5.



  D NMR (DMSO) comprises: 2.78 (2H, t, SO2NHCH2CH2); 2.85-3.2 (9H, mWO2NHCH2, CH2CH2NH2 and creatinine N-Me); 7.2-7.4
 EMI43.2
 (3H, indole-7 and SO2NH); phdnyle and indole-4) and 10, 9 The following examples illustrate pharmaceutical formulations according to the invention, containing as active ingredient N-L2-LJ-l2-Cméthy1aminO) IH - indole-5-yl7thyi7-methane-sulfonatnide ' 'm, indole-2, Other compounds of the invention may be formulated in a similar manner.

  <Desc / Clms Page number 44>

 TABLETS FOR ORAL ADMINISTRATION DIRECT COMPRESSION
 EMI44.1
 
 <tb>
 <tb> mg / tablet
 <tb> Principle <SEP> active <SEP> 2.4
 <tb> Hydrognophosphate <SEP> from <SEP> calcium <SEP> 95, <SEP> 10 <SEP>
 <tb> B. <SEP> P. <SEP> *
 <tb> Croscarmellose <SEP> sodium <SEP> USP <SEP> 2, <SEP> 0 <SEP>
 <tb> Stearate <SEP> from <SEP> magnesium <SEP> B.P.

    <SEP> 0.50
 <tb> Weight <SEP> from <SEP> compression <SEP> 100 <SEP> mg
 <tb>
 * of a degree 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 polyethylene bag. The powders are mixed by vigorous stirring then the magnesium stearate is weighed and added to the mixture which is still stirred. The mixture is then compressed using a Manesty F3 tablet machine equipped with 5.5 mm flat punches with bevelled angles, in tablets, in order to achieve a compression weight of 100 mg.



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



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

  <Desc / Clms Page number 45>

 



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



   Alternatively, the tablets can be coated with sugar.



  INJECTION FOR INTRAVENOUS ADMINISTRATION
 EMI45.1
 
 <tb>
 <tb> mg / ml
 <tb> Principle <SEP> active <SEP> 0.6 <SEP> mg
 <tb> Chloride <SEP> from <SEP> sodium <SEP> BP <SEP> like <SEP> required
 <tb> Water <SEP> for <SEP> injection <SEP> BP <SEP> 1.0 <SEP> ml
 <tb>
 
Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted, using an acid or a base, so as to obtain optimal stability and / or to facilitate the solution of the active ingredient. Alternatively, suitable buffer salts can be used.



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



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


    

Claims (1)

 CLAIMS 1-Compounds corresponding to the general form  EMI46.1  in which R represents a hydrogen atom, an alkyl group C1-6 or C3-7 cycloalkyl or a phenyl or phdnyl- group  EMI46.2  alkyl (C); R2 represents a hydrogen atom or an alkyl group C1-3; R3 represents a hydrogen atom or an alkyl group C1-3; R4 and RS, which may be the same or different, each represents a hydrogen atom, a C1-3 alkyl group or a 2-propenyl group;  EMI46.3  A represents -CO-or-SO- and n represents an integer from 2 to 5; (provided that R, does not represent a hydrogen when A represents -S02-) and their physiologically acceptable salts and solvates.    2 - Compounds according to claim 1 or, in the general formula (I), R1 represents a group al-  EMI46.4  kyle in C. ,, phenyleouphenyl-alkyl (C <.). 3 according to claim 2 wherein, in the general formula (I), R1 represents a methyl or phenyl group.     - Compounds4 - Compounds according to any one of Claims 1 to 3 or, in the general formula (I),  <Desc / Clms Page number 47>    EMI47.1  n represents annuitant 2.  5-Compounds according to any one of claims 1 to 4 or, in the general formula (I), R2 represents a hydrogen atom.  6-Compounds according to any one of claims 1 to 5 wherein, in the general formula (I), R3 represents a hydrogen atom.  7-Compounds according to any one of claims 1 to 6 wherein, in the general formula (I), R4 and Re which may be similar or different each represent a hydrogen atom OR a methyl or ethyl group.  EMI47.2   8- 2-3-- le-5-y17éthyJ7-méthane-sulfonamide its salts and solvates! j & N-physiologically acceptable.  9 - Pharmaceutical composition comprising at least one compound of general formula (I) or a physiologically acceptable salt or solvate thereof with one or more physiologically acceptable carriers or excipients.    10 - process for the preparation of a compound of general formula (I) as defined in claim 1 or of a physiologically acceptable salt or solvate thereof which comprises: (A) reacting a compound of general formula (II):  EMI47.3  (wherein R2, R3, R4, R5 and n are as defined in claim 1) or a salt thereof or a derivative  <Desc / Clms Page number 48>  N-silyl thereof or a protected derivative thereof, with an agent for introducing the group R1A (where R1 and A are as defined in claim 1); or (B) the cyclization of a compound of general formula (III):    EMI48.1  (wherein R1, R2, R3, A and n are as defined in claim 1 and 0 is the group NR4R5 (where R4 and Rus are as defined in claim 1) or a protected derivative thereof or an atom or labile group); or (C) the writing of a compound of general formula (VI):  EMI48.2  (where R1, R2, R3, A, Y and n are as defined in claim 1 and Y is an easily displaceable atom or group) or a protected derivative thereof, with an amine of formula R4R5-NH (where R4 and R5 are as defined in claim 1); or (D) reduction of a compound of general formula (VII):      <Desc / Clms Page number 49>    EMI49.1  wherein R1, R2, R3 and A are as defined in claim 1 and W is a group which can be reduced to provide the group - (CH2) 2NR4R5 required, where R4 and Rc are as defined in claim 1, or to provide a protected derivative of- (CH2) 2NR4R5, and B represents the group  EMI49.2  - (CH)., - / or as defined in z n a group which can be reduced to- (CH) n-) or a protected salt or derivative thereof;  or (E) for preparing a compound of general formula (I) as defined in claim 1 or a physiologically acceptable salt or solvate thereof, consisting in subjecting another compound of general formula (I) or a salt or solvate of the latter in a mutual conversion reaction, or (F) subjecting a protdgd derivative of general formula (I) or a salt thereof a reaction to remove the protective group (s); and if necessary and / or if desired, subjecting the compound obtained in any one of the methods (A) to (E) b one or two complementary reactions comprising:  (i) removal of protecting groups; and (ii) converting a compound of general formula (I) or a salt thereof to a physiologically acceptable salt or solvate thereof.  11 - Compounds of general formula (II):  <Desc / Clms Page number 50>    EMI50.1  wherein R2 represents a hydrogen atom or a C1-3 alkyl group;  EMI50.2  R3 r * 13 R4 and Rus may be the same or different represents a hydrogen atom or an alkyl group each having a hydrogen atom, a C1-3 alkyl group or a 2-propenyl group; and n represents an integer from 2 to 5 and their salts.