FR2488606A1 - INDOLIC DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATIONS AS MEDICAMENTS - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS COMPOUNDS OF GENERAL FORMULA 1: (CF DRAWING IN BOPI) OR SYMBOLS HAVE IN PARTICULAR THE FOLLOWING MEANINGS: R REPRESENTS A CHO GROUP; R, R, R, R AND R EACH REPRESENT A HYDROGEN ATOM OR A C TO C ALKYL GROUP; R REPRESENTS A HYDROGEN ATOM OR AN ALCOHYL, CYCLOALCOYL, ALCENYL OR ARALCOYL GROUP OR R AND R FORM TOGETHER AN ARALCOYLIDENE GROUP, OR A SATURATED 5 TO 7 CHAIN MONOCYCLIC CORE; N IS ZERO OR 1; ET ALC REPRESENTS AN ALCOHYLEN CHAIN CONTAINING 2 OR 3 CARBON ATOMS.

Description

The present invention relates to heterogeneous compounds

  cyclic processes, processes for their preparation,

  pharmaceutical companies that contain them and their application

medical cation.

  The invention provides an indole of the general formula (I): R 2 N (C 1 R 3) n 4 / "u 'Alc" R 4 R 5

-_ N '' "R- R

  R is CHO, COR8, CO2R8, CONRgR10, CSNRgR910 or SO2NR9; R1 or R8 is alkyl, cycloalkyl, aryl or aralkyl; R9 represents a hydrogen atom or an alkyl group and R10 represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group; R2, R3, R4, R6 and R7, which may be the same or different, each represents a hydrogen atom or a C1-C3 alkyl group; R5 represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or aralkyl group or R4 and R5 together form an aralkoylidene group or R4 and R5 together with the nitrogen atom to which they are attached form a 5 to 5 saturated monocyclic ring; 7 links; n is zero or 1; and Alk represents an alkylene chain containing 2 or 3 carbon atoms which may be unsubstituted or substituted by at most two C 1 to C 3 alkyl groups; with the proviso that when n is zero and Ci) R4 and R5 are both alkyl groups, R1 is not CHO or COR8; and Cii) R1 does not represent the group 02NHa; and their salts, solvates Cp. ex.hydrates) and

  physiologically acceptable bioprecursors.

  The compounds according to the invention all comprise

  their optical isomers and racemic mixtures.

  With reference to general formula (C1), the alkyl groups may be straight or branched chain alkyl groups and preferably contain from 1 to 6 carbon atoms unless otherwise indicated. The

  alkyl groups represented by R8 may be unsubstituted

  killed or substituted with 1 to 3 halogen atoms, e.g. of fluorine. The cycloalkyl groups preferably contain from 5 to 7 carbon atoms. The term aryl, used as

  or in the expression aralkyl, preferably represents

  phenyl which may be unsubstituted or substituted by one or more alkyl groups, e.g. ex. a methyl, halogen atom, p. ex. fluorine, or hydroxy or alkoxy groups, e.g. ex. methoxy. The alkyl fraction of the groups

  aralkyl preferably contains from 1 to 4 carbon atoms.

  The aralkylidene group is preferably an aryl

  methylidene. Alkenyl groups preferably contain

from 3 to 6 carbon atoms.

  Suitable physiologically acceptable salts of the indoles of general formula (I) include acid addition salts formed with organic or inorganic acids, e.g. ex. hydrochlorides, hydrobromides, sulphates, fumarates and maleates. Other salts may be useful in the preparation of the compounds of formula CI),

  p. ex. creatinine sulfate adducts.

  The term "bioprecursors" used herein denotes compounds that have a different structure from that of

  composed of the formula [I] but who, when

  to an animal or to a human being, are transformed into

  the body is a compound of formula CI).

  The compounds of the invention mimic the methysergide by contracting an isolated flap of saphenous vein of dog

  (E. Apperley et al., Br. J. Pharmacol., 1980, 68, 215-

  224) and, like methysergide, have little effect on the blood pressure of the DOCA hypertensive rat. Methysergide is known to be useful in the treatment of migraine

  and produces a selective increase in

  carotid artery in anesthetized dogs; it has been hypothesized (P.R. Saxena, Eur J. Pharmacol, 1974, 27s

  99-105) that this is the basis of its effectiveness. The components

  that the Applicant has experienced have a similar effect in the anesthetized dog and the compounds according to

  the invention are thus potentially useful for processing

of migraine.

  The invention therefore provides a pharmaceutical composition

  adapted to the application in human

  takes at least one compound of general formula [I]) one of its physiologically acceptable salts, solvates (eg hydrates) or bioprecursors and formulated

  for administration purposes in any appro-

  prayed. These compositions can be formulated

  using one or more media or exci-

  pharmaceutically acceptable pients.

  Thus, the compounds according to the invention can be

  formulated for Oral Oral Oral Administration Purposes

  rectal or in a form appropriate to the administration

  by inhalation or insufflation.

  For oral administration, pharmaceutical compositions can take, e.g. eg, the form of

  tablets or capsules prepared by conventional means

  with pharmaceutically acceptable excipients

  as binders- [p. ex. maize starch pre-

  gelatinized, polyvinylpyrrolidone or hydroxypropyl-

  methylcellulose); fillers (eg, lactose, microcrystalline cellulose or calcium phosphate); lubricants [p. ex. magnesium stearate, talc or silica); disintegrants (eg, potato starch or sodium starch glycolate); or

  wetting agents [p. ex. sodium lauryl sulphate).

  The tablets can be coated by well-known methods

  specialists. Liquid preparations for administration

  may take Form, for example, solutions, syrups or suspensions, or may be

  presented as a dry product which can be reconstituted

  stored with water or other suitable vehicle before use. These liquid preparations can be

  prepared by conventional means with pharmaceutical additives

  as suspending agents (eg, sorbitol syrup, methylcellulose or

  hydrogenated edible fats); emulters

  sifiants [p. ex. lecithin or acacia); non-aqueous vehicles [p. ex. Almond oil, oily esters or ethyl alcohol); and preservatives [p. ex. methyl or propyl p-hydroxybenzoates or

sorbic acid).

  For oral administration the composition may

  take the form of tablets or lozenges formulated

classic way.

  The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Injectable formulations can be

  presented in unit dose form, p. ex. in ampou-

  or in multidose containers, with the addition of a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents, such as suspending agents,

  stabilizing agents and / or dispersing agents. The ingre-

  The active ingredient may also be in the form of powder for reconstitution with a suitable vehicle, e.g. ex. sterile pyrogen-free water, before use. The compounds of the invention may also be formulated as rectal compositions such as suppositories or enemas to keep, e.g. ex. containing conventional suppository bases like butter

cocoa or other glyceride.

  For the purposes of administration by inhalation,

  poses according to the invention are conveniently presented as an aerosol in a pressure package or nebulizer, using a suitable propellant, e.g. ex. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to provide a measured amount. Capsules and cartridges of gelatin can be formulated, e.g. ex.,

  for use in an inhaler or insufflator

  containing a powder mixture of a compound of the invention and a suitable powder base such as

lactose or starch.

  For oral, parenteral or oral administration to man for the treatment of migraine, it is suggested for the compounds of the invention a dosage of 0.1 to mg of active ingredient per unit dose which can be

  administered, p. eg, 1 to 4 times a day.

  Aerosol formulations are preferably available

  so that each measured dose or "puff" of

  rosol contains from 20 to 1000 g of the compound of the invention.

  I tion. The overall daily dose with an aerosol is in a range of 100 μg to 10 mg. The administration can be done several times a day, p. ex. 2, 3, 4 or B times with, p. eg, 1, 2 or 3 doses each time. The dose

  overall daily dose and the measured dose provided by

  sules and cartridges in an inhaler or insufflator

  may be twice that of Aerosol Formulations. A preferred class of compounds represented by the general formula CIJ is where Alc represents a chain

  unsubstituted alkylene containing 2 carbon atoms.

  Another preferred class of compounds of general formula C [I] is that where R 4 and R 5 each represent a hydrogen atom or a methyl or ethyl group and R 6 and R 7 each represent a hydrogen atom. It is preferred that the total number of carbon atoms in R4 and R5 together

does not exceed 2.

  Another Preferred Class of Formula Compounds

  [I) is where R3 represents a hydrogen atom

  gene. Another even more preferred class of compounds represented by the formula C (I) is where R2 represents

  a hydrogen atom or a methyl group.

  A preferred class of compounds according to the invention is represented by the general formula Ia1): ## STR2 ## wherein R1 represents a CHO group, CONH X CORSE or C02R Sa oRBa is an alkyl group containing from 1 to 4 atoms

  carbon, p. ex. a methyl, ethyl or isopropyl group

  butyl, or a trifluoromethyl group; R2 represents a hydrogen atom or a methyl group; n is zero or 1; and R4a and R5a, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group [with the precision that the total number of carbon atoms in R4a and R5a together does not exceed two and that when R1 represents a CHO group or a CORa group when n is zero, then R4 represents a group 1c (hydrogen atom), and their salts, solvates [p. ex. hydrates)

  or physiologically acceptable bioprecursors.

  A class of compounds according to the particular invention

  The most preferred is represented by the general formula lbz): ## STR1 ## wherein Rib represents a CHO, CONH 2 or COaR 8b group; Rab is a methyl, ethyl or isobutyl group; ; R2b represents a hydrogen atom or a methyl group; and R4b and RSb, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group [with the precision that the total number of carbon atoms in R4b and% 5b together does not exceed two and that when Rib is the CHO group, R4b is a hydrogen atom), and their salts, solvates (eg hydrates)

  and physiologically acceptable bioprecursors.

à488606

  Another group of compounds according to the invention

  Preferably, PreFere is represented by the general formula CII2CH2NR 4c5c 4c50 wherein S or B represents a CHO group or a COR group, where RE3 is an alkoxy group containing from 1 to 3 carbon atoms, e.g. ex. a methyl group; represents a hydrogen atom or a methyl group; 4o .. 5c _ _ and 1n group AoyetR, tire tires or di fferents,

  each represent a hydrogen atom or a methyl group

  or ethyl with the precision that the total number of carbon atoms in B4o and RBc together does not exceed two, and their salts, solvates (eg hydrates)

  16 and physiologically acceptable bioprecursors.

  According to another aspect of the invention, it is possible

  compounds of the general formula CI) and their salts, solvates [p. ex. hydrates) or physiologically acceptable bioprecursors, following the general methods set forth below. In the processes below, 1, f 2, R 3, R 4, R 5, R 5, R 7, n and Al are as defined for the general formula Cl) unless otherwise indicated. According to a general process (A), a compound of the general formula (I) can be prepared by reacting a compound of the general formula (II): ## STR2 ## or a protected derivative thereof, with a suitable reagent

  which serves to introduce the group R1.

  Suitable reagents which serve to introduce the R1 group include the acids of Formula R1OH or the

  corresponding acylating agents, cyanates

  appropriate organic isocyanates or iso-

organic thiocyanates.

  Acylating agents which can be conveniently employed

  in the above process include acid halides (eg acid chlorides and chlorides

  sulphamoyl) alkyl esters (e.g.

  that or the ethyl ester), activated esters [p. ex. 2- [1methylpyridinyl) ester, symmetrical anhydrides or

  mixed anhydrides, haloformates [p. ex. chlorine

  formate) or other activated carboxylic acid derivatives such as those conventionally used in

peptide synthesis.

  The process can be conducted in a reaction medium

  suitable aqueous or non-aqueous

  to a temperature between -70 and +150 C.

  Thus, the process using an activated ester or anhydride can be conducted in a suitable reaction medium such as an amide [e.g. ex. dimethylformamide), an ether

  [P..ex. tetrahydrofuran), a nitrile [p. ex. acetonitrile

  nitrile), a haloalkane [p. ex. dichloromethane) or a mixture thereof, optionally in the presence of a base,

  such as pyridine or a tertiary amine such as triethyl

  amine. The reaction is preferably conducted at a temperature of

between -5 and +25 C.

  The reaction using an alkyl

  ester in a suitable reaction medium as a

  alcohol [p. ex. methanol), a CP amide. ex. dimethyl

  formamide), an ether [p. ex. tetrahydrofuran) or a mixture thereof and conveniently at a temperature comprised

  between 0 and 100C. When the reagent is an in vivo cyanate

  organic isocyanate or organic isothiocyanate, the reaction can be carried out in water,

  alcohol [p. ex. ethanol), an amide [p. ex. dimethyl

  formamide), an ether [p. ex. tetrahydrofuran) or a mixture thereof, optionally in the presence of a base

  such as pyridine or a tertiary amine such as triethyl

  amine and conveniently at a temperature between O

and 1000C.

  The acids of formula R1OH can themselves be

  used in the preparation of compounds of formula [I].

  It is desirable to conduct the reaction with such an acid in the presence of a coupling agent, e.g. ex. the

  carbonyl diimidazole or N, N'-dicyclohexylcarbodiimide.

  The reaction can be carried out in a suitable reaction medium such as a haloalkane [e.g. ex. dichloromethane), a nitrile [p. ex. acetonitrile), an amide (eg dimethylformamide) or an ether (eg tetrahydrofuran)

  conveniently at a temperature between -5 and +30 C.

  The reaction may also be conducted in the absence of a coupling agent in a suitable reaction medium such as a hydrocarbon [e.g. ex. toluene or xylene],

  conveniently at a temperature of between 50 and 120C.

  A compound of the general formula (Ii) can be prepared wherein R1 is CHO by heating a compound of the formula

  [II) in formic acid, preferably in the form of

  flux. In a particular embodiment of this process, it is also possible to prepare a compound of formula CI) where R1 represents the group CONRgR9 or -CSNR gR10 by reaction of a compound of formula [II], or a derivative thereof protected, with phosgene or thiophosgene followed by an appropriate amine of formula RgRIONH. It is convenient to conduct the reaction in an inorganic solvent,

  as an aromatic hydrocarbon (eg toluene).

  Certain compounds of the general formula CII) 2 can be prepared by hydrogenation by reduction of a corresponding compound having a suitable reducible group as a 5-position substituent such as -ON or

  CH3-g-sen using, p. eg, lithium hydride-

  NOH aluminum. According to another general method (B), it is possible

  to prepare the compounds of general formula CI) by cyclisa-

  a compound of the general formula CIII): RR 2N (CHR 3) n-1 (III) NR 7 N = CR 6 CH 2 AlQ wherein Q is NR 4 R 5 Cou one of its protected derivatives) or an leaving group such as a halogen [p. ex. chlorae,

acetate, tosylate or mesylate.

  The appropriate cyclization processes are

  in "A Chemistry of Heterocyclic Compounds -

  Indoles Part I, Chapter II, eds., W. J. Houlihan, 1972 Wiley Interscience, New York.

  below, particularly useful embodiments

process ticks.

  When Q is the NR4R5 Cou group one of its protected derivatives), it is desirable to conduct the process in an aqueous reaction medium, such as an aqueous alcohol

  [P. ex. methanol) in the presence of an acid catalyst.

  (In some cases, the acid catalyst may also act as the solvent for the reaction.) Suitable acid catalysts include inorganic acids such as sulfuric acid or hydrochloric acid or organic carboxylic acids such as acetic acid. can also lead cyclization in the presence of a Lewis acid such as zinc chloride in ethanol or boron trifluoride in acetic acid.

  convenient to conduct the reaction at temperatures

  its 20 to 200 Cs preferably 50 and 125 C.

  When Q is an outgoing group like chlorine, 2nd. the reaction can take place in an organic solvent

  as an aqueous alcohol (eg, ethanol, ethanol).

  or the isopropanol), in the absence of a mineral acid, conveniently at a temperature between 20 and 200 C, preferably between 50 and 1250C. This process results in the formation of a compound of formula () I] o R4 and H5 are all

two of the hydrogen atoms.

  According to a particular embodiment of this process, the compounds of general formula CI) can be prepared directly by reacting a compound of general formula (IV): R 1 R 2 (CHR 3) n

| | 7 (IV) -

+ /, NR7NH2

  or a salt thereof, with a compound of formula CV), R6COCH2AlcQ CV) where Q is as defined above, or a protected salt or derivative thereof [such as an acetal or

  ketal p. ex. Formed with an appropriate alkyl orthoformate

  requested), using the appropriate conditions as it is

said above.

  The compounds of formula CIII) can be isolated as intermediates during the process for the preparation of compounds of general formula (I).

  compound of formula [IV], or a salt or protein derivative thereof

  with a compound of formula CV) or a protected salt or derivative thereof, in a suitable solvent, such as an aqueous alcohol [e.g. ex. methanol] and at a temperature of, for example, 20 to 300C. If an acetal or a ketal of a compound of formula [V] is used, it may be necessary to conduct the reaction in the presence of a Cp acid. ex.

  acetic acid or hydrochloric acid).

  As indicated in general procedures CC) and (0D below, the aminoalkyl substituent -AlcNR4R5 can be introduced at position 3 by various

  classical techniques which can, for example,

  tolerate a 3-substituent substituent modification or the direct introduction of the aminoalkyl substituent into

position 3.

  Thus another general method CC) for the preparation of compounds of general formula CI) involves reacting a compound of formula CVI): A1cY

R1R2 (CIIR3 Al-

  I1 t21 (CIIR3 - (VI) I iiI9k1 R6 R7 [where Y is an easily movable group] or one of its

  protected derivatives, with an amine of formula R4R 5NH.

  It may be convenient to carry out the displacement reaction on the compounds of the general formula [VI] where the substituent group Y is a Cp halogen atom. ex. chlorine, bromine or iodine) or a group OR OR G is, e.g. eg, an acyloxy group, such as acetoxy, chloroacetoxy, dichloroacetoxy, triFluoroacetoxy or p-nitrobenzacetoxy

  or a sulfonate group [p. exo p-toluenesulfonate

  It is convenient to carry out the above reaction in an organic solvent [optionally in the presence of water],

  examples of which include alcohols, e.g. ex. l1étha-

  nol; ethers, p. ex. tetrahydrofuran; esters,

  p. ex. ethyl acetate; amides, p. ex. the NYN-

  dimethylformamide; and ketones, p. ex. acetone, at a temperature between -10 and + 150aCP preferably

between 20 and 500C.

  The compounds of formula (VI) where Y is a halogen atom can be prepared by reacting a hydrazine of general formula [IV] with an aldehyde or a ketone Cou one of their protected derivatives] of general formula CV] o Q is a halogen atom in an aqueous alkanol [e.g. ex. methanol) containing an acid (e.g., acetic acid or hydrochloric acid) or treating a compound of the general formula CVI] o Y is a hydroxyl group with the appropriate phosphorus trihalide. We can also

  use intermediate alcohol where Y is a hydro-

  xyl to prepare compounds of Formula (VI) where Y is the OR group by acylation or sulfonylation with the appropriate activated species [e.g. ex. sulFonyl anhydride or chloride) using standard techniques. The intermediate alcohol can be prepared by cyclizing a compound of Formula CIII) where Q is a hydroxyl group

  protected derivatives) using standard conditions

  Sees. Compounds of general formula CI) can also be prepared by another general method [C) which involves reducing a compound of general formula CVII): Rilq2N (CHIR3) n1 (VII) N1 W is a group capable of being reduced to give is desired group AlcNR4R5 or one of its protected derivatives

  or a salt or a protected derivative thereof.

  The desired Alo and NR4R5 groups can be formed by

  reduction steps which are carried out separately or

  seems of any appropriate way.

  The groups which can be reduced to the Al group include the corresponding unsaturated groups and the corresponding O20 groups containing either a hydroxyl group,

a carbonyl function.

  The groups that can be reduced to the NR4R5 group where R4 and R5 are both hydrogens include the

  nitro, azido, hydroxyimino and nitrile groups. The reduction

  tion of a nitrile group gives the group C-NHO and

  thus a methylene group of the group Alc.

  The desired NR4R5 group o R4 and / or

  R5 are different from hydrogen by reduction of a nitrite

  the [CHR11] CHR12CN or aldehyde [CHR11] -CHR12CHO

  [o R1 and R12, which may be similar or diffe-

  each represents a hydrogen atom or a C 1-3 alkyl group and wherein x is zero or 1) in the presence of an amine, R 4 R 5 NH. The R 4 R 5 NH group may also be prepared by reaction of the corresponding compound o R 4 and / or R 5 represents hydrogen with an aldehyde or a

  appropriate ketone in the presence of a suitable reducing agent

  prayed. In some cases [p. ex. for the introduction of

  R5 or R5 is a benzyl group).

  hyde [p. ex. benzaldehyde) with amine then reduce

  intermediary thus formed using a reducing agent

appropriate.

  Examples of groups represented by substituent group W include:

  tNO2 [o T represents Alc or a corresponding alkenyl group

  ant to the Alc group); AlcN3; [CHR1i] xCHR12CN; COCHR12Z; HR] XCR1 = NOH; or CH [OH] CHR 2NR 4 R 5 [o R 11, R 2 and X Dnt as defined above and Z is an azido group

  N3 or the NR4R5 group or a protected derivative thereof).

  It will be appreciated that the choice of the reducing agent and the reaction conditions depend on the nature of the reaction.

  W group and other groups already present on the molecule.

  Suitable reducing agents that can be

  use in the above process include hydro-

  gene in the presence of a metallic catalyst

  R is the group CSNR9R10) B a borohydride or cyanoboro

  alkali metal hydride, p. ex. sodium borohydride or cyanoborohydride [pfW When W contains a nitrile or hydroxyimino group] or a metal hydride, e.g. ex. lithiumaluminium hydride (where R1 is CSNRgR10 and one of R2, R9 and R10 is hydrogen)). The metal catalyst can be, e.g. eg, Raney nickel or a noble metal catalyst, such as platinum, platinum oxide, palladium or rhodium, the support of which can be p. eg, charcoal or kieselgur. In the case of Raney nickel, we can also

  use hydrazine as a source of hydrogen.

  It may be convenient to conduct the reduction in the presence of hydrogen and a metal catalyst in a solvent such as an alcohol, e.g. ex. ethanol, an ether, p. ex. dioxane or tetrahydrofuran, or an ester, e.g. ex. ethyl acetate, at a temperature of between -10 and +500 ° C., preferably -5 and +30 ° C. It may be convenient to conduct the reduction with borohydride or cyanoborohydride

  alkali metal in an alcohol such as propanol or ethanol.

  nol and at a temperature between 0 and 100DC.

  In some cases, borohydride reduction may occur

  kill in the presence of cobalt chloride. The reduction with the metal hydride can be carried out using an ether, e.g. ex. tetrahydrofuran, as a solvent, and conveniently

  21 at a temperature between -10 and +100 C.

  Particular embodiments of this process include the reduction of a compound of formula [VII] where W is CHR 2CN, CHRiCHR 2NOD, CH = CR 2NOO or CHR11CR12 = NOH, for example, by catalytic reduction with

  hydrogen, p. ex. hydrogen in the presence of a catalytic

  lyser such as palladium, possibly in the presence of a

* mineral acid such as hydrochloric acid or sulfuric acid

America.

  A second embodiment of the process makes

  for example, the reduction of a compound of formula [VII] where W is the group CHR12CN in the presence of an amine

  HNR4R5 using hydrogen in the presence of an oataly-

  like palladium, except that R1 can not be

-CSNR9IO.0

  According to a third embodiment, it is possible to reduce a compound of formula (VII) where W is the group COCHR12Z, preferably by heating, using, for example, sodium borohydride in propanol. When Z is an azido group, the process results in the formation of a compound of the general formula [I] o R4 and R5 are all

two of the hydrogen atoms.

  According to a fourth embodiment, it is possible to reduce a compound of formula CVII) where W is the group AlcN3 or CH [OH] CHR12NR4R5, for example using

  hydrogen in the presence of a catalyst [p. ex. the pallat

  dium) or sodium borohydride. These reducing agents are also suitable for the reductive alkylation of, e.g. eg, AlcNHR5 in the presence of an aldehyde or a ketone

suitable [e).

  The starting materials or intermediate compounds of General Formula CVII) can be prepared by methods analogous to those described in British Patent Application No. 2,035,310 and in "A Chemistry of Heterocyclic Compounds - Indoles Part II". "

  chapter VI, dir. pubil W.J. Houlihan (1972) Wiley Inter-

science, New York.

  Compounds of formula [VII] where W is the [CHR11] CHR12CHO group by oxidation [p. ex. with Jones's reagent) a compound of general formula (VI) where Y is a hydroxyl group. A compound can be prepared

  of general formula [VII] where W is the group (CHR11) x-

  CR1 = NOH by treatment of the corresponding aldehyde

  with hydroxylamine hydrochloride using

standardized standards.

  The intermediate compound of the general formula (VII) can be prepared where W is the group AlcN3 from a compound of the general formula [VI] where Y is an atom

  halogen using conventional methods.

  Standard reducing agents such as sodium borohydride can be used to prepare a compound of general formula (VII) where W is CH (OH) CHR1tNR4R5 from the corresponding compound of formula [VII] where W is COCHR12NR4R5. The following reactions CE) can be carried out in any suitable order, if necessary and / or if desired, after any of the processes described above: C 1) Transformation of a Compound of General Formula (I) or one of its salts or protected derivatives to another compound of General Formula CI);

  Cii] removal of the protective group (s)] if

  presently, and Ciii) converting a compound of general formula CI) or a salt thereof to one of its salts; solvates Cp. ex. hydrates] or bioprecursors

physiologically acceptable.

  Thus, a compound of Formula (II) 2C according to the invention can be converted into another compound of the present invention.

  using conventional methods.

  For example, it is possible to prepare a compound of the general formula C1) R2, R4, R5 and / or R7 are alkyl groups from the corresponding compounds of formula [I]

  o one or more radicals R2 * R4, R5 and R7 represent

  feel a hydrogen, by reaction with a suitable alkylating agent such as an alkyl halide, a tosylate

  of alkyl or a dialkyl sulfate. The alkylation reaction

  is conveniently carried out in an inert organic solvent

  as an amide [p. ex. dimethylformamide), a Cp ether.

  ex. tetrahydrofuran) or an aromatic hydrocarbon

  (eg toluene), preferably in the presence of a base.

  The appropriate bases include, p. eg, alkali metal hydrides, e.g. ex. sodium hydride, alkali metal amides, such as sodium amide, carbonates of

  alkali metals, such as sodium carbonate or an alkoxy-

  of alkali metal such as methoxide, ethoxide or t-

Sodium or potassium butoxide.

  A particularly suitable method of preparing

  S tion of a compound of Formula [I) or R f and R5 is different.

  of hydrogen is the reducing alkylation of the

  where R4 and / or R5 are hydrogen, with an appropriate aldehyde or ketone [e.g. ex. the

  benzaldehyde or acetone) in the presence of a reducing agent

  appropriate. It is also possible to condense the aldehyde or

  ketone with the primary amine and then reduce the

  area thus formed using a suitable reducing agent.

  It will be appreciated that the choice of reducing agents and reaction conditions depends on the nature of the substituent groups already present on the

  formula CI) that it is to alkylate. Reducing agents

  appropriate agents that can be used in this reaction.

  tion include hydrogen in the presence of a metal catalyst, a metal borohydride or cyanoborohydride

  alkaline [p. ex. sodium borohydride or cyanoboro

  sodium hydride) using the conditions described above, or formic acid C e using the carbonyl compound as the reaction solvent), at a temperature between 0 and 100 C, the most convenient range.

being 0-500C.

  According to another embodiment, it is possible to

  a compound of the general formula [I] o R5 is a hydrogen atom by reduction of a corresponding compound of the general formula [I) where R5 is a benzyl group, for example with hydrogen in the presence of a catalyst , p. ex. the

10% palladium on charcoal.

  It must be appreciated that in some of the transfor-

  In addition, it may be necessary or desirable to protect sensitive groups that may be present in the molecule of the compound in question to avoid undesirable side reactions. Thus, during one of the reaction sequences described below, it may be necessary to protect the NR4R5 group, where

  R4 and / or R1 represent hydrogen, with a group of

  detachable at the end of the reaction sequence.

  These groups may include, p. eg aral groups

  such as benzyl, diphenylmethyl or triphenyl-

  methyl; or acstyl groups, such as N-benzyloxycarbo-

  nyl, t-butoxycarbonyl or phthaloyl.

  In some cases, it may also be necessary

  re to protect the nitrogen of indole o R7 is a hydrogen.

  Subsequent cleavage of the protecting group may be by conventional methods. So we can

  cleave an aralkyl group such as benzyl by hydrogen

  lysis in the presence of a catalyst [p. ex. palladium on charcoal); an acyl group such as N-benzyloxycarbonyl can be removed by hydrolysis with, e.g. eg, hydrobromic acid in acetic acid or by reduction, e.g. ex. by catalytic hydrogenation. The phthaloyl group can be removed by hydrazinolysis (e.g., treatment with hydrazine hydrate) or by treatment with an amine

primary [p. ex. methylamine).

  When it is desired to isolate a compound of the invention in salt form, e.g. ex. in the form of acid addition salt, it can be done by treating the free base of general formula CI) with an appropriate acid, preferably

  with an equivalent amount or with sulphate of

  in a suitable solvent (eg, aqueous ethanol).

  The starting materials or intermediate compounds can be prepared for the preparation of the compounds according to the invention by methods analogous to those described in the British patent application published under the

No. 2,035,310.

  In addition to their use as the last major step in the preparation sequence, the general methods indicated above for the preparation of

  the invention may also be used for the introduction of

  production of the desired groups at an intermediate stage in the preparation of the required compound. Thus, p. For example, the required group can be introduced at position 5 either before or after cyclization to form the indole nucleus. It must therefore be appreciated that in such multistep processes, the reaction sequence must be chosen in such a way that the reaction conditions do not affect groups present in the molecule and that it is desired to have

the final product.

  The invention is specified by the following examples.

  All temperatures are in degrees Celsius.

  Preparation 1 N- (3- [cyanomethyl) -1H-indol-5-yl) Formamide A solution of 5-amino-1H-indole-3-acetonitrile (0.5 g) in formate is stirred at room temperature for 24 hours. methyl [20 ml]. The resulting solid precipitate was filtered off, washed with ether (2 x 20 ml) and dried in vacuo to give the title compound (0.41 g) as a microcrystalline solid.

  white, Pf 196-200 [softening at 194).

  Preparation 2-Methylamino) -1H-indole-3-acetonitrile 1/4 hydrate A solution of -amino-1H-indole-3-acetonitrile (3.6 g) in ortho

  triethyl formate [80 ml] containing trifluorinated

  roacetic [3 drops]. The solvent is evaporated in vacuo and the residue is dissolved in absolute ethanol (50 ml), cooled to 0 ° C., treated with excess sodium borohydride (4.5 g) and refluxed for 5 h. .

  The cooled solution is then poured into a mixture of

  2N hydrochloric acid [400 ml] and ice cream washed

  with ethyl acetate [2 x 100 ml) and then basified

  (Na 2 CO 3) the acidic solution and extracted with ethyl acetate (2 x 200 ml). These combined extracts are dried (Na 2 SO 4), filtered and evaporated.

  solvent under vacuum which gives a brown oil. Chromatography

  column chromatography [silica gel 60, 250 g) eluting with ether gives the title compound as

  of a tawny solid C1.5 g), mp 120-122e.

Preparation 3

  2- [2- [2- [5-Cminomethyl] -1H-indol-3-ylethyl] -1H-isoindole;

  1.3C2H] -dione, hemisulFate, hydrated The mixture is hydrogenated at room temperature and pressure on 10% palladium. on charcoal 50% aqueous paste; 2.0 g) for 45 hours a suspension of

  3- [2- [1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl] ethyl) -IH-

  indole-5-carbonitrile [4.7 g] in methanol (250 ml) and sulfuric acid [1.5 ml]. The catalyst was removed by filtration, and the filtrate was evaporated to dryness to give an orange oil, which was dissolved in hot water [70 ml]. On cooling, the title compound crystallizes as a cream solid [3.8 g],

Mp 235-238 °.

Preparation 4

  Phenylmethyl C2-S5-Caminomethyl-1H-indol-3-yl] ethyl

carbamate

  i) PhenylmethylC2- [5-hydroxymethyl) -1H-indol-3-yl) ethyl]

  carbamate vigorously stirred under nitrogen at room temperature

  ambient for 5 hours a solution of 3- [2-C [phenyl]

  methoxy) carbonyl] amino] ethyl) -1H-indole-5-carboxylic acid [9 g] and carbonyldiimidazole [5.2 g] in tetrahydrofuran

  dry [THF] [150 ml]. A solution for 70 minutes

  Lithium borohydride [t, 6 g] in dry THF [70 ml] was added and the mixture was stirred for 18 h. Aqueous acetic acid (30% to 25 ml) is added slowly to

  mixture cooled with ice and the solution

  between brine (25%, 300 ml) and ethyl acetate (250 ml) The organic layer is washed with -D sulfuric acid (0.4 M, saturated with sodium chloride, 3 ml). x 80 ml), brine [100 ml] and a solution of

  potassium carbonate [25%, 2 x 100 ml). We evapo-

  The dried solution (MgSO4) is evaporated under vacuum, the residue is taken up in dichloromethane (150 ml) and the insoluble material is filtered off. The filtrate is evaporated in vacuo to leave the alcohol [9 g] as a colorless oil containing a certain amount of

  (at about 45 mol%) of ethyl acetate.

  Thin layer chromatography (TLC) SiO2 / EtO, Rf 0125.

  ii) Phenylmethyl (2- [5-C [aminomethyl) -1H-indol-3-yl) ethyl)

carbamate

  Poured for 2 minutes, keeping its temperature

  at 25, a solution of diethyl azodicarboxylate [1.48 g) in dry tetrahydrofuran (THF) (C ml), in

  a stirred solution of phenylmethyl - ([- [5 - (- hydroxymethyl) -

  1H-indol-3-yl) ethylcarbamate (2.6 g), triphenylphosphine (2.35 g) and phthalimide (1.75 g) in THF (20 ml). After 4 hours, the solvent is evaporated under vacuum and

  the residue is dissolved in a hydrazine hydrate solution

  [15 ml] in ethanol (100 ml)).

  After 5 days the mixture is partitioned between sulfuric acid (0.5 N, 500 ml) and ethyl acetate [2 x 300 ml]. The aqueous layer is basified with potassium carbonate and the product is extracted into ethyl acetate (200 ml). The dried extract (CNa2SO4) was evaporated under vacuum to leave the crude amine (0.7 g)

  in the form of a brown oil which subsequently solidifies

  surely. Crystallization from ethyl acetate gives the title compound [0.15 g] as crystals

cream color, mp 123.5-126.5.

Example 1

  N - [[3- [2-aminoethyl) -1H-indol-5-yl) methyl) acetamide, compound with creatinine, sulfuric acid and water

[1: 1: 1: 1)

  (f) N- [3- [2-fi, 3-dihydro-1,3-dioxo-2H-isoindol-2-yl] ethyl-1H-indol-5-yl) methylacetamide A cooled slurry is treated dropwise

  with ice, 2- [2- [5-Caminomethyl-1H-indol-3-yl] -

  ethyl] -1H-isoindole-1,3 [2H] -dione, hemisulfate, hydrated [1-, 01g) in pyridine [40ml] with acetic anhydride [0.6ml]. The mixture is stirred at room temperature for 1 hour and then water [15 ml] is added and after 15 minutes the solution is acidified with 2 N hydrochloric acid and extracted with sodium acetate. ethyl [3 x 150 ml]. The combined extract is washed with sodium carbonate [2 N; 300 ml), dried [MgSO4] and evaporated to dryness to give a yellow foam. Triturating with ethyl acetate Cenv. 10 ml) this gives the title amide in the form of a solid

  pale yellow crystalline [0.79 g, mp 180-1822.

  fii) N- [3- [2-aminoethyl) -1H-indol-5-yl) methyl) acetamide, compounded with creatinine, sulfuric acid and water

(1: 1: 1: 1).

  Refluxed for 4 hours a solution of

  N- [3- [2- [1,3-dihydro-1,3-dioxo-2H-isoindol-a-yl) ethyl) -

  1H-indol-5-ylmethyl) acetamide [0, EZ g) in ethanol

  f90 mi) and hydrazine hydrate [0.45 ml]. After cooling

  The solution is evaporated to dryness and the resulting white solid is partitioned between ethyl acetate (100 ml) and sodium carbonate [E N; 100 ml]. The aqueous phase is further extracted with ethyl acetate (3 x ml) and the combined organic phase is dried (MgSO 4) and evaporated to dryness to give

  yellow oil. This is dissolved in a hot mixture of ethanol

  [50 ml) and water [6 ml] and treated with an aqueous solution of creatinine and sulfuric acid [1: 1, 2 M, 0, SB5 ml3 to give, after cooling, the title compound under the form of a white crystalline solid (0.48 g),

Pf 233-235 (Dec.).

  Analysis Found: C 43.9, H 6 O, N 17.8; C13H17N30.C4H7N3 O.H2SO4.H2O requires: C 44.3, H-621, N 18.2%

Example 2

  Ethyl- [3- (2-aminoethyl) -1H-indol-5-yl] carbamate, compounded with creatinine, sulfuric acid and water (2: 2: 2: 1) [i] Ethyl- [3] cyanomethyl] indol-5-yl] carbamate

  A solution of 5-amino-1H-indole-3 is treated

  acetonitrile [1.5 g] in dimethylformamide (35 ml) with potassium carbonate [4.2 g] and chloroformate

  of ethyl [0.9 ml] added dropwise over 20 minutes.

  your. After waiting another S minutes, pour the

  reaction mixture in water [150 m] (i), the mixture is left

  The mixture is stirred for 30 minutes and then extracted with ethyl acetate [3 x 130 ml]. The acetate extracts are washed

  combined with water [2 x 150 ml), a solution of

  8% sodium bicarbonate [2 x 150 ml] and water [2 x 100 ml] and dried CMgSO 4) and the solvent was removed under vacuum under reduced pressure to give an oil.

  Brown. The oil is crystallized from ethyl acetate.

  and cyclohexane to give the title compound

  [1655 g) as a brown crystalline solid, mp 119-

  1230. Cii] Ethyl- [3- [2-aminoethyl)] - 1H-indol-5-yl] carbamate, compounded with creatinine, sulfuric acid and water

(2: 2: 2: 1]

  Catalyst is catalytically hydrogenated.

  [cyanomethyl] -IH-indol-5-yl) carbamate [1.5 g] on 5% rhodium on alumina [0.5 g] in a mixture of ethanol [50 ml] and ammonia [0]. 6 ml) for 40 h to 40 then 500 for another 8 h. The mixture is filtered through hyflo and evaporated to dryness to give

  a brown oil. This oil is purified by chromatography.

  column on 6 liters [25 9g) using ethyl acetate / 2-propanol / water / ammonia [25: 15: 4: 1] as eluent to give a brown oil [0.58 g] that one

  dissolved in ethanol and treated with a

  aqueous solution of creatinine and sulfuric acid [1: 1, 2 M, 1 ml] to give an off-white solid which is recrystallized from aqueous acetone to give the title compound as a -Solid colorless

[0.65 g], mp 184.5-187.50.

  Analysis Found: C 43.4, H 5.9, N 17.65; C13H17N302.C4H7N30.H-204.0.5H0 requires C 43.7, H 5.8;

N 18.0%

Example 3

  N-C [3- [2-aminoethyl) -1H-indol-5-yl) methyl) formamide, compound with oretinine. sulfuric acid and water

(1: 1: 1: 1)

  C1] Phenylmethyl-C [2- [5- [formylamino] methyl) -1H-indol-3-yl) -ethyl) carbamate A mixture of

  phenylmethyl [2- [5- [aminomethyl) -IH-indol-3-yl) ethyl) -

  carbamate [0.25 g), ethyl formate E5 ml) and ethanol (C1 ml). The solvent was evaporated in vacuo and the residue was evaporated with ethanol (2 x 5 ml) to give the title compound [0.27 g] as the title compound.

cream crystals, PF 114-116.

  C11] N-CC3- [2-aminoethyl)] - 1H-indol-5-yl] methylformamide, compounded with creatinine, sulphuric acid and water

(1: 1: 1: 1)

  A solution of phenylmethyl-C (-C 5 - [CFormylamino) is hydrogenated at ambient temperature and pressure.

  methyl] -1H-indol-3-yl) ethyl)] carbamate [0.34 g in the ethanol

  nol (30 ml) on palladium oxide on charcoal

  (10%, 0.3 g pre-reduced) until the absorption stops

  hydrogen. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residual oil is dissolved in a hot mixture of ethanol (8 ml) and water (0.8 ml) and an aqueous solution of creatinine and sulphuric acid (1: 1, 2 M; 0.8 ml Filtration of the cooled solution gives the compound of

  title in the form of a white solid (0.33 g), PF 197-

  (foam].

  Analysis Found: C 43.2, H 5.8, N 19.0 C1 H1 N30.C4H7N3O.H2504. HO requires C 43.05, H 5.85, N 16.85%

12 15 3 4 7 30.2S4.O

Example 4

  N- (3- (2-aminoethyl) -1H-indol-5-yl) f] oramide, compound with oretinine, sulFuric acid and water (1: 1: 1: 1,3). of the'. hydrazine hydrate '[30 ml]

  for 3 h in a mixture of N- [3- [cyanomethyl] -1H-

  indol-5-yl] Formamide (1.0 g) and Raney nickel (C2 g) in ethanol [100 ml] at reflux under nitrogen. The catalyst was removed by filtration and the filtrate evaporated to give an oil [1.1 g] which was dissolved in a hot mixture of ethanol (60 ml) and water (30 ml) and that it is treated with a solution of creatinine sulphate 24886 v C1.2 9g) in water [4 ml]. Dilution with ethanol [150 ml] precipitated the title compound as a

white solid [1.4 g], mp 175-183.

  Analysis Found: C 41.5, H 5.6, N 18.7 C11H13N3O.C4H7N3O.H2SO4.1.3H2O requires C 41.1, H 5.7, N 19.2%

- ,. .-,

Example 5

  N-C3- [2-aminoethyl-1-H-indol-5-yl) -N-methylformamide, compound with oretinine, sulfuric acid and water

[8: 10: 9: 16)

  Ci) N- [3-cyanomethyl] -1H-indol-5-yl) -N-methylformamide A solution of 5-methylamino-1H-indole-3-acetonitrile (0.2 g) is kept at ambient temperature for 36 hours. Formiatedemethyl [7 ml]. The solvent is evaporated under vacuum and the residue is partitioned between the acetate

  ethyl [10 ml] and hydrochloric acid [2 N, 10 ml).

  The organic layer is dried (NS 04) and evaporated in vacuo to give the title compound as

  of a tawny solid [0.13 g] l Pf 11 = 120c.

  C11] N-C3-C2-aminoethyl-1H-indol-5-yl] -N-methylformamide compound with creatinine, sulphuric acid and water

[8: 10: 9: 16]

  Following the procedure described in Example 4,

  N- [3-Ccyanomethyl) -IH-indol-5-yl) -N-methyl-

  Formamide [1.2g] in ethanol- [150ml] with Raney nickel [0.03g) and hydrazine hydrate [23ml] for 8h. The title compound [1.4 g] is obtained in the form of a buff solid; Mp 20-210 after sulfate formation

creatinine.

  Analysis Found: C 40.8, H 5.6, N 18.7;

  C12H15N30.1.25C4H7N30.1.125H2 S04.2H20

requires: - 0 40.4, H 6.0, N 18.7;

Example 6

  Ethyl- [3- [2-aminoethyl) -1H-indol-5-yl) methylcarbamate, compounded with creatinine, sulfuric acid and water

[1: 1: 1: 2]

  [i] Ethyl- [3- [cyanomethyl]] - 1H-indol-5-yl] methylcarbamate Ethyl chloroformate was added dropwise

  [0121 ml) in a stirred solution of 5- [methylamino) -IH-

  indole-3-acetonitrile (0.4 g) in dimethylformamide (15 ml). After 10 minutes the solution is diluted with water (30 ml), stirred for 30 minutes and extracted with ethyl acetate (2 x 100 ml). We wash the extracts

  combined with 10% brine [2 x 100 ml], bicarbonate

  8% sodium bonate (2 x 100 ml) and water [2 x 100 ml], dried (Na 2 SO 4) and evaporated in vacuo to give

  the crude product in the form of a brown oil. The tritu-

  ration with ether gives a tawny solid [0.4 g]. A sample is crystallized from ether to give the title compound as a white solid,

PF 104-1060.

  Cii) Ethyl- (3-c2-aminoethyl) -IH-indol-5-yl) methylcarbamate, compounded with creatinine, sulfuric acid and water

(1: 1: 1: 2]

  We hydrogenate at temperature and pressure

  ambient a solution of ethyl- [3- [cyanomethyl] -1H-indol-

  5-yl) methylcarbamate (0.2 g) in absolute ethanol (30 ml) containing concentrated hydrochloric acid (8 drops) over palladium on charcoal (10%, 0.4 g) that the absorption of hydrogen ceases [Bh, 23 m) 1]. The catalyst is removed by filtration, washed with absolute ethanol, and the filtrate is evaporated in vacuo to give a brown oil. The amine is dissolved in a hot solution of ethanol and water (8: 1, 18 ml) and treated with an aqueous solution of creatinine and sulFuric acid [1: 1, 2 M, 0.38 ml ). Filtration of the mixture

  reFrokdi gives the title compound in the form of

  white solid, PF 210-212 [dec.] [0.15 g).

  Analysis Found: C 42.7, H 5.9, N 16.7;

C14H19N302 -C4H7N30.H2S04.2H20

requires: C 42.5, H 6.3, N 16.5%

Example 7

  N- [3-C2-aminomethyl] -1H-indol-5-yl) urea, compound with creatinine, sulfuric acid and water [1: 1: 1: 1] [i) N- [3] [Cyanomethyl] -1H-indol-5-yl) urea A solution of sodium cyanate [1.2 g] is poured in.

  in water [10 ml) in a stirred solution of 5-amino-1H-

  indole-3-acetonitrile [1.5 g] in glacial acetic acid [5 ml] and water [10 ml]. Stirring is continued until a brown gum precipitates [10 minutes]. The aqueous layer is then decanted off, and extracted with ethyl acetate [2 x 100 ml]. The combined extracts are washed with 2 x 100 ml sodium carbonate solution (2N), dried (Na 2 SO 4) and evaporated.

  under vacuum to give the raw urea in the form of one (c-

  off-white solid [0.3 g). The brown gum was purified by column chromatography [silica gel 60, 25 g) using ethyl acetate as eluent to give

  an additional amount of the crude urea [0.1 g].

  Crude urea is then crystallized from isopropanol.

  to give the title compound in the form of a

Fawn solid (0.3 g), PF 200-204.

  Cii) N- [3-C2-aminoethyl] -1H-indol-5-yl) urea, compounded with creatinine, sulphuric acid and water [1: 1: 1: 1) Following the procedure of example 4, we reduce the

  N- [3-cyanomethyl) -1H-indol-5-yl) urea [0.2 g] in the ethanol

  (30 ml) with Raney nickel (0.03 g) and hydrazine hydrate (6 ml) for 5 h.

* COS title, 15 g) in the form of a solid creams Pf 208-

  212a after formation of creatinine sulFate.

  Analysis Found: C 40.1, H 5, G, N 1.05;

C11HI4N40.C4H7N30 H2S04 CH2

  requires: C 40.3, H 5s6, Nt 21.9%; TLC Silica - ethyl acetate / 2propanol / water / ammonia

0.88 (25: 15: 8: 2) BF 0.44.

Example 8

  Methyl-3-C2-aminoethyl) -IH-indol-5-yl) carbamate, compounded with creatinine, sulfuric acid and water [1: 1: 1: 1) Ci) Methyl- (3Ccyanomethyl) -IH -indol-5-yl) carbamate Following the procedure of Example 6Si], 5-amino-1H-indole-3-acetonitrile (0.8 g) in dimethylformamide [10 ml] is reacted with chloroformate. methyl [0.5 m] i) to give the title compound [0.44 g] as a white solid, mp 146-148 after column chromatography [silica gel 60, 100 g) eluting with ether. Cii] Methyl- [3- [2-aminoethyl)] - 1H-indol-5-yl) carbamate, compounded with creatinine, sulphuric acid and water

(1: 1: 1: 1)

  Following the procedure of Example 6 (ii), methyl [3Ccyanomethyl) -1H-indol-5-yl) carbamate (0.7 g) in ethanol [100 ml] on palladium on carbon dioxide was hydrogenated. wood C 10% ,. 1.0 g) for 24 hours to give, after formation of creatinine sulfate, the title compound

  [0.5 g] as a white solid, mp 197-200v.

  Analysis Found: C 41.4, H 5, 7, N 18.1;

C12H15N302.C4H7N30. H2SO 4.H20

requires: C 41.55, H 5.7, N 18.2%.

Example 9

  N- [3- [2-methylamino) ethyl) -1H-indol-5-yl) Formamide,

  with creatinine, sulfuric acid and water

[10: 12: 11: 20)

  A solution of N- [3-cycyanomethyl) is hydrogenated

  1H-indol-5-yl] Formamide [0.3 g] in absolute ethanol [30 ml] containing methylamine [33% in ethanol, 2 ml) at room temperature and with ambient pressure on 1: palladium on charcoal (at 10%, 0, OS g) for 24 h until the hydrogen uptake ceases [90 ml].

  The catalyst is filtered off, washed with absolute ethanol, and the filtrate is evaporated.

empty which gives a brown oil.

  The amine is dissolved in a hot mixture of ethanol and water (8: 1, 18 ml) and an aqueous solution of creatinine and sulfuric acid [1: 1, 2 M, 0.6 ml) is added . Filtration of the cooled mixture gives the title compound

  in the form of an off-white solid [0.35 g], mp 205-

2070.

  Analysis Found: C 40.6, H 5.5, N 18.8;

  C12H15N30.1,2C4H7N30.1,1H2 S04.2 20O

requires: C 40.7, H 5.8, N 18.6 '.

Example 10

  N-C [3- [2-aminoethyl] -1H-indol-5-yl) methyl) -N'-methylurea, compounded with creatinine, sulfuric acid and water

(2: 2: 2: 3)

  (i) N - ([3- [2- (1,3-dihydro-1,3-dioxo-H-isoindol-2-yl) ethyl] -1H-indol-Èylimethyl] -N'-methylurea Hemihydrate is cooled in an ice bath a suspension of

  2- (2 - [(5-Caminométhyl) -IH-indol-3-yl) ethyl) isoindole--LH

  1,3 [2H] -dione, hydrated hemisulfates [1.53 g) in the pyridine

  dine [50 ml] and treated dropwise with methyl isocyanate (2.5 ml). The mixture is stirred at room temperature for 4 h and water is added.

  C15 ml] to the white suspension obtained. After 10 minutes

  The yellow solution is acidified with chlorine

  water (2 N], and extracted with ethyl acetate} 3 x 100 ml.) The combined organic extract is washed with sodium carbonate solution (2N, 100 ml) and dried. magnesium) and evaporated to dryness resulting in a pale yellow solid. After trituration with ether, this gives the product of the pure title under the

  Crystalline Crystalline Form (1.22 g), mp 210-2120.

  The following compounds are prepared in a similar manner

  from 2 [2- [S- [aminomethyl)] - 1H-indol-3-yl] ethyl) -

  1H-isoindole-1,3 [(2H) -dione, hemisulfate, hemihydrate, and suitable isocyanate or isothiocyanate as described in detail in Table I.

Tablelu I

  Expression Duration Weight produced Reagent Vg1. of Reaction Vol. c Weight of No. of repair rea F pyridine product formula

(mi) (h) (ml) (g) mol.

(q) À- -

1 I 0 23 0; 8 0.4

C26N28N403. H20

C26H22N403- H20

C21H20N402S-

0> 4 C4H802

219 - 2.1

218 - 20 1

  8. Crystallized from methanol 2. Purified by column chromatography eluted with ether and then re-crystallized

silica gel 60, 20 g).

from ethyl acetate.

  t4 10 (i) b 10 (i) c o (i) d Q NCO PhNCO MeNCS 2.0 1.1 0.88 1.2 4.75 ro Co 0% o Example 10 [continued]

  [ii) N - [[3- [2-aminoethyl) -1H-indol-5-yl) methyl) -N'-

  methylurea, composed with creatinine, sulfuric acid and water [2: 2: 2: 3) Following the procedure described in Example I [ii]),

  "solution" of N- [3- [2- [1,1,3-dihydro-1,3-

  dioxo-2H-isoindol-2-yl) éthyli-indol-5-yl) méthyli-N, -

  methylurea, hemihydrate [0.81 g] in ethanol [80 ml] with hydrazine hydrate [0.8 ml] to give, after formation of creatinine sulfate, the title compound

  [0.32 9) as a white solid, mp 205-207D (dec).

  Analysis Found: C 42.5, H 5.9, N 20.0;

C1 3H1N4 C4H7N3O-H20S4. 1XH20

requires: C 42.1, H 6.2, N 20.2%.

  The following compounds are likewise prepared by

  protection "of the appropriate starting material as stated

in detail in Table II.

BOARD. II

  -l II ....... Jr Weight of starting material (g) Vol. EtOH (ml) = prod. (g) Vol.

N2H4.H20

(Ml)

soft formula

  ii) (i) b NHCO-0.73 75 1 0.56 18l26N40.C4H7N3O.H2SO4.H20! i) c 10 (i) c PhNHCO- 0.57 100 1 0> 48 C18H2oN40.C4H7N30O.H2SO4 ## STR6 ## ## STR13 ##

__. I ....... ......

  Table.II [continued]] C Found Required _, ..... c H H N Analysis e ex.

of the prod.

  P ((aCi (.i) b 220 - 222 48.8 6) 6 17.85 48) 6 6.9 18) 0 (dec)) iic 196 - 9 48> 9 5> 8 18> 15 49> 15 5) 8 18> 2 (d6c) 1 (ii) d 204 - 6 41.7 5.8 19> 7 41> 6 5, ,, 9519; 9 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ i _ _ _ _ _ _ _ _ _ _ _ _ _ ON CD UT dfex. prod. N of the

of, ex.

prod. departure R1 o A C

H N

Example 1 1

  [(i) N-CC3-C2-t1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indol-sylimethyl) benzamide Benzoyl chloride [0.9 mi) to a stirred suspension of 2- [2- [S-Caminomethyl) -1H-indol-3-yl)! ethyl) -1Hisoindole-1s, 3C2H) -dione, hydrated hemisulfate

  [1.0 g] in dry pyridine [40 mi]. The mixture is agitated

  at room temperature for 2.5 hours and then water (10 ml) is added. The resulting solution is stirred for 1 h and acidified with 2 N hydrochloric acid. The precipitated solid is filtered off, washed with water (30 ml) and dried (1.04 g). . Recrystallization from aqueous dimethylformamide gives the title amide

  in the form of yellow crystals [0.77 g], mp 227.5-229.

  The following compounds are likewise prepared from

  2- [2- [5- [Aminomethyl) -1H-indol-3-yl) ethyl) -1H-iso

  indole-1,3 [2H) -dione, hydrated hemisulfate and 4 appropriate chloro compound ER1-Cl] as described in detail in

Table III.

  C. Following the procedure described in Example 10 (ii), the following compounds are likewise prepared by "deprotection" of the appropriate starting material as described in detail.

in Table IV.

TABLE III

  N "Weight of Quantity O Weight Duration of eg product of Rc R1-C1 'reaction, product form P

starting 1 (ml) ti qh) (g) mol.

(g) mtol.

  (g) 11 (i) b 1> 0 Q COCl 1X2 5 0.62 C25H27N33 198-1985o

J 25 2 7N30319_985

  ) 11 (i) c 1; 4 PhCH 2 COCl 4) 8 6X 25 085 C 27 H 23 N 3 O 3 .H 2 20252035

0 85CH N 0 0 202; 5-203; 502

  11 (i) d 1X14 EtOCOCI 0) 5 1 0.92 C22H21N3O4. H2 15 158-9 11 (i) e 1.15 MeOCOCl 0.77 1J05 C21H19N304 150-1 1. Recrystallized from ethylenetate 2. Fermented to yield chloroform / ether. Cu OP

Example 12

  Ci) [3- [2- [1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl] ethyl) -

1H-indol-5-YLJ) methylurea

  A solution of 2-C2- [S- [aminomethyl) -IH-

  indol-3-yl) ethyl) -H-isoindole-1,3- [2H] -dione, hemisulFate

  hydrated [1.01 g] in hot water [27 ml] with a solution

  sodium cyanate (0.25 g) in water (9 ml) and

  heated on a steam bath for 1 hr.

  Said the reaction mixture and filtered to give the title urea as a white crystalline solid

[0.82 g], mp 230-2320.

  Cii) Following the procedure as described in Example Cii) a, the above product is "deprotected" as it is

detailed in Table IV.

TABLE & U I V

  Ex. NI dtex. Weight of the prod. of the prod. product Vol.EtOH Vol. of 3

  starting material R1 (ml) N2H4.H20 prod. Soft formula

(g) (g) (ml)

  ......., .., .. DTD: (il) a 11 (i) PhC0- 0.51 60 0; 3 0.24 C18H19N30.C4H44 2 (il) b 11 (i) b CO- - 0.61 30 0.35 0> 35 C 18 H 25 N 3 O.C 4 H 4 O 4 (c) (i) c PhCH 2 CO-0.68 50 0.53 0) C₁HH₁NN30O.C4H7N30O.H₂SO0, H₂O (ti) d 11 (i) d EtO 2 C 0.4 H 2 O 4 O 2 O (C 1 H) N 3 O 2 .C 4 H 7 N 3 O. H 2 O 4 .H 2 O (Li) e (i) MeO 2 C 0 O 52 60 0.70 0> 52 C 13 H 17 N 3 O 2 .C 4 H 7 N 3 H 2 SO 4 .H 2 O (11) f 12 (i) H 2 NCOO , 56 80 0.4 0.3 C12H16N4O. C4H7N30.H2S04. H20

Table IV

Csui you]

N ex! P. Analysis.

  that prod. C) Found N -c (OC) C n C H N

,. _.1

  (i i) (ii) (ii) (ii) a b c d (ii) e (ii) f

167 - 71

147 - 9

230-231 5

213 - 5

(Dec)

216 - 8

(Duke)

208 - 10

(d ('& <' 64) 1

6 3) 6

63) 6 51) 3

4 4) 1

  44.1 42) 9 41.8> 6 7> 0) 85 6 1, 85 6> 1; 8 9; 9 9) 8) 4 17 6 647 5 51 5 44; 5 17) 4) 7) 7 7) 0 6) 0 6> 1, 9) 9 j 3, 1) 7 17.3 17j6 21) 2 o o co oo co co o oe t TABLE IV Csuite]

  1. Transformed into a maleate salt with maleic acid in methanol / ether.

  Recrystallized from methanol / ethyl acetate.

  2. Transformed into a maleate salt with 1. maleic acid in methanol / ether.

  Re-crystallized from isopropanol / ethyl acetate.

t.

Example 13

  N- [3- [2-aminoethyl] - 1H-indol-5-yl) acetamide, compound with creatinine, sulfuric acid and water [2: 3: e: 5) i) N- [3 [Cyanomethyl] -1H-indol-5-yl) acetamide Acetyl chloride is added dropwise

  [0.21 ml) in a stirred solution of 5-amino-1H-indole-3

  acetonitrile [0.5 g] and pyridine [0.24 ml) in the acetonitrile

  dry nitrile [10 ml] at 0-20 under nitrogen. When the addition is complete, the solution is stirred at 0 for 30 minutes, poured into water [50 ml] and extracted with water.

  ethyl acetate [3 x 25 ml]. The combined extracts are dried

  [MgSO4), filter and evaporate under a slight pressure.

  reduced to give a brown solid [0.5 g9) that is

  recrystallises from a mixture of ethanol and cyclohe-

  hexane to give the title compound [0.43 g) in the form

  needles off-white, Pf 171.5-175.

  ii] N- [3C2-aminoethyl] -1H-indol-5-yl) acetamide, compound with creatinine, sulfuric acid and water [2: 3: 2: 5) Following the procedure described in Example 4, N- [3- [cyanomethyl) -1H-indol-5-yl) acetamide [0.3 g) in C15 ml ethanol) was reduced with RFaney nickel [0.06 g] and hydrazine hydrate [6.2 ml] for 6 hours. The title compound is obtained as a white crystalline solid, mp 177-182 [dec.] Analysis: Found: C, 40.6; H, 5.7; N 20.1%

  C12H15N3H7N3O.H15S4.2, SH20: C, 40.8; H 6, Z; N 19.8%

Example 14

  N- [3-C2-aminoethyl-1H-indol-5-yl] -2-methylpropanamide, compound with hydrochloric acid and water [4: 4: 3]

  Cii) A solution of N-C3- [cyanomethyl) -1H-

  indol-5-yl) -2-methylpropanamide [0.4 g) in ethanol

  absolute [SO ml] containing concentrated hydrochloric acid

  [10 drops] at room temperature and pressure on palladium on charcoal [10%, 1.5 g]

  for 16 h, before replacing the catalyst [at 10.1 g].

  After having waited again for 4-h, when the absorp-

  hydrogen (75 ml) has ceased, the catalyst is separated

  The mixture is filtered off, washed with absolute ethanol, and the filtrate is evaporated in vacuo to give a brown solid. The crude hydrochloride is crystallized from a mixture of methanol and ethyl acetate, to give the title compound as a solid

light brown [0.2 g], mp 274-276.

  Analysis: Found: C, 56.7; H, 7.4; N, 13.7; C14H19N30. 0.75H 2 O requires: C, 56.95; H, 7.3; N 14.2%

Example 15

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

[1: 1: 1: 2)

  Cii) N- [3- [cyanomethyl) -1H-indol-5-yl) is hydrogenated -

  trifluoroacetamide [1.3 g] in ethanol [50 ml] and ammonia (0.6 ml) at room temperature and pressure on rhodium-on-alumina (0.5 g) for 48 h.

  The mixture is filtered through hyflo and

  poring to dryness under reduced pressure to give

  a brown oil. The brown oil is purified by chromatography.

  column chromatography (silica gel 60, 25 g) using a

  mixture of ethyl acetate, 2-propanol, water and am-

  moniac [25: 15: 4: 1) as eluent. The solid obtained is dissolved

  naked in hot ethanol and treated with an aqueous solution of creatinine and sulfuric acid [2 M, 1: 1, 1 ml]

  then the solid obtained from the acetonitrile is recrystallized

  aqueous solution to give the title compound in the form

  of a pinkish solid, mp 186-215 Cdec.).

  Analysis: Found: C 37.2; H F5, i; N 16.2; C12H12F3N3O.C4H7N3O.H25042HO20 requires:

C, 37.1; H, 4.9; N 1.2%.

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

TABLE V

  A1 weight of ex. product t4 Vol. flight. of Vol, Solvent Weight of reactive reagent pyridine CH3CN recrystalline starting formula (ml) (m) (m) predefined. (C) _ _ _ _ _ _ _ _ (g) _ _ _ _ _ _ _ _ _ _ _ _ __ (m) _ _ i 14 (i) 2,8 PriCOC1 1,8 2 50 118 * C14 15 3 138-140 (i) 2.0 (CF3CO) 20 2 45 1 40 1.46.cetate C12H8F3N3O 165-6 diethyl / cyclohexane. Purified by column chromatography on silica gel 60 (150 g) eluted with ethyl acetate.

Example 16

  N-C3- [2-aminoethyl) -IH-indol-5-yl) -N'-methylthiourea, compound with creatinine, sulfuric acid and water

[1: 1: 1: 1)

  S C1] N- [3-Ccyanomethyl) -1H-indol-5-yl] -N'-methylthiourea compound with ethanol [2: 1] Methyl isothiocyanate [0.40 ml) was added to a stirred solution of 5-amino-1H-indole-3-acetonitrile

  [1 g] in dry acetonitrile [20 ml). The solution is stirred

  at room temperature for 3 days. Additional methyl isothiocyanate (0.05 ml) was added and the mixture was heated at 50 for 5 h. The solution was evaporated in vacuo to give a viscous oil which solidified when triturated with a mixture of ethanol and ether. The solid obtained is filtered off and dried in vacuo to give the title compound [1.17 g] as a solid.

  off-white crystalline, Pf 103-110.

  [(ii)] N- [3- [2-aminoethyl] -1H-indol-5-yl] -N'-methylthiourea, compounded with creatinine, sulfuric acid and water

[(1: 1: 1 13

  Lithium aluminum hydride (0.19 g) was added in small quantities to 18-ol to a stirred suspension of N- [3-cyanomethyl) -IH-indol-5-yl) N-methylthiourea.

  [0.4 g] in dry tetrahydrofuran [10 ml] under nitrogen.

  When the addition is complete, the yellow suspension is refluxed for 2 hours. The suspension is cooled to room temperature and the excess lithium aluminum hydride is destroyed by carefully adding a mixture of ethanol and water [1: 1] [30 ml]. The suspension obtained is separated by filtration and the filtrate is evaporated under

  reduced pressure to give a yellow semi-solid.

  Ethanol [50 ml) and water (10 ml) were added and the solution was filtered to remove a small amount of insoluble material. The Filtrat is heated to reflux and

  the features with a warm solution of creatine sulfate

  not [0.6 g] in water [2 ml]. After cooling, the title compound is obtained in the form of a solid of

  buff color, PF 226-229e [Dec.].

  Analysis Found: C 40.3, H 5.5, N 20.1;

C12H16N4S.C4H7N3O H2SO4. %

requires C 40.2, H 5.7, N 20.5%.

Example 7

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

  [i) Ethyl [[[3- [cyanomethyl] -1H-indol-5-yl) amino) thio-

  carbonyl carbamate Isothiocyanate is added dropwise

  of ethoxycarbonyl [1.2 ml] in a stirred solution of 5-

  amino-1H-indole-3-acetonitrile [1.7 g] in dry acetonitrile [50 ml]. After 10 minutes dilute with water

  [40 ml] the suspension obtained and stirred for 20 minutes.

  The precipitate is filtered off, washed with dry acetonitrile, and dried in vacuo to give the title compound as a cream solid.

[1.5 g], HP 201-202 C.

  Cii) N- [3- [cyanomethyl] -1H-indol-5-yl) thiourea

  A solution of ethyl [[[3- (C) is stirred at 40 ° C. for 2 hours.

  Ccyanomethyl) -1H-indol-5-yl] amino) thiocarbonyl) carbamate [0.5 g] in 2 N sodium hydroxide [3 ml] and ethanol [(10 ml)). The precipitate obtained is filtered off, triturated with water (40 ml), washed with ethanol (~ 30 ml) and dried in vacuo to give the title compound as the title compound. 'a white solid

[0.21 g], mp 212-2140C.

  [(iii) N- [3-C2-aminoethyl) -1H-indol-5-yl) thiourea fumarate hemihydrate Lithium aluminum hydride (0.5 g) was added under several times under nitrogen. ) to a stirred suspension of N- [3- [cyanomethyl] -1H-indol5-yl] thiourea 0.6 g) in THF (150 mL). When the addition is complete, aluminum chloride (1.74 g) is added, and the resulting gray suspension is stirred at reflux for 1 h.

  The mixture is cooled in ice and decomposed

  apply the excess reagent by carefully adding 10% water in the THF. Brine [100 ml] and ethyl acetate [100 ml] are added, the insoluble material is filtered off and the aqueous layer is extracted with water.

ethyl acetate (100 ml).

  The combined organic solutions were washed with brine (100 mL), dried (NaHCO4) and evaporated in vacuo to give a pale yellow oil. The oil was dissolved in a solution of Fumaric acid [0.3 g] in methanol E 5 ml] and the fumarate was precipitated by the addition of ethyl acetate [250 ml]. We crystallize the salt from

  isopropanol and is recrystallised from a mixture of

  methanol and ethyl acetate to give the title compound as a cream solid (0.15 g)],

PF 147-150.

  Analysis Found: C, 50.1, H 5.4, N 15, a; C11H14N4S.G 4H404. 0SHO

requires: C 50.1, H 5.3, N 15.6;

Example 18

  N-C [1- [3- [2-aminoethyl) -1H-indol-5-yl) ethyl) acetamide, compound with creatinine, sulfuric acid and water

[1: 1: 1: 2)

  C1) 2- [2- [5-acetyl-1H-indol-3-yl) ethyl]] - 1H-isoindole-1,3- [C2H] -dione A suspension of -acetyl-1H is refluxed for 3 hours. -indole-3-ethanamine ([1.0 g), phthalic anhydride [0.83 g] and sodium acetate (1.0 g) in acetic acid [15 ml]. After cooling, the title compound is deposited as an off-white crystalline solid

[1.5 g], mp 234-235.

  Cii) 2- [5- [1-Chroxyimino) ethyl) -1H-indol-3-yl) -IH-iso

indole-1,3 [2H) -dione

  A suspension of 2- [2- [5-acetyl-1H]

  indol-3-yl) ethyl) -1H-isoindole-1,3 (2H) -dione [1.0 g] in

  ethanol (20 ml) with a solution of hydroxyl acetate

  amine [produced from a solution of hydroxylamine hydrochloride [0.5 g] and sodium acetate [0.5 g] in water (5 ml) diluted with ethanol [75 ml] to deposit sodium chloride). The reaction mixture is refluxed for 2 h. After cooling, the title compound crystallizes out as a solution.

yellow solid [1.0 g], mp 220-Z230.

  [iii) N-C1- [3- [2- [1,3-dihydro-1,3-dioxo-2H-isoindol-2H]

  isoindol-2-yl) ethyl) -1H-indol-5-yl) ethyl) acetamide

  A suspension of Z- [5- [1-chloroimidimide) is hydrogenated.

* no) ethyl) -IH-indol-3-yl) -1H-isoindole-1,3 [2H) -dione [0.8 g]

  in methanol (150 ml) and hydrogen sulfide

  concentrate (0.18 ml) on palladium pre-reduced palladium on charcoal (0.8 g) at room temperature and

  the ambient pressure until the absorption of hydro-

  gene ceases [4h, 120 ml). The catalyst is separated by

  The mixture is washed with methanol and dimethylformamide [10 ml] is added to the filtrate before the methanol is removed by evaporation under reduced pressure. The brown solution obtained is cooled in an ice-bath and treated successively with pyridine [10 ml] and anhydride.

  acetic acid [0.8 ml]. The reaction mixture is left to

  warm to room temperature overnight, then partitioned between ethyl acetate (250 ml) and the acid

  diluted hydrochloric acid, 500 ml). The organic phase is washed

  that with water [5 x 100 ml, dry ENSO4) and evaporated to give a brown gum which is purified on a silica column (silica gel 60, 70 g) eluted with ethyl acetate to give the title compound as a solid

  yellow crystalline (0.45 g), mp 224-26.

  (iv) N-C1-C3- [2-aminoethyl) -IH-indol-5-yl) ethyl) acetamide, compounded with creatinine, sulfuric acid and water

(1: 1: 1: 2).

  Following the procedure described in Example 1 (ii)),

  we "deprotect" a solution of N-ú1- [3-C2-ú1,3-dihydro-

  1,3-dioxo-2H-isoindol-2-yl) ethyl) -IH-indol-5-yl) ethyl) -

  acetamide [0.38 g] in ethanol [50 ml] with hydrazine

  hydrated (0.25 ml) to give, after formation of creatinine sulfate, the title compound in the form of

  of a white crystalline solid [0.35 g], mp (O 5 - 1Z Edec.).

  Analysis Found: C 43.4, H 6.15, N 17.65;

CHN.H H

  14H19N3. C4H7N30. H2S04.2Ho requires: C 43.9, H 6.5, N 17.1%

Example 19

  N-1 [3- [2-aminoethyl) -1-methyl-IH-indol-5-yl) methyl) -

  Formamide, compound with creatinine, sulFuric acid and water [10: 12: 11: 10] Ci) NC [[3-2- [C13-dihydro-1,3-dioxo-2H-isoindol-2- yl] ethyl)] - 1H-indol-5-yl] methyl] formamide

  For 1 minute, formic anhydride is added.

  acetic acid [5 ml) to a solution cooled with ice-cream

  stirred, 2- [2- [5- [aminomethyl) -1H-indol-3-yl) ethyl] -.

  1H-isoindole-1,3 (2H) -dione, hemisulFate, hydrated [0.65g) in dry pyridine [25ml]). After 10 minutes we

  remove the mixture from the ice bath and stir it at

  room temperature during h. The mixture is then cooled in ice and water [10 ml] is added. After 10 minutes, the mixture is slowly diluted with water to 400 ml while scraping. Filtration gives yellow needles

  pale [0.53 g], P 174-176 [partial melting at 145].

  A sample was recrystallized [0.14 g] from ethyl acetate to give the title compound

  (0.11 g) as a yellow powder, mp 176-178.

  (ii) N-C [3- [2- [1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]

  ethyl] - (1-methyl-1H-indol-5-yl) methyl)] Formamide, hemihydrate Sodium hydride is added to the oil [to

  80%, 0.045 g, under nitrogen to a stirred solution of N - [[3-

  [2- [C1,3-dihydro-1,3-dioxo-2H-isoindol-2-ylJéthyl) -IH-indol

  -yl-] methyl] formamide [0.5 g] in dimethylformamide (20 m) 1] and stirring is continued for 30 min. We treat

  then the solution with methyl iodide [0.2 ml].

  After 3 hours, the solution is diluted with ethyl acetate (150 ml), washed with brine (10%, 3 x 50 ml) and dried [sodium sulphoxide], filtered. and evaporated to dryness to give a yellow solid which is crystallized from ethyl acetate to give the title compound [0.2 g] as a

off-white solid, Pf 189-191D.

  C11] N-C [3- [2-aminoethyl) -1-methyl-1H-indol-5-yl] methyl] -

  Formamide, composed with creatinine, sulfuric acid and water [10: 12: 11: 1O0 kept at room temperature for 2 h

  a solution of t4N - [[3- [2- [1,3-dihydro-1,3-dioxo-2H-iso]

  indol-2-yl] 6thyl] -1-methyl-1H-indol-5-yl) méthylJformamide

  [0.3 g] in ethanolic methylamine [33%, 10 ml).

  The solvent is evaporated under vacuum and evapo-

  rinse the residue with C3 x 50 ml ethanol). The residue is dissolved in a hot mixture of ethanol (50 ml) and water (11 ml) and an aqueous solution of creatinine and sulfuric acid [1: 1, 2Ms 0.4 ml] is added. Filtration of the cooled mixture gives the title compound (0.26 g) under

  the form of an off-white solid, Pf 204-2-08.

  Analysis Found: C 43.8, H 6.1, N 19s3%

C13H17N30.1.2C4H7N301.1H2 S04.H20

requires: C 43.4, H 6.1, N 18.8%.

Example 20

  N-C [3- [3-aminopropyl] -1H-indol-5-ylmethyl] formamide,

  with creatinine, sulfuric acid and water [1: 1: 1: 2) C [i] 2- [3-SC [aminomethyl] -1H-indol-3-yl) propyl) -1H-iso Indole-1,3 [2H] -dione, sulfate is stirred under an atmosphere of hydrogen for

  h suspension of 3- [3-C1,3-dihydro-1,3-dioxo-2H-

  isoindol-2-yl) propyl) -1H-indole-5-carbonitrile [2.0 g] and palladium on charcoal catalyst [SD% aqueous paste, 0.85 g) in aboslu methanol [100 ml] containing sulfuric acid [0.64 ml). The catalyst is separated

  by filtration and the filtrate is evaporated under vacuum.

  The yellow solid obtained was washed with ether [2 x 50 ml], crystallized from water [10 m] and dried in vacuo to give the title compound as a

  green-pale yellow solid (1.77 g), mp 175-180 ° (dec).

  [(ii) N - [[3- [3- [1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl]]

  propyl) -1H-indol-5-yl) methyl) formamide Following the procedure described in Example 19 (i) a solution of 2-C3- [5- [aminomethyl) -1H indol-3-yl is reacted. ) propyl) -1H-isoindole-1,3 [2H) -dione, sulfate [0.75 g) with Formic Acetic anhydride (15 ml) in pyridine [27.5 ml] to give the title compound. title in the form of a yellow solid [0.49 g], mp 150-1520 after

  crystallization from ethyl acetate.

  [iii] N - ([3- [3-aminopropyl] -IH-indol-5-yl) methyl Formamide, composed with creatinine, sulfuric acid and water

(1: 1: 1: 2)

  Stir at room temperature for 2 hours.

  a solution of N-C [3- [3- [1,3-dihydro-1,3-dioxo-2H-

  isoindol-2-yl) propyl) -IH-indol-5-yl) methyl) formamide [0.2 g] in ethanolic methylamine (33%, 5 ml), then

  Evaporate to dryness under vacuum below 5.

  2S The off-white solid obtained is dissolved in cold ethanol (25 ml), filtered, diluted with hot ethanol [25 ml) and water [10 ml] before treatment with an aqueous solution of creatinine and of sulfuric acid [1: 1, 2M, 0.25ml] to give, after recrystallization from aqueous acetone, the title compound as a

  off-white solid [0.11 g), mp 175-1780.

  q6 Analysis Found: C 42.45; H 5; 17.6; C13 17N, C4H730. H2s04.2H2O

requires: C 42.7, H 6.3, N 17.5.

Example 21

  N - [[3- [2-aminoethyl) -1H-indol-5-ylmethyl) acetamide [i] N [[4-hydrazinophenylmethyl)] acetamide hydrochloride A solution of sodium nitrite ú0 is added during 2 g] in water 2CE ml), to a stirred suspension of N- [(4-aminophenyl) methyl] acetamide hydrochloride [0.5 g] in water [1.5 ml] and concentrated hydrochloric acid C2 ml], keeping the temperature below 0. The solution is stirred while cooling with

  ice for 40 minutes then add for 3 minutes.

  To a solution cooled with stirred ice, sodium acetate [2.3 g] and sodium sulfite [1.3 g] in water [14 ml] were added. After 1 hour, the ice bath is removed and the mixture is allowed to stand at room temperature.

ambient during the night.

  The mixture is acidified with concentrated hydrochloric acid and then heated at 859 for 15 minutes. The solvent was evaporated in vacuo and the residue was evaporated again with ethanol [2 x 20 ml). The residue is extracted with ethanol (2 x 25 ml) and the filtered extracts are evaporated in vacuo to give a brown gum.

  which crystallizes when ethanol [about 3 ml] is added.

  Filtration gave a cream crystalline solid (0.21 g), mp 205-2100, which was recrystallized from ethanol to give the title compound as a solid

  beige crystalline [0.1 g], mp 212-214 °.

  [(ii) N - [[3- [2-aminoethyl] -1H-indol-5-yl) methyl) acetamide

  A solution of chlorine is refluxed for 7 hours.

  N- [(4-hydrazinophenyl) methyl) acetamide hydrate [0.05 g], 4-chlorobutanal diethyl acetal [0.05 ml] and sodium acetate [0.02 g] in a mixture of methanol [ 1.5 ml),

  of acetic acid [0.3 ml] and water [10 drops].

  TLC on silica, ethyl acetate / 2-propanol / water / ammonia at 0.88 [25: 15: 8: 2] shows that the compound of

  title is the main commodity, Hf 0.3.

Example 22

  N - [[3- [C-Cmethylamino) ethyl-1H-indol-5- hydrochloride

yl) methyl) Jacétamide

  5- [Aminomethyl) -N-methyl-N- [phenylmethyl) -) H-indole

3-ethanamine

  A solution of 3- [2- [methyl [phenyl]

  methyl) amino) ethyl] -1H-indole-5-carbonitrile [1.3 93g) in dry tetrahydrofuran [100ml] under nitrogen with lithiumaluminum hydride [1.09g) and heated to room temperature.

  reFlux for 3 hours. The excess lithium hydride is destroyed

  aluminum with wet tetrahydrofuran, the reaction mixture was diluted with ethyl acetate [200 ml], filtered and the filtrate evaporated to dryness to give a pale yellow oil which crystallized slowly to give the title compound title under the fonme of a solid

cream C [1; 29g), mp 84-85.

  [ii] 4- [3- [2- [methyl [phenylmethyl) amino) ethyl]] - 1H-indol-

  -yl) methyl) acetamide, compounded with creatinine, sulfuric acid and water [2: 2: 2: 3) Cooled solution is treated dropwise

  with ice, 5-Caminomethyl) -N-methyl-N-phenyl-

  methyl) -1H-indole-3-ethanamine [1.3 g) in pyridine

  5 ml] with acetic anhydride (0.9 ml) for 10 minutes.

  utes. The solution is stirred at room temperature for 1 hour and then evaporated to dryness to give a brown oil which is purified on a silica column (silica gel 60SO, 50%), which is eluted with ethyl acetate / methanol (5: 1) to give the free base of the title compound as a pale brown oil (1.0 g). A sample of this oil (100 mg) is dissolved in a hot mixture of ethanol (ml) and water [1 ml] and treated with an aqueous solution of creatinine and sulfuric acid [2E M, 1 : 0.15 ml). By cooling and scraping the title compound is deposited as a gummy off-white solid, mp 160-1651 (which begins

to foam around 1200).

  [iii) N - [[3- [2- (methylamino) ethyl) -IH- hydrochloride

indol-5-yl) methyl) acetamide

  A solution of N - ((3- [2- [methyl-

  [phenylmethylamino) ethyl) -1H-indol-5-yl] methyl) acetamide (059 g) in absolute ethanol (100 ml) on palladium on charcoal (10%, 50% aqueous paste 0.2 g) ) at ambient temperature and pressure until the hydrogen uptake ceases (4 h 70 ml). The catalyst was filtered off, washed with ethanol and the filtrate evaporated to a small volume and treated with ethereal hydrochloric acid and then with ether to deposit the title compound as of a white crystalline solid (0.24 g), mp 240-242 (m.p.

  220) after recrystallization from ethanol.

  Analysis Found: C 59.6, H 7.1, N 14.75;

  C14H sN30.HC1 requires C 59.7, H 7.15, N-14.9%.

14 1 ..

Example 23

  N - ([3- (2- [cyclopentylamino) ethyl) -IH-indol-5-yl) methyl) -

  Formamide, composed with creatinine, sulFuric acid and water (4: 6: 5: 6) A solution of N-C [3-CZ-aminoethyl) -

  1H-indol-5-yl) methyl) formamide (0.3 g) and cyclopentane

  none C1 ml] in absolute ethanol (40 ml) at room temperature

  and at ambient pressure on palladium oxide at 1X.

  on charcoal (50% aqueous paste, pre-reduced, 0.3 g)

  until the absorption of hydrogen ceases.

  The catalyst is filtered off, washed with ethanol (20 ml) and the filtrate is evaporated in vacuo. The residual pale yellow oil is partitioned between ethyl acetate (20 ml) and 2 N hydrochloric acid (1 x 20 ml, 2 x 10 ml) The aqueous layer is basified with sodium carbonate. solid sodium, saturated with sodium chloride and extracted with ethyl acetate

  1 x 10 ml; 8 x 10 ml]. The [Na2SO4) extracts are dried

  combined and evaporated to dryness.

  The residual white gum (0.22 g) is dissolved in a warm mixture of acetone (15 ml) and water (C2 ml) and

  adds an aqueous solution of creatinine and sulphate

  furicum C2 M; 1: 1, 0.35 ml). After cooling and grating

  the title compound crystallizes in the form of

  pale yellow solid [0.25 g], mp 196-198 [retracts to 190].

. .....

  Analysis Found: C 45.4, H 6.7, N 17.2;

  C17H23N3O1 ·, 5C4H7N3O.1.25H 2 SO4. 1,5H20

  need:...-. C 45.7, H 6.5, N 17.4%.

Example 24

  2-methylpropyl- [3-C2-aminoethyl] -IH-indolhydrochloride

  -yl) carbamate [i) 2-methylpropyl-t3- [cyanomethyl-1H-indol-5-yl]] carbamate, 1/4 hydrate

  Iso-chloroformate is added dropwise

  butyl [1.5 ml] in a stirred solution of 5-amino-1H-

  indole-3-acetonitrile (1.7 g) in dry DMF (20 ml). After 10 minutes the solution is diluted with water (150 ml) and stirring is continued for 30 minutes. The resulting solution was extracted with ethyl acetate [2 x 100 ml) and the combined extracts washed with brine (10%, 100 ml), water [100 ml], dried

  (Na2SO4) and evaporated in vacuo to give the

  raw dung in the form of a brown oil. We purify

  by column chromatography (silica gel 60, 100 g)

  using ether as eluent, to give the composition

  Titrate in the form of a colorless gum [1.08 g]

  who goes to become a brown eraser when it is kept.

  This product can not be crystallized from solvents

habitual organic substances.

  Analysis Found: C 65.8, H 6.4, N 14.7; C15H 17N302.0s25H20O requires C 65 H3, H 6.4, N 15.2%

  Cii) 2-methylpropyl- [3-È2-aminoethyl] -1H- hydrochloride

indol-5-yl] carbamate

  A solution of 2-methylpropyl- [3-

  [cyanomethyl] -1H-indol-5-yl) carbamate, 1/4 hydrated (0.5 g) in ethanol absolute (30 ml) containing concentrated hydrochloric acid (E drops) at ambient temperature and pressure on palladium on carbon [(at 10%, I g)

  for 24 hours before replacing the catalyst (10%, 0.5 g).

  After an additional 4 hours when the hydrogen uptake has ceased (90 ml), the catalyst is filtered off, washed with absolute ethanol, and the reaction is carried out.

  evaporate the filtrate under vacuum giving a pink solid.

  The crude hydrochloride is crystallized from a mixture of methanol and ethyl acetate, to give the title compound as a white solid (0.15 g),

P 258-160.

  Analysis Found: C 57.7, H 7, O, N 13.1;

  C15H21N302.HC1 requires: C 57s8; H7-, 1; N 13.5%.

Example 25

  N-C [3- [2-C-phenylmethylidenamino) ethyl) -H-indol-5-ylmethyl) formamidea compound with toluene and water [6: 2: 3]

  A solution of N - [[3- [2-

  -aminoethyl)] - 1H-indol-5-yl) methyl) Formamide (0.3 g) in absolute ethanol (1 ml) in a stirred solution of benzaldehyde D (0.15 g) in dry toluene t15 ml ]). Stir the mixture for 5 minutes and then evaporate

  to dryness under reduced pressure. We add

  luene (15 ml) and the mixture was redissolved to give the title compound as a dark brown oil

(0.35 g).

  Analysis Found: C 73 P 9, H 6.5, N 1 Z, O;

  C19H19N30.1 / 3C7Ha.1 / 2 HO requires C 74.2, H 6, S, N 12, Z.

tC [OMSO] 1.7 [1H, S) N = CHPh

Example 26

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

dimethylsulfamide

  C1] N-C3-Ccyanomethyl] -li-indol-5-yl) -N ', N'-dimethyl-

sulfa drug

  Dimethyl chloride is added dropwise

  sulfamoyl (1.2 ml) in a stirred solution of 5-amino

  1H-indole-3-acetonitrile [1.7g) in dry dimethylformamide (50ml) containing triethylamine C2, Bml). After 3 hours, the suspension obtained is diluted with water [20 ml]

  and stirred for 30 minutes. The solution obtained is

  in water (100 ml) and extracted with ethyl acetate [2 x 100 ml). The organic extracts were washed with water (100 ml) and brine (2 x 100 ml), dried (Na2SO4) and evaporated in vacuo to give a dark brown oil which was purified by chromatography. on column (silica gel 60, 100 g) eluting with ether / ethyl acetate (S: 1) to give the title compound as a white solids

[0s75 g), mp 147-150.

  Cii) N- [3- [2-aminoethyl] -1H-indol-5-yl) -N ', Nt.- maleate

dimethylsulfamide

  A solution of N- [3- (cyanomethyl) -

  1H-indol-5-yl)] - N ', N'-dimethylsulFamide (0.3 g) in the étha-

  absolute volume ú50 ml] containing hydrochloric acid con-

  centered (6 drops) at room temperature and pressure on palladium on charcoal (10%, 0.2 g) for 24 h before replacing the catalyst (at 10%, 0.5 g).

  4 hours later, when the absorption of hydro-

  stopped (60 ml), the catalyst is removed by filtration.

  The mixture is washed with ethanol and the filtrate is evaporated in vacuo to give a brown oil. The oil is then partitioned between ethyl acetate [2 × 20 ml] and 2 N sodium carbonate [10 ml], dried [Na 2 60 4]

  combined organic extracts and evaporates under -

  empty to give a tawny froth. The foam is dissolved in a solution of maleic acid (0.16 g) in methanol (4 ml) and the maleate is precipitated by addition.

  ethyl acetate (100 ml) and ether [150 ml). We shout

  salt from a mixture of methanol and

  ethyl acetate to give the title compound [0.06 g]

  in the form of a tawny solid, Pf 138-142.

  Analysis Found: C 48.3, H 5.5, N 13.8; C12H1IN402S.C4H404 requires: C 48, Z; H 5.6, N 14.1%

Example 27

  N-C [3- [2-aminoethyl) indol-5-yl) methyl) -N ', N'-dimethyl

  sulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1)

  [i) N - ([3- [2- [1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl]]

  ethyl) -IH-indol-5-yl) methyl) -N ', N'-dimethylsulFamide hemihydrate A suspension, cooled, is treated dropwise

  with ice, 2- [2- [5- [aminomethyl) -1H-indol-3-

  yl) ethyl) -1H-isoindole-1,3 [2H) -dione, hemisulfate, hydrated

  [2.0 g] in pyridine [40 ml] with dimethyl chloride

  thylsulfamoyl (0.75 g) for five minutes. We let

  then the solution will warm up to room temperature.

  After 16 hours the orange solution is poured into water

  (100 mL) and extracted with ethyl acetate [3 x 70 mL).

  The combined organic extracts are washed with saturated copper sulphate [7 x 50 ml], sodium carbonate [2 N, 2 x 40 ml], dried and concentrated in vacuo to give an orange oil [1.3 g ). Column chromatography (silica gel 60, 50 g) with chloroform as eluent

  gives the title compound o (0, E2 g) in the form of a

pale yellow, Pf 174-176.

  (ii) N-C (3- (2-aminoethyl-1H-indol-5-yl) methyl] -N ', N'-

  dimethylsulfamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1) heated for 2 hours with a solution of

  N-C ((3- (2- (T1,3-dihydro-1,3-dioxo-2H-isoindol-o-ylJéthyl] -

  1H-indol-5-yl) methyl) -N ', N'-dimethylsulfamide, hemihydrate [0.45 g] and hydrated hydrazine (0.2 mil) in ethanol (20 ml). The filtrate is concentrated under vacuum to give a cream which is distributed between ethyl acetate

  (30 ml) and sodium carbonate (2 N, 25 ml) and

  extract the aqueous phase with ethyl acetate

  (1 x 25 ml, 2 x 15 ml). The organic extracts are washed

  bined with water [3 x 25 ml), dried and evaporated to give the amine in the form of an oil

  pale yellow which gives, after formation of sulphate of

  nine, the title compound (0.3 g) as a solid

white crystalline, mp 220-2220.

  Analysis Found: C 38.9, H 598, N 18.4% C1 3H20N4O2S. -C4H7N03 H20 $ D4.O

requires: C 38.9, H S, O, N 18.7%.

  Pharmaceutical Examples Tablets They can be prepared by direct compression or wet granulation. The direct compression method is preferred but may not be suitable for all cases because

  depends on the dose and the physical characteristics of the

active.

  A. Direct Compression Active Ingredient Microcrystalline Cellulose (British Pharmacopoeia) Magnesium Stearate mg / tablet, 0 89.5, 0 The active ingredient is sieved through a sieve of tm, mixed with the excipients and compressed using punctures. 6.0 mm. Omprimes of different concentrations can be prepared by modifying the

  compression weight and using suitable poisons.

  B. Wet Granulation Active Ingredient Lactose (PB) Starch (PB) Pregelatinized Maize Starch (PB) Magnesium Stearate [PB] Compression Weight mg / tablet, 0 74.5, 0.01 O1 $, 0 Sieve active ingredient through a 250 μm sieve and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, granulated, dried, sieved and mixed with magnesium stearate. Lubricated granules are compressed to give tablets

  as it says for Formulas in direct compression.

  The tablets can be coated with materials suitable for the formation of dandruff,

  p. ex. methylcellulose or hydroxypropyl-methyl-

  cellulose using conventional techniques. We can

  also coat the tablets with sugar.

  Capsules mg / capsule Active Ingredient 10.0 * Starch 1500 8915 Magnesium Stearate [BW] 0.5 Weight in the filled state 100.0 * Directly available form of starch supplied by

  Coloron Ltd, Orpington, Kent (Great Britain).

  The active ingredient is screened through a 250 mesh screen and mixed with the other materials. We pay

  mixture in hard NO 2 gelatin capsules using

  -20 feels a proper machine to fill. Other doses can be prepared by changing the weight in the filled state and if necessary by appropriately changing the size.

capsules.

  Syrup Active Ingredient Sucrose [BP] Glycerin (BP) Buffer) Flavoring Agent J Colorant J Preservative) Distilled water mg / 5 ml dose 500.0 q.s. The active ingredient, the buffer, the flavoring agent, the colorant and the preservative are dissolved in a portion of the water, and the glycerin is added. The rest of the water is heated to 80 ° C. and the sucrose is dissolved and cooled. We combine the two solutions, we adjust to

  necessary volume and mix. It is clarified by Filtra-

syrup obtained.

  Suppositories Active Ingredient * Witepsol H15 10 mg -1, O g q.s.p.

* * Adeps Solidus ph. Eur. $ Quality deposited.

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

dt1 g.

  Injection for Intravenous Administration% w / v Active Ingredient O, O20 Injectable Water (P.B.) q.s. 100.00 Sodium chloride can be added to adjust the effective osmotic pressure of the solution and the pH can be adjusted to that of maximum stability and / or to facilitate the dissolution of the active ingredient using an acid or alkali diluted or by adding buffer salts

appropriate.

  The solution is prepared, clarified and verified.

  fit into molds of appropriate size, sealed by fu.

  glass. The injection is sterilized by heating

  in an autoclave using one of the acceptable cycles.

  The solution can also be sterilized by filtration and poured into sterile ampoules under aseptic conditions. We can condition the solution under an at_

inert atmosphere of nitrogen.

CARTRIDGES OF INHALATION

  mg / cartridge Micronized active ingredient 1.00 Lactose (PB) 39.0 The active ingredient is micronized in a micronizer to achieve a small particle size before mixing with normal tablet grade lactose in a high energy mixer. . The powder mixture is distributed in # 3 hard gelatin capsules on a suitable encapsulator. The contents of the cartridges are administered using a powder inhaler [e.g. ex. a

Rotahaler Glaxo).

248860 <

  AEROSOL SOUE QUANTUM DOSE PRESSURE Ingredient micronized acetic acid oleic acid [B.B.] TrichloroFluoromethane CP.S.] DichlorodiFluoromethane [P.B.) mg / quantized dose 0.500 0.050

22.125

  , 90 micronise the active ingredient in a micronizer

  to have an interval of Low particle size.

  The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 C and the micronized drug is mixed in this solution with a high cutting power mixer. The suspension is quantitatively distributed in aluminum aerosol tubes and

  metering valves, providing a quantitative dose of

  85 mg of suspension are crimped onto the tubes and the dichlorodiFluoromethane is introduced by pressure

in the tubes by the valves.

per tube, 34 14.62 mg mg g g

24886G6

U

EXPERIMENTAL METHODS

Equipotent concentration index

  The concentration indices of the compounds

  of the invention with respect to 5-hydroxy-

  tryptamine by the method described in W. Feinink, P.P.A. Humphrey and A.D. Watts in Br. J. Pharmacol., 1981, 73,

pages 1918-1928.

  Systolic blood pressure Metacorticode-induced hypertension was induced in hooded rat AH male [Lister / from PVG] by

  implantation of a 75 mg tablet of deoxyacetate acetate

  corticosterone. They are left with physical salt

  Siological [0.89%] ad libitum. The active compound is administered intraperitoneally (i.p.) at a dose of 10 mg / kg and the systolic blood pressure is measured after 1 hour.

BIOLOGICAL RESULTS

  When tested on an isolated saphenous vein flap, the products of Examples 1 to 3, 5 to 10, 11 [c], 11 [e), 12 [c] and 14 and 17 are up to ten times more

  powerful and a hundred times less powerful than 5-hydroxy-

  tryptamine. There is no significant change in systolic blood pressure in rats after administration

compounds of the invention.

  In general, the compounds of the invention have no toxic effect when administered to rats at a

  dose of 10 mg / kg intraperitoneally.

Claims (20)

  1. Compound of general formula CI): R 1 R 2 N (CHR 3) AlCrCIR R 16 R 7 O R 1 represents a group CHO, COR 8, COeRa, CONRgR 10, CSNR 9 R 10 or SO 2 NRR 10, where R 8 represents an alkyl, cycloalkyl, aryl or aralkyl group, R9 represents a hydrogen atom or an alkyl group, and R10 represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group; R3, R4, R6 and R7, which may be the same or different, each represents a hydrogen atom or a C1-C3 alkyl group; R5 represents a hydrogen atom or an alkyl, cycloalkyl, alkenyl or aralkyl group or R4 and R5 together form an aralkylidene group, or R4 and R5 together with the nitrogen atom to which they are attached form a 5-membered saturated monocyclic ring; 7-chain; n is zero or 1; and Alk represents an alkylene chain containing 2 or 3 carbon atoms which may be unsubstituted or substituted by at most two C 1 -C 3 alkyl groups; with the precision that when n is zero and Ci) 84 and R5 are both alkyl groups, R1 does not   does not represent the CHO or COR8 group; and Cii) R1.ne   does not have the group SO2NN; and their salts, solvates and bioprecursors physiologically acceptable.   2. A compound according to claim 1, wherein Alc represents an unsubstituted alkylene chain containing two carbon atoms. 3. A compound according to claim 1, wherein R4 and R5, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group and   R6 and R7 each represent a hydrogen atom.   4. Compound according to claim 1, wherein R3 represents a hydrogen atom.   5. Compound according to claim 1, wherein Rf represents a   hydrogen atom or a methyl group.   6. Compound according to claim 1, corresponding to the general formula [Ia): R R N (CH) CH CH NR R   2a2n 2 2 2 4a 5a -N (la) wherein R 1a is CHO, CONH 2, COR 8sa or CORa, wherein RSa is an alkyl group containing from 1 to 4 carbon atoms   carbon or a trifluoromethyl group; -   R represents a hydrogen atom or a methyl group; n is zero or 1; and R4a and R5a, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R4a and R5a together does not exceed two and that when R1a represents a CHO group or a CORBa group when n is zero, then R4a represents a hydrogen atom, and their salts, solvates and bioprecursors biologically acceptable.   7. Compound according to claim I having the general formula (lib): ## STR1 ## is a methyl, ethyl or isobutyl group; Rab represents a hydrogen atom or a methyl group; and R4b and RSb, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R4b and RSb together does not exceed two and when Rlb is the CHO group, R4b represents a hydrogen atom, ..   and their salts, solvates and bioprecursors physiologically acceptable.   8. Compound according to claim 1 having the general formula [Ic]: RlcR2c NCH2 ____ CH CH NR4CRSC (   ## STR2 ## represents a CHO group or a COR 8 group where R is an alkyl group containing from 1 to 3 carbon atoms. carbon; -   f2c represents a hydrogen atom or a methyl group; and R4c and RSc, which may be the same or different, each represents a hydrogen atom or a methyl or ethyl group with the precision that the total number of carbon atoms in R4 and R5c together does not exceed two,-   and their salts, solvates and bioprecursors physiologically acceptable.   9. Ethyl [3- [2-aminoethyl) -1H-indol-5-yl) carbamate, 2-methylpropyl [3- (2-aminoethyl) -1H-indol-5-yl) carbamate and N- [C 3 -C 2] aminoethyl) -1H-indol-5yl) methyl) acetamide and their salts, solvates and bioprecursors physiologically acceptable.   10. A compound according to claim 1, wherein the physiological salt   gically acceptable is a hydrochloride, hydrobromide, sulfate, fumarate or maleate.   A pharmaceutical composition comprising at least one compound of the general formula CI 1 as defined in claim 1 or a physiologically acceptable salt, solvate or prodrug thereof with one or more physiologically compatible carriers or excipients. acceptable.   Process for the preparation of a compound of general formula [I] as defined in claim 1 or one of its   solvents, solvates or biopros-   logically acceptable, process which involves: CA] reacting a compound of general formula CII): R2NH (CHR3 '- AlCNR4R5 2 3 R6 R7 o   R2, R4, R5, R7 n and Alc are as defined   nis for the general formula CI), or a protected derivative thereof, with a suitable reagent which serves to introduce the group R1; or (B) cyclizing a compound of the general formula [III]: R2N (CHR 3) n '"/ NR7N = CR6CH2AlcQ wherein Q is NR4R5 or a protected derivative thereof or an leaving group and R1 I R2 R3, R4, R5, R6, R7, Alk and n are as defined for general formula (C1) or (C) reacting a compound of general formula (VI): R1R2N (CHR3)   ## STR5 ## R.sub.2, R.sub.3, R.sub.6, R.sub.7, Al.sub.2 and n are as defined   for the general formula CI) and o Y is an easy group   detachable, or a protected derivative thereof, with a compound of the formula R4R5NH, where R4 and R5 are as defined for the general formula (I), or [O) of reducing a compound of the general formula CVII): R1R2N (CHR 3   W (VII) R7O W is a group capable of being reduced to give the required group AlcNR4R5 or a protected derivative thereof and wherein R1, R3, R3, R4, R5, R6, R7, Alc and n are such that defined for General Formula C [I], or a protected salt or derivative thereof; and, if necessary and / or if desired, subjecting the compound thus obtained to one or more other reactions involving: CF) (i) converting the compound of general formula (I) obtained or a salt or protected derivative thereof in another compound of general formula [I); and / or [ii) removing any protecting group (s) present and / or Ciii) from transforming a compound of the general formula (II) or a salt thereof into a salt product of solvation   or physiologically acceptable bioprecursor.   13. The process according to claim 12, wherein reaction [A) involves the reaction of the compound of general formula CII) with an acid of formula R1OH, where R1 is such that deFini for general formula CI] in the presence of a coupling agent at a temperature between -5 and +30 ° C or, in order to prepare a compound of the general formula [I) where R1 represents -CHO, with formic acid under reflux; or [ii) reacting the compound of the general formula [II] with an acylating agent corresponding to an acid of the formula R1OH, wherein R1 is such that defined for the general formula   CI) at a temperature between -70 and +150 C.   Ciii) in order to prepare a compound of the general formula C1) where R1 represents the group -CONR9R10 or -CSNR9R10, to react the compound of the general formula [II] with phosgene or thiophosgene and an appropriate amine of the formula RR 910NH, o R6 and R10 are as defined for   the general formula [I], or a salt thereof.   14. Process according to claim 12, wherein the cyclization reaction (B) involves reacting a compound of general formula CIV]: 7 2 R1R2N (CHR 3). (/ I - t (Iv) O 'N.R.7NH 2   R 1, R 2, R 7 and n are as defined for general formula [I]), or a salt thereof, with a compound of Formula [V]: R 6 COCH 2 AlCO (V) o R 6 and Alk are as defined for the general formula CI) and Q is as defined in claim 12   or a salt or protected derivative thereof. -   15. Process according to claim 12 or 14, wherein the reaction   cyclization [B) steFFectue at a temperature   between 20 and 200 ° C and when Q is NR4R5 or a protected derivative thereof, the reaction is carried out in an aqueous reaction medium in the presence of an acidic catalyst and when Q is an leaving group, the reaction is is carried out in an aqueous organic solvent in the absence of a mineral acid.   16. The process according to claim 12, wherein in the reaction   - [C], Y represents a halogen atom or a group OR OR is an acyloxy group or a sulphonate group and the reaction [C] C) is carried out in an inert organic solvent   at a temperature between -10 and + 1500C.   17. The process according to claim 12, wherein reaction [D) involves: ci] reducing a compound of Formula CVII], where W is CHR12CN t CHR11CHR12NOa, CH = CR1aNOD or CHR1RCH 12 = NOH by catalytic reduction with hydrogen ; or [ii) reducing a compound of Formula CVII), wherein W is CHR12CN, in the presence of an amine of Formula HNR4R5 using hydrogen in the presence of a catalyst; or (iii) reducing a compound of Formula (VII) wherein W is COCHR12Z by heating using an alkali metal borohydride in a solvent; or (iv) reducing a compound of Formula [VII], wherein is AlcN3 or CHCOH) CHR12NR4R5 using hydrogen in the presence of a catalyst; R 11 and R 12, which may be the same or different, each represents a hydrogen atom or a C 1 to C 3 alkyl group; Z is an N 3 azido group or the NR 4 R 5 group or a protected derivative thereof and R 4, R 5 and Alc are   as defined for the general formula CI).   18. The process according to claim 12, wherein the reaction CECi)] involves preparing a compound of the general formula CI) o R4 and / or R5 is different from a hydrogen by reductive alkylation of the corresponding compound of the general formula [I] o R4 and / or R5 is hydrogen using a suitable aldehyde or ketone and a suitable reducing agent. 19. As new drugs, particularly useful in the treatment of migraine, the compounds of general formula (I) as defined in claim 1 or a salt thereof, solvates or bioprecursors physiologically acceptable.   20. Pharmaceutical composition, especially useful in the treatment of migraine, characterized in that it contains as active substance at least one compound   of general formula (I) as defined in the claim   1 or a salt thereof, solvates or solvates   physiologically acceptable bioprecursors.