DE3700407A1 - Indole derivatives, processes for their preparation and pharmaceutical preparations containing them - Google Patents

Abstract

There are described chemical compounds of the formula (I): <IMAGE> in which R1 denotes H, C1-6-alkyl, C3-7-cycloalkyl, phenyl or phenyl(C1-4)-alkyl, R2 and R3 independently of one another denote H or C1-3-alkyl, R4 and R5 independently of one another denote H, C1-3-alkyl or 2-propenyl, A denotes -CO- or -SO2-, n denotes 2 to 5, with the proviso that R1 does not denote H if A denotes -SO2-, and their physiologically acceptable salts and solvates, for example the hydrates. The compounds have a potent and selective vaso-constrictor activity and are useful for the treatment of migraine. The compounds can be formulated as pharmaceutical preparations containing physiologically acceptable excipients or dilutents for administration in any suitable manner. Various processes for the preparation of the compounds of the formula (I) are described.

Description

The invention relates to indole derivatives, processes for their Manufacture of pharmaceutical preparations containing them and their medical use. It affects in particular Compounds and preparations for the treatment of Migraine.

Migraine pain is with excessive dilation associated with the cranial vasculature, and the known ones Treatments for mites include administering Compounds with vasoconstrictive properties, such as Ergotamine. However, ergotamine is a non-selective one Vasoconstrictor, which is the blood vessels within the entire Body contracts and it has unwanted and dangerous side effects. Migraines can also go through Administration of an analgesic, usually together with an antimemetic. Such treatments are of limited value, however.

There is therefore a need for a safe and effective one Medicines for the treatment of migraines, which either prophylactically or to relieve an existing one Headache can be used and a connection with selective vasoconstrictive activity would fulfill such a role.

A group of indole derivatives has now been found what potent and selective vasoconstrictive activity having.

The invention relates to an indole of the general formula (I): wherein
R _{1 represents} a hydrogen atom, a C _1-6 alkyl or C _3-7 cycloalkyl group or a phenyl or phenyl (C _1-4 ) alkyl group;
R _{2 represents} a hydrogen atom or a C _1-3 alkyl group;
R _{3 represents} a hydrogen atom or a C _1-3 alkyl group;
R ₄ and R ₅ , which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl group or a 2-propenyl group;
A represents -CO- or -SO ₂ -;
and n is an integer from 2 to 5 (provided that R _{1 is} not hydrogen when A is -SO ₂ -) and their physiologically acceptable salts and solvates (e.g. the hydrates).

The invention further relates to all optical isomers of compounds of formula (I) and their mixtures including their racemic mixtures.

With reference to the general forms (I), the Straight-chain or branched-chain alkyl groups, such as methyl, ethyl or isopropyl groups. The cycloalkyl group can, for example, be a cyclopentyl or be cyclohexyl group.

The alkyl moiety of the phenyl (C _1-4 ) alkyl group can be, for example, a methyl or ethyl moiety.

in the case of a class of compounds of the formula (I), the Group R a C_1-6-Alkyl-, phenyl- or phenyl (C_1-4) be an alkly group.

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

In the compounds of formula (I), n can be an integer such as 3, 4 or 5, but it is preferably the integer 2.

A preferred class of compounds represented by the general formula (I) is that in which R _{2 represents} a hydrogen atom. Another preferred class of compounds is where R _{3 represents} a hydrogen atom.

Another preferred class of compounds is that in which R ₄ and R ₅ , which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group. It is preferred that the total number of carbon atoms in R ₄ and R ₅ does not exceed two.

A particularly important compound according to the invention is N- [2- [3- [2- (methylamino) ethyl] -1H-indol-5yl] ethyl] methanesulfonamide and its physiologically acceptable salts and solvates (for example the hydrates).

Suitable physiologically acceptable salts of indoles of the general formula (I) are the acid addition salts, which are formed with inorganic or organic acids, for example the hydrochlorides, hydrobromides, sulfates, Nitrates, phosphates, oxalates, tartrates, citrates, fumarates, Maleates, succinates and sulfonates, for example the Mesylates.

Other salts can be used in the preparation of compounds of formula (I) may be useful, for example the Creatine sulfate adducts.

The invention further relates to other physiologically acceptable Equivalents of compounds of the invention, i. H. physiologically acceptable compounds which in vivo in the parent connection can be transferred. Examples of such Equivalents are the physiologically acceptable metabolic ones labile N-acyl derivatives.

The compounds of the invention selectively narrow the Carotid artery layer of the anesthetized dog, while being negligible on blood pressure Have an effect. Your selective vasoconstrictive effect has been shown in vitro.

The compounds of the invention are for the treatment of Pain useful due to dilation of the vascular Carotid artery layer is caused, especially by Migraines and cluster headaches or headache spurts.

The invention also relates to pharmaceuticals Preparations used in human medicine can and which at least one compound of the formula (I) or one of its physiologically acceptable salts or Solvates, for example hydrates, contain and are prepared in this way are that they are on any suitable Way can be administered. Such preparations can in a manner known per se using an or several pharmaceutically acceptable carriers or Drug diluents can be formulated.

The compounds according to the invention can be used for oral, formulated buccal, parental or rectal administration or they can be in one for administration by Inhalation or insufflation in a suitable form.

For oral administration, pharmaceutical Preparations in the form of, for example, tablets or Capsules made according to known methods with pharmaceutical formulated acceptable drug carriers were, as with binders (e.g. pre-gelatinized Corn starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose), Fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate), lubricants, (for example magnesium stearate, talc or silicate), Disintegrants (e.g. potato starch or Sodium starch glycolate) or wetting agents (e.g. Sodium lauryl sulfate). The tablets can are coated according to methods known per se. Liquid Preparations for oral administration can, for example in the form of solutions, syrups or suspensions or they can be a dry product for the constitution with water or another suitable vehicle of use. Such liquid preparations can according to known methods with pharmaceutical acceptable additives such as suspending agents (for example sorbitol syrup, methyl cellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or Acacia), non-aqueous vehicles (e.g. Almond oil, oily esters or ethyl alcohol) and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the preparations can be made in Form of tablets or lozenges that are in themselves were formulated in a known manner.

The compounds of the invention can be used for parenteral Administration can be formulated by injection. Preparations for injection can be taken in unit dose form, for example in ampoules or in containers Multiple dose units, with an added preservative are available.

The preparations can be in the form of suspensions, solutions or emulsions are present in oily or aqueous vehicles, and they can use formulations such as suspending agents, Stabilizers and / or dispersants. Alternatively can be the active ingredient in powder form for the Constitution with a suitable carrier, for example sterile, pyrogen-free water, before use are available.

The compounds of the invention can also in rectal preparations, such as suppositories or retention enemas, the known suppository base materials, such as Cocoa butter or other glycerides are included.

For administration by inhalation, the invention Connections useful in the form of a Aerosol spray presentation from pressurized cans issued, with a suitable blowing agent, for example Dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, Carbon dioxide or another suitable gas, is used. You can also use a nebulizer use. In the case of a pressurized aerosol the dose unit can be determined by using a valve provides which dispenses a measured amount. Capsules and cartridges, for example made of gelatin, for use in an inhalation device or in an insufflation device can be formulated so that they are a Powder mixture of the compound of the invention and one suitable powder raw material, such as lactose or starch, contain.

A suggested dose for the compounds of the invention for oral, parenteral, buccal or rectal Human administration (with an average Body weight of about 70 kg) for the treatment of Migraines are 0.1 to 100 mg of active ingredient per Dose unit, for example one to four times a day can be administered. It is obvious that there may be routine dose variations perform depending on the age and weight of the patient, as well as the severity of the patient to be treated Condition.

A unit dose is preferred for oral administration contain from 2 to 50 mg of active ingredient. A Dose unit for parenteral administration preferably contain 0.2 to 5 mg of active ingredient.

Aerosol preparations are preferably provided in such a way that every metered dose or "bump" by one pressurized aerosol is delivered, 0.2 to 2 mg contains compound of the invention and that each dose, over capsules or cartridges in an inhalation device or is administered to an insufflation device, Contains 0.2 to 20 mg. The total daily dose by inhalation will be in the range of 1 to 100 mg. The administration can be repeated several times a day, for example two to eight times, take place, for example 1, 2 or 3 each time Dose units are given.

The compounds of the invention can optionally along with one or more other therapeutic Agents such as analgesics, anti-inflammatory agents and Anti-vomiting agents can be administered.

The invention further relates to the general processes described below for the preparation of compounds of the formula (I), their physiologically acceptable salts or solvates (for example hydrates). In the following processes, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , A and n have the definition given in the general formula (I), unless stated otherwise.

According to a general process (A), a compound of general formula (I) can be prepared by using a compound of general formula (II): or one of its salts (for example an organic or inorganic acid addition salt such as the hydrochloride, hydrobromide, maleate, sulfate or creatinine sulfate adduct) or an N-silyl derivative thereof or a protected derivative thereof with a reagent which serves to introduce the group R ₁ A.

Suitable reagents which serve to introduce the group R ₁ A are acids of the general formula R ₁ AOH or their corresponding acylating agents.

Acylating agents useful in the above Methods that can be used include the acid halides (for example the carboxylic acid chlorides and sulfonyl chlorides), the alkyl esters (for example the methyl or Ethyl esters), activated esters (e.g. 2- (1-methylpyridinyl) esters), symmetrical anhydrides, mixed anhydrides or other activated carboxylic acid derivatives, such as those conveniently used in peptide synthesis will.

The process is carried out in a suitable aqueous or non-aqueous Reaction medium useful at a temperature from -70 to + 150 ° C. The procedure at which is an acid halide, an activated ester or a Anhydride used can be in a suitable reaction medium, such as an amide (e.g. N, N-dimethylformamide) or hexamethylphosphoramide, an ether (e.g. Tetrahydrofuran), an ester (e.g. ethyl acetate), a nitrile (e.g. acetonitrile), one Haloalkane (e.g. dichloromethane) or their Mixtures, optionally in the presence of an organic Base, for example a tertiary amine such as triethylamine or pyridine, or an inorganic base, such as Potassium carbonate or sodium bicarbonate. The organic base can also act as a reaction solvent serve. The reaction is preferred at one Temperature from -5 to + 25 ° C carried out.

The reaction using an alkyl ester can in a suitable reaction medium, such as an alcohol (e.g. methanol), an amide (e.g. dimethylformamide), an ether (for example tetrahydrofuran), or their mixtures and conveniently at one temperature from 0 to 100 ° C.

If A is -CO-, carboxylic acids of the formula R ₁ COOH can also be used in the preparation of the compounds of the formula (I). The reaction is preferably carried out in the presence of a coupling agent, for example N, N'-carbonyldiimidazole, or a carbodiimide, such as N, N'-dicyclohexylcarbodiimide. The reaction can be carried out in a suitable reaction medium, such as a haloalkane (for example dichloromethane), a nitrile (for example acetonitrile), an amide (for example dimethylformamide) or an ether (for example tetrahydrofuran), suitably at a temperature of -50 to + 50 ° C, preferably from -5 to + 30 ° C. The reaction can also conveniently be carried out in the presence of a coupling agent in a suitable reaction medium such as a hydrocarbon, for example toluene or xylene, at a temperature of 50 to 120 ° C.

A compound of general formula (I), wherein R ₁ A is -CHO, can be prepared by reacting a compound of general formula (II) with ethyl formate, optionally in the presence of a solvent, e.g. B. ethanol heated.

The compounds of general formula (II) are new and are also the subject of the present invention.

The compounds of the general formula (II) in which R _{2 represents} a hydrogen atom can, for example, by reducing a corresponding compound having a suitable reducible group with a substituent in the 5-position, such as - (CH ₂ ) _{n -1} CN, or a corresponding cyano-substituted alkenyl group can be prepared. The reduction can be carried out by catalytic hydrogenation or with a reducing agent such as lithium aluminum hydride.

Such nitrile compounds are new and are also a subject of the present invention. These connections can for example by cyclization of a suitable hydrazone in an analogous manner to that described below general process (B) can be prepared. Alternatively can intermediates with a 5- (cyanoalkenyl) substituent be made by using an appropriate one Indole-5-carboxaldehyde with a cyanoalkyl phosphonate implements.

Compounds of the general formula (II) in which R _{2 represents} an alkyl group can, for example, by reducing the corresponding nitrile in the presence of an amine R ₂ NH ₂ or by reacting a compound of the formula (II) in which R _{2 represents} a hydrogen atom with a suitable alkylating agents are prepared.

According to a further general process (B), compounds of the formula (I) can be cyclized by cyclizing a compound of the general formula (III): wherein Q represents the group NR ₄ R ₅ (or one of its protected derivatives) or a removable atom or a group such as a halogen atom (e.g. chlorine or bromine) or an acyloxy group (e.g. a carboxylic or sulfonic acid acyloxy group such as an acetoxy or chloroacetoxy -, Dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group) are produced.

The reaction becomes useful in aqueous or non-aqueous Reaction media and at temperatures from 20 to 200 ° C, preferably from 50 to 125 ° C.

Particularly suitable embodiments of the method are described below.

If Q represents the group NR ₄ R ₅ (or one of the protected derivatives thereof), the process is preferably in the presence of a polyphosphate ester in the reaction medium, which may contain one or more organic solvents, preferably halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or their mixtures. A polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the procedure described in "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sons 1967).

Alternatively, the cyclization can be carried out in an aqueous or non-aqueous reaction medium in the presence of an acidic Be carried out catalyst. If an aqueous medium is used, this can be an aqueous organic solvent, such as an aqueous alcohol (e.g. methanol, Ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran). Man can also use mixtures of such solvents. The acid catalyst can be, for example, an organic one Acid such as concentrated hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid (In some cases the acid catalyst can also serve as a reaction solvent). In an anhydrous Reaction medium, for example one or more Ether (for example as previously described) or can contain esters (for example ethyl acetate), the acidic catalyst generally becomes a Lewis acid, such as boron trifluoride, zinc chloride or magnesium chloride.

When Q represents a substitutable atom or group such as a chlorine or bromine atom, the reaction in an aqueous organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) can be conveniently carried out at a temperature in the absence of an acid catalyst from 20 to 200 ° C., preferably from 50 to 125 ° C. This process gives a compound of formula (I) wherein R ₄ and R _{5 are} both hydrogen atoms.

According to a preferred embodiment of this process, compounds of the formula (I) can be obtained directly by reacting a compound of the general formula (IV): (where T is the group -NR ₃ NH ₂ )
or one of their salts,
with a compound of formula (V):

OHC (CH ₂ ) ₃ Q (V)

(where Q has the meaning given above) or one their salts or protected derivatives thereof (such as an acetal or ketal, for example formed with a suitable one Alkyl orthoformate or diol, or protected as a bisulfite addition complex) using the appropriate conditions as they above for the cyclization of compounds of general Formula (III) have been described. At this embodiment of the cyclization process (B) a compound of general formula (III) as an intermediate formed, and this can be in situ to form the desired compound of general formula (I) implemented will.

The compounds of the general formula (III) can optionally as intermediates during the process for the preparation of compounds of formula (I) isolated be, wherein a compound of formula (IV) or one their salts or protected derivatives with a compound of formula (V) or a salt or protected derivative in water or a suitable solvent, such as aqueous Alcohol (e.g. methanol) at a temperature of for example, 20 to 30 ° C is implemented. Becomes an acetal or uses a ketal of a compound of formula (V), the reaction may be required in the presence an acid, for example acetic acid or hydrochloric acid, perform.

Compounds of the general formula (IV) can be prepared, for example, from the corresponding nitro (ie if T is NO ₂ ) compounds using methods known per se.

Another general process (C) for the preparation of compounds of the general formula (I) comprises the reaction of a compound of the general formula (VI): (wherein Y represents an easily substitutable atom or group) or a protected derivative thereof with an amine of the formula R ₄ R ₅ NH.

The substitution reaction can conveniently be carried out with the compounds of formula (VI) wherein Y represents a halogen atom (e.g. chlorine, bromine or iodine) or a group OR ₆ , wherein OR _{6 represents} an acyloxy group which is derived from a carbon or sulfonic acid such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group.

The substitution reaction can conveniently be carried out in one inert organic solvents (optionally in the presence of water). Examples are alcohols, for example ethanol, cyclic ethers, for example Dioxane or tetrahydrofuran, acyclic ethers, for example diethyl ether, esters, for example ethyl acetate, Amides, for example N, N-dimethylformamide, and Ketones, for example acetone or methyl ethyl ketone. The Reaction is useful at a temperature of -10 to + 150 ° C, preferably from 20 to 50 ° C, performed.

The compounds of the general formula (VI) in which Y represents a halogen atom can be obtained by reacting a hydrazine of the general formula (IV) with an aldehyde or ketone (or a protected derivative thereof) of the formula (V) in which Q represents a halogen atom, in an aqueous alcohol (e.g. methanol) containing an acid (e.g. acetic or hydrochloric acid). Compounds of formula (VI) in which Y represents the group OR ₆ can be prepared from the corresponding compound in which Y represents a hydroxyl group by acylation with suitably activated species (e.g. the anhydride or bisulfonyl chloride) using methods known per se. The intermediate, namely the alcohol, can be prepared by cyclization of a compound of formula (III) in which Q represents a hydroxyl group (or one of its protected derivatives) under standard conditions.

Compounds of formula (I) can also be prepared by another general process (D) in which a reduction is a compound of general formula (VII): he follows,
(where W is a group which can be reduced to the desired - (CH ₂ ) ₂ NR ₄ R ₅ group or the protected derivative of - (CH ₂ ) ₂ NR ₄ R ₅ ), and B the group - (CH ₂ ) _n - as previously defined, or a group which can be reduced to - (CH ₂ ) _n -) or a salt or protected derivative thereof).

The desired - (CH ₂ ) ₂ - and -NR ₄ R ₅ groups in the 3-position can be formed by reduction stages, which can be carried out separately or together in a suitable manner.

Groups B, which can be reduced to the desired - (CH ₂ ) _n group, include the corresponding unsaturated groups, such as C _2-5 alkenyl or alkynyl groups.

Examples of the groups represented by the substituent W are - (CH ₂ ) ₂ NO ₂ , -CH = CHNO ₂ , - (CH ₂ ) ₂ N ₃ , -CH ₂ CN, -CH ₂ CHO, -COCH ₂ Z, -CH ₂ CH = NOH, -CH (OH) CH ₂ NR ₄ R ₅ , - (CH ₂ ) ₂ NR ₄ COR ′ ₅ , -COCONR ₄ R ₅ and -CH ₂ COZ (where Z is an azido group or the Group -NR ₄ R ₅ or one of its protected derivatives thereof and R ′ _{5 represents} a hydrogen atom or a methyl or ethyl group or R ′ _{5 represents} the group OR ₇ , in which R _{7 represents} an alkyl or aralkyl group).

Groups which can be reduced to the - (CH ₂ ) ₂ groups are the corresponding unsaturated groups and corresponding groups which contain one or more hydroxyl groups or carbonyl functions.

Groups which can be reduced to the group -NR ₄ R ₅ , in which R ₄ and R _{5 are} both hydrogen, are nitro, azido, hydroxyimino and nitrile groups.

In the latter case, the reduction gives the group -CH ₂ NH ₂ , and thus a methylene group of the - (CH ₂ ) _{2 part of the} molecule is obtained.

A compound of general formula (I) in which R _{5 represents} a hydrogen atom can also be prepared by reducing the corresponding compound in which R _{5 represents} a benzyl group, for example with hydrogen in the presence of a catalyst, for example 10% palladium on activated carbon.

The desired -NR ₄ R ₅ group, in which R ₄ and / or R _{5 have} a meaning other than hydrogen, can be reduced by reducing a nitrile -CH ₂ CN or an aldehyde -CH ₂ CHO in the presence of an amine R ₄ R ₅ NH getting produced.

A particularly preferred process for the preparation of a compound of the formula (I) in which R ₄ and / or R _{5 have} a meaning other than hydrogen is the reductive alkylation of the corresponding compound in which R ₄ and / or R _{5 are} hydrogen with a suitable aldehyde or ketone (e.g. acetaldehyde or acetone) in the presence of a suitable reducing agent. Suitable reducing agents for use in this process are hydrogen in the presence of a metal catalyst or an alkali metal borohydride or cyanoborohydride (e.g. sodium borohydride or cyanoborohydride) using the conditions previously described for the reduction of compounds of formula (VII). In some cases (e.g. when introducing the R ₅ groups when R _{5 is} ethyl) the aldehyde (e.g. acetaldehyde) can be condensed with the amine and the intermediate so formed can then be reduced using a suitable reducing agent.

The desired -NR ₄ R ₅ group, in which R ₄ and / or R _{5 have} a meaning other than hydrogen, can also be prepared by reducing an appropriate amide group, for example of the formula - (CH ₂ ) ₂ NR ₄ COR ' ₅ , wherein R ' _{5 has} the definition given above.

It is obvious that the choice of the reducing agent and the reaction conditions depend on the nature of the Groups W, B and others already present in the molecule Groups. It is also evident that when A -CO- means group W will not contain an amide function.

Suitable reducing agents which can be used in the above process for the reduction of compounds of the formula (VII), in which W, for example, the groups - (CH ₂ ) ₂ NO ₂ , -CH = CHNO ₂ , - (CH ₂ ) ₂ N ₃ , -CH ₂ CN, -CH ₂ CH = NOH and -CH (OH) CH ₂ NR ₄ R are hydrogen in the presence of a metal catalyst, for example Raney nickel, or a noble metal catalyst such as platinum, platinum oxide, palladium, palladium oxide or Rhodium, which can contain a carrier and can contain, for example, activated carbon, diatomaceous earth or aluminum. In the case of Raney nickel, hydrazine can be used as the hydrogen source. This process is conveniently carried out in a solvent, such as an alcohol, for example ethanol, an ether, for example dioxane or tetrahydrofuran, an amide, for example dimethylformamide, or an ester, for example ethyl acetate, and at a temperature of -10 to + 50 ° C, preferably from -5 to + 30 ° C.

The reduction process can also be carried out with compounds of the formula (VII), in which W, for example, the groups - (CH ₂ ) ₂ NO ₂ , -CH = CHNO ₂ , - (CH ₂ ) ₂ N ₃ , -CH (OH) CH ₂ Is NR ₄ R ₅ or -COCH ₂ Z (in which Z has the definition given above), and wherein an alkali metal or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, is used and the process is expediently in an alcohol, such as propanol or ethanol, or a nitrile, such as acetonitrile, and at a temperature of 10 to 100 ° C, preferably from 50 to 100 ° C. In some cases, the reduction can be carried out using borohydride in the presence of cobalt (II) chloride.

If A denotes -SO ₂ -, the reduction of compounds of the formula (VII) in which W is, for example - (CH ₂ ) ₂ NO ₂ , -CH = CHNO ₂ , - (CH ₂ ) ₂ N ₃ , - (CH ₂ ) ₂ NR ₄ COR ′ ₅ , -CH ₂ CH = NOH, -CH (OH) CH ₂ NR ₄ R ₅ , -COCONR ₄ R ₅ , -CH ₂ COZ and -COCH ₂ Z (where R ′ ₅ and Z have the definitions given above), also using a metal hydride such as lithium aluminum hydride. This process can be carried out in a solvent, for example an ether such as tetrahydrofuran, and it is conveniently carried out at a temperature of -10 to + 100 ° C, preferably 50 to 100 ° C.

A preferred embodiment of the general process (D) comprises the reduction of a compound of the formula (VII), in which W is the group --CH ₂ CN, for example by catalytic reduction with hydrogen in the presence of a catalyst, such as palladium on activated carbon or rhodium on aluminum oxide, optionally in the presence of an amine HNR ₄ R ₅ .

Suitable reducing agents, which in the reduction of Group B can be used are hydrogen in the presence a metal catalyst. Suitable metal catalysts and conditions for the reduction process are as they were described in the reduction of group W.

The starting materials or intermediates of the formula (VII) can be determined according to methods that are analogous to which are as in the UK patent application 20 35 310 and "A Chemistry of Heterocyclic Compounds - Indoles Part II ", Chapter VI, edited by W. J. Houlihan (1972) Wiley Interscience, New York.

Compounds of formula (VII) in which W represents the group -CH ₂ CHO can be prepared by oxidation (for example with Jones Reagent) of a compound of formula (VI) in which Y represents a hydroxyl group. A compound of formula (VII) wherein W is -CH ₂ CH = NOH can be prepared by treating the corresponding aldehyde with hydroxylamine hydrochloride using standard conditions.

The intermediate of formula (VII) in which W represents the group - (CH ₂ ) ₂ N ₃ can be prepared from a compound of formula (VI) in which Y represents a halogen atom and using standard procedures.

Standard reducing agents, such as sodium borohydride, can be used to prepare a compound of formula (VII) in which W is -CH (OH) CH ₂ NR ₄ R ₅ from the corresponding compound of formula (VII) in which W is - COCH ₂ NR ₄ R ₅ means.

A compound of formula (VII) in which W is the group - (CH ₂ ) ₂ NR ₄ COR ' ₅ can be prepared by acylation of the corresponding unsubstituted amine using methods known per se.

The intermediate compounds of formula (VII), in which B represents a C _2-5 alkenyl group, can be obtained by reacting a compound of general formula (VIII): (wherein W has the definition given for general formula (VII) and n is zero or an integer from 1 to 3) with, for example, a suitable phosphonium salt using standard conditions.

According to another general method (E) can a compound of formula (I) or one of the invention of their salts or protected derivatives thereof into another Compound of formula (I) using known per se Proceedings are transferred.

For example, a compound of the general formula (I) in which one or more of the substituents R ₃ , R ₄ and / or R ₅ denotes alkyl groups can be obtained from the corresponding compounds of the formula (I) in which one or more of the substituents R ₃ , R ₄ and R _{5 are} hydrogen atoms, by reaction with a suitable alkylating agent, such as a compound of the formula R _x L (in which R _{x is} the desired R ₃ , R ₄ or R ₅ group and L is a substitutable atom or group, such as a halogen atom or a tosylate group), or a sulfate (R _x ) ₂ SO ₄ . The alkylating agent can be, for example, an alkyl halide (e.g. methyl tosylate) or dialkyl sulfate (e.g. dimethyl sulfate).

The alkylation reaction is conveniently carried out in an inert organic solvents such as an amide (e.g. Dimethylformamide), an ether (e.g. Tetrahydrofuran) or an aromatic hydrocarbon (for example toluene) preferably in the presence of a base carried out. Suitable bases are, for example, alkali metal hydrides, such as sodium or potassium hydride, alkali metal amides, such as sodium amide, alkali metal carbonates, such as sodium carbonate, or alkali metal alkoxide, such as sodium or potassium methoxide, Ethoxide or t-butoxide or tetrabutylammonium fluoride. If an alkyl halide as an alkylating agent is used, the reaction can be carried out in the presence of a Acid initiating agents such as propylene or ethylene oxide will. The reaction can conveniently be carried out at a temperature from -20 to + 100 ° C.

Compounds of formula (I) wherein one or both of the substituents R ₃ and R _{4 is} propenyl can be prepared in a similar manner using a suitable compound of formula R _x L or (R _x ) ₂ SO ₄ .

According to another general method (F) can a compound of the general formula according to the invention (I) or one of their salts can be prepared by the protected derivative of the general formula (I) one of its Subjecting salts to a reaction in which the protecting group or groups will be removed.

Thus, at an early stage in the reaction sequence in the preparation of a compound of general formula (I) or one of its salts, it may be necessary or desirable to protect one or more sensitive groups in the molecule in order to avoid undesirable side reactions. For example, the group NR ₄ R ₅ , where R ₄ and / or R _{5 are} hydrogen, may need to be protected by protonation with a group that can be easily removed at the end of the reaction sequence. Such groups can be, for example, aralkyl groups, such as benzyl, diphenylmethyl or triphenylmethyl, or acyl groups, such as N-benzyloxycarbonyl or t-butoxycarbonyl or phthaloyl.

In some cases, it may still be desirable the indole nitrogen with, for example, an aralkyl group, like benzyl.

The subsequent splitting off of the protective group or Protecting groups can take place according to methods known per se. Thus, an aralkyl group, such as a benzyl group, can be used Hydrogenolysis in the presence of a catalyst (e.g. Palladium on activated carbon) or sodium and liquid Ammonia, an acyl group such as an N-benzyloxycarbonyl group, by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, for example by catalytic hydrogenation. The phthaloyl group can by hydrazinolysis (for example by Treatment with hydrazine hydrate) or by treatment with a primary amine (e.g. methylamine) removed will.

It is obvious that some of the general Methods (A) to (E) described above are required or may be desirable, any sensitive Groups in the molecule, as just described protect. A reaction stage in which a Deprotection of a protected derivative of the general Formula (I) or its salt thereof occurs after each the previously described methods (A) to (E) will.

According to a further embodiment according to the invention can the following reactions in any suitable Sequence optionally and / or if desired on any of processes (A) to (E) are carried out as follows:

• (i) removal of any protecting groups; and
• (ii) Conversion of a compound of the general formula (I) or one of their salts in a physiological acceptable salt or solvate (e.g. the hydrate) from that.

If a compound according to the invention is intended as a salt, for example as an acid addition salt, can be isolated do this by using the free base of the general Formula (I) with a suitable acid, preferably with a equivalent amount or with creatinine sulfate, in one suitable solvent (e.g. aqueous ethanol) treated.

The raw materials or intermediates for the Production of the compounds according to the invention can be carried out according to analogous processes are produced, as in the British patent application 20 35 310 are described.

The general procedures above for making of the compounds of the invention have been explained and the last main step in the preparation sequence were also used for the introduction of the desired groups at any intermediate level at the Production of the desired compounds can be carried out. For example, the desired group in the 5- Position before or after cyclization for formation of the indole core. It is obvious, that in such multi-step processes, the reaction sequences should be chosen so that the reaction conditions none groups present in the molecule, which are also in the final product should be present.

The following examples illustrate the invention. All Temperatures are given in ° C.

Chromatography was carried out in a manner known per se using silica gel (Merck, Kieselgel 60, Art. 7734) or by flash chromatography (WC Still, M. Kahn and A. Mitra, J. Org, Chem. 2933, 43, 1978 ) on silica (Merck 9385). Thin layer chromatography (tlc) was carried out on silica (Macherly-Nagel, Polygram), unless stated otherwise. The following abbreviations define the eluents used for chromatography and tlc: (A) ethyl acetate-2-propanol-water-0.88-ammonia 25: 15: 8: 2, (B) CH ₂ Cl ₂ -ethanol-0.88 -Ammoniak 89: 10: 1, (C) ethyl acetate, (D) CH ₂ Cl ₂ -ethanol-0.88-ammonia 83: 5: 15: 1.5, (E) ethyl acetate-cyclohexane 1: 1, (F ) Ether-methanol 9: 1, (G) ethyl acetate-methanol 9: 1, (H) ether, (I) ethyl acetate-2-propanol-water-0.88-ammonia 200: 15: 8: 2, (J) Ethyl acetate-2-propanol-water-0.88-ammonia 100: 15: 8: 2, (K) Ethyl acetate-2-propanol-water-0.88-ammonia 50: 15: 8: 2, (L) CH ₂ Cl ₂ ethanol-0.88-ammonia 87: 12: 1.2, (M) CH ₂ Cl ₂ -ethanol-0.88-ammonia 95: 5: 0.5, (N) CH ₂ Cl ₂ -ethanol- 0.88 ammonia 91: 8: 0.8.

The intermediates were routinely checked for purity by tlc, using UV light for the detection and spray reagents such as potassium permanganate (KMnO ₄ ). In addition, Indole intermediates were detected by spraying with aqueous cerium (IV) sulfate (CeIV) and tryptamines, by spraying with a solution of iodine (IV) platinic acid (IPA) or cerium (IV) sulfate.

Proton ( ¹ H) nuclear magnetic resonance spectra (nmr) are determined either at 90 MHz using a Varian EM 390 instrument or at 250 MHz using a Bruker AM or WM 250 instrument. s = singlet, d = doublet, t = triplet, m = multiplet and Q = quartet.

Intermediate 1 4-hydrazinobenzene acetonitrile hydrochloride

A solution of sodium nitrite (4.0 g) in water (34 ml) is added dropwise at -5 to -2 ° to a suspension of 4- Aminobenzene acetonitrile (7.6 g) in concentrated hydrochloric acid (80 ml), and then stirred at -2 ° during 20 minutes. The mixture is filtered and the filtrate is added dropwise at 0 to 5 ° to a solution of Tin (II) chloride dihydrate (65 g) in concentrated Added hydrochloric acid (130 ml). The mixture can warm to room temperature overnight (17 h), and the Precipitate is filtered off with concentrated hydrochloric acid, cold absolute ethanol and dry ether washed and dried, using the title salt as Powder (6.05 g), mp. 207 to 210 ° (foams).

Intermediate 2 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H- indole-5-acetonitrile

A mixture of intermediate 1 (3.15 g) and 4- (1,3- Dihydro-1,3-dioxo-2H-isoindol-2-yl) butanaldiethylacetal (4.95 g) in aqueous acetic acid (25%, 150 ml) on Reflux heated for 2 h, cooled, and the precipitate is filtered off, with water (2 × 20 ml) and then with ether (100 ml) washed. The crude product is mixed with ethyl acetate triturated, whereby the title compound as a solid (3.2 g), mp 185-186 °.

Intermediate 3 2- [2- [5- (2-aminoethyl) -1H-indol-3-yl] ethyl] -1H-isoindole- 1,3- (2H) dione sulfate

A suspension of intermediate 2 (0.96 g) in methanol (100 ml), which is concentrated sulfuric acid (0.58 g) contains, is over PdO on activated carbon (50% aqueous paste, 0.96 g) at room temperature and 4.76 bar (70 psi) during Hydrogenated for 24 h. The catalyst is filtered off with methanol washed, and the filtrate is evaporated to dryness, where the title compound as an oil (1.4 g) receives.

Intermediate 4 2- [2- [5- (2-aminoethyl) -1H-indol-3-yl] ethyl] -1H-isoindole- 1,3- (2H) dione hydrochloride

A solution of intermediate 2 (1.5 g) in methanol (400 ml) which concentrated hydrochloric acid (0.6 ml) contains, is over PdO on activated carbon (50% aqueous paste, 3.0 g) hydrogenated at room temperature and pressure for 24 h. the catalyst is filtered off, washed with methanol, and the filtrate is evaporated to dryness receives the title compound as a foam (1.2 g). T. l. c. (A) Rf 0.6.

Intermediate 5 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H- indole-5-carboxaldehyde, 1/4 hydrate

Raney nickel (about 2 g) become a stirred solution of 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -1H-indole-5-carbonitrile (4.98 g) and sodium hydrophosphite (10.06 g) in pyridine (100 ml), water (50 ml) and acetic acid (50 ml). The mixture is heated at about 50 ° for 6 h, periodically additional Raney nickel (5 × about 2 g) is added. After cooling, the mixture is filtered and the filtrate is diluted with water (1250 ml) and extracted with ethyl acetate (3 x 500 ml). The combined organic extracts are washed with hydrochloric acid (2N; 2 × 500 ml), dried (MgSO ₄ ) and evaporated in vacuo and azeotroped with toluene (2 × 100 ml), giving the title aldehyde as a solid (4.6 g ) receives. a sample (0.53 g) is purified by chromatography (C) to give the pure title aldehyde as a solid (0.49 g), mp. 202 to 203 °.

Intermediate 6 (E) -3- [3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] - 1H-indol-5-yl] -2-propenenitrile

A solution of diethylcyanomethylphosphonate (1.6 ml) in dry tetrahydrofuran (THF; 40 ml) is slowly added to a stirred suspension of NaH (80%; 0.30 g) in THF (40 ml) under nitrogen. After 10 min, a solution of intermediate 5 (1.70 g) in THF (40 ml) is added to the resulting clear solution and the mixture is stirred at room temperature for 19 h. The solution is then partitioned between hydrochloric acid (1N; 200 ml) containing NaCl 850 g) and ethyl acetate (3 x 150 ml). The combined organic extracts are dried (MgSO ₄ ) and evaporated to dryness to give a solid (1.53 g) which is purified by chromatography (E), giving the title compound as a crystalline solid (1.13 g), Mp 232 to 234 °.

Intermediate 7 4- [2- [4- (dimethylamino) butylidene] hydryzino] benzene acetonitrile

4,4-Diethoxy-N, N-dimethylbutanamine (9.45 g) is added to a stirred suspension of intermediate 1 (9.2 g) and deionized water (200 ml) at room temperature under nitrogen. 2N hydrochloric acid (22 ml) is added (pH 2) and then stirred at room temperature for a further 5 h. The clear solution is made basic with 8% aqueous NaHCO ₃ (200 ml) and extracted with CHCl ₃ (3 × 200 ml). The organic layers are dried (MgSO ₄ ) and evaporated to give the title compound as an oil (15.6 g). T. lc (silica, B), Rf 0.35.

Intermediate 8 5- (cyanomethyl) -N, N-dimethyl-1H-indole-3-ethanamine oxalate

Intermediate 7 (15.4 g) is refluxed with polyphosphate ester (108 g) in CHCl ₃ (200 ml) by stirring under nitrogen for 8 min. The mixture is poured onto ice, 8% aqueous NaHCO ₃ (500 ml) is added and after stirring for 20 minutes the layers are separated and the aqueous layer is further extracted with CHCl ₃ (3 M 400 ml). The aqueous layer is further treated with 2 N Na ₂ CO ₃ (200 ml) until the basic reaction pH 9, solid NaCl is added, and the mixture is extracted with CHCl ₃ (3 × 400 ml). The combined organic layers are dried (MgSO ₄ ) and evaporated to give an oil (40.2 g). The oil is partitioned between ethyl acetate (200 ml) and 2N hydrochloric acid (4 × 40 ml), the aqueous layers are made basic (200 ml 2N and 20 ml 5N NaOH) and extracted with ethyl acetate (4 × 100 ml). The latter organic layers are washed with brine, dried (MgSO ₄ ) and evaporated to give an oil (9.3 g). Purification by flash chromatography (B and D) gives a first batch (1.91 g) as an oil and a second batch (4.0 g) also as an oil. The oil from the second batch is dissolved in hot methanol (10 ml) and oxalic acid (1.59 g) in hot methanol is added. Crystals separate on cooling and, after cooling in ice, the crystals are filtered off, washed with methanol and dried to give the title compound (4.0 g), mp. 183.5 to 187 °.

Intermediate 9 N ³ , N ³ -dimethyl-1H-indole-3,5-diethanamine dioxalate

Intermediate 8 (3.17 g) is partitioned between 8% aqueous NaHCO ₃ (100 ml) and CH ₂ Cl ₂ (3 × 80 ml), and the organic layers are dried (MgSO ₄ ) and evaporated to give the free base as an oil (2.41 g). The oil is hydrogenated at 45 ° and 4.76 bar (70 psi) over 5% rhodium on aluminum oxide (1.0 g) in 7% by weight ethanolic ammonia (200 ml) for 15.5 h. The catalyst is filtered off and the solvent is evaporated to give an oil (2.58 g). A portion (1.37 g) of the oil is dissolved in methanol (6 ml) and oxalic acid (1.12 g) is added in methanol (2 ml). The addition of dry ether (80 ml) gives a gum which is triturated with dry ether to give the title compound as a solid (1.79 g), mp 160-170 ° (foams).

Intermediate 10 N ³ , N ³ -dimethyl-1H-indole-3,5-diethanamine dihydrochloride

The intermediate 8 (2.40 g) is at 3.74 bar (55 psi) over 10% palladium on activated carbon (50% paste with water; 1.2 g at the beginning, another 2.4 g after 25 h and 1.2 g added after 70 h) in ethanol (240 ml) containing concentrated hydrochloric acid (2.4 ml), hydrogenated for 138 h. The catalyst is filtered off and the solvent is evaporated to give a foam (2.81 g). A sample (about 0.7 g) of it is partitioned between saturated aqueous Na ₂ CO ₃ (100 ml) and butanone (3 x 70 ml). The organic layers are washed with brine, dried (MgSO ₄ ) and evaporated to give an oil (0.57 g). A sample (169 mg) of the oil is purified by flash chromatography to give an oil (46 mg). T. lc (A) Rf 0.35.

example 1 N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] methanesulfonamide, Combination with creatinine, sulfuric acid and water (1: 1: 1: 1). (i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] - 1H-indol-5-yl] ethyl] methanesulfonamide

A solution of intermediate 3 (1.4 g) in pyridine (10 ml) at 5 ° with methanesulfonyl chloride (0.46 ml) treated. After 24 h at room temperature the mixture on concentrated hydrochloric acid (20 ml) and ice (100 g) poured. The resulting solid is collected and purified by chromatography (F), giving the title compound as a foam (0.45 g). T. l. c. (C) Rf 0.2.

(ii) N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] methyl] methanesulfonamide, Compound with creatine, sulfuric acid and Water (1: 1: 1: 1)

A solution of the product of step (i) (0.29 g) in ethanol (5 ml) and tetrahydrofuran (2 ml) is treated with hydrazine hydrate (0.2 ml) and heated at reflux for 3 hours. After cooling, the solution is evaporated to dryness and the resulting solid is partitioned between ethyl acetate (50 ml) and a saturated solution of K ₂ CO ₃ (10 ml). The aqueous layer is extracted with ethyl acetate (3 x 50 ml) and the organic layer is dried (MgSO ₄ ) and evaporated to give an oil. This is dissolved in a hot mixture of ethanol-water (9: 1, 20 ml) and treated with an aqueous solution of creatinine and sulfuric acid (1: 1, 2 M, 0.3 ml). The title compound (0.16 mg), mp 209 ° to 210 °, crystallizes on cooling.
N. mr: δ (D ₂ O) 2.8-3.5 (14H, m, -CH ₂ CH ₂ NHSO ₂ Me and CH ₂ CH ₂ NH ₂ and creatine N-Me); 7.2 (1H, dd, indole -6) and 7.5-7.7 (2H, m, indole-4 and indole-7).

Example 2 N- [2- [3- [2- (methylamino) ethyl] -1H-indol-5-yl] ethyl] methanesulfonamide, compound with creatinine, sulfuric acid and Water (2: 2: 2: 1) (i) N- [2- [3- [2 - [(methylsulfonyl) amino] ethyl] -1H-indole- 5-yl] ethyl] formamide, 1/4 hydrate

A solution of the product of Example 1 as a free base (0.98 g) in ethyl formate (50 ml) and ethanol (50 ml) is refluxed for 48 hours. The solvent is evaporated in vacuo and the residue is partitioned between sulfuric acid (1N, 25 ml) and ethyl acetate (50 ml). The aqueous layer is extracted with ethyl acetate (25 ml) and the combined organic extracts are washed with brine (25 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an oil. Purification by column chromatography (C and F) gives a foam. Trituration with ethyl acetate gives the title compound as a solid (0.15 g), mp 89-91 °.

(ii) N- [2- [3- [2- (methylamino) ethyl] -1H-indol-5-yl] ethyl] - methanesulfonamide, compound with creatinine, sulfuric acid and water (2: 2: 2: 1)

A solution of the product of step (i) (0.6 g) in dry tetrahydrofuran (THF, 20 ml) is added dropwise under nitrogen to a stirred suspension of LiAlH ₄ (0.7 g) in dry THF (15 ml). The mixture is heated to reflux for 5 h, cooled in ice and excess reagent is decomposed by carefully adding 10% water in THF. Brine (50 ml) and ethyl acetate (100 ml) are added, the insoluble material is filtered off and the aqueous layer is extracted with ethyl acetate (100 ml). The combined organic extracts are washed with brine (50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an oil. The oil is dissolved in a hot mixture of ethanol (24 ml) and water (3 ml) and an aqueous solution of creatine and sulfuric acid (1: 1, 2 M, 0.5 ml) is added. Filtration of the cooled mixture gives the title compound as a solid (0.37 g), mp 222-224 °.
N. mr: δ (D ₂ O) 2.6-3.6 (17H, m, CH ₂ CH ₂ NHMe and CH ₂ CH ₂ NHSO ₂ Me and creatinine N-Me).

Example 3 N- [3- [3- (2-aminoethyl) -1H-indol-5-yl] propyl] methanesulfonamide, Combination with creatinine, sulfuric acid and water (1: 1: 1: 1) (i) 2- [2- [5- (3-aminopropyl) -1H-indol-3-yl] ethyl] -1H- isoindole-1,3- (2H) -dione hemisulfate

A solution of intermediate 6 (0.95 g) in methanol (550 ml) and sulfuric acid (1.0 ml) is at room temperature and pressure over pre-reduced 10% palladium on activated carbon (50% aqueous paste, 2.08 g) hydrogenated for 0.5 h, until the hydrogen uptake (201 ml) stops. The catalyst is filtered off, and the filtrate is in vacuo evaporated to give an oil (4.7 g). T. l. c. (A) Rf 0.3.

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

A mixture of the product of step (i) (4.7 g), methanesulfonyl chloride (1.0 ml), NaHCO ₃ solution (8%, 300 ml) and ethyl acetate (250 ml) is stirred vigorously at room temperature for 24 h, then further methanesulfonyl chloride (1.0 ml) is added after 17 h. The mixture, which contains an insoluble solid, is separated off and the aqueous phase is further extracted with ethyl acetate (2 × 200 ml). The combined organic extracts are washed with hydrochloric acid (2N, 200 ml), dried (MgSO ₄ ) and evaporated to give an oil (0.49 g) which is purified by chromatography on a silica column (H). If the corresponding fractions are left to stand briefly, the title compound crystallizes as a solid from (0.1 g), mp. 165 to 167 °.

(iii) N- [3- [3- (2-aminoethyl) -1H-indol-5-yl] propyl] methanesulfonamide, Compound with creatinine, sulfuric acid and Water (1: 1: 1: 1)

A solution of the product of step (ii) (0.48 g) in ethanol (100 ml) is treated with hydrazine hydrate (1.0 ml) and heated at reflux for 1 h and 20 min. After cooling, the solution is evaporated in vacuo and distilled azeotropically with ethanol (2 × 50 ml), giving a solid which is between Na ₂ CO ₃ solution (2 N, 100 ml) and ethyl acetate (3 × 100 ml) is distributed. The combined organic extracts are dried (MgSO ₄ ) and evaporated to dryness to give an oil which is dissolved in a hot mixture of ethanol (64 ml) and water (8 ml). An aqueous solution of creatinine and sulfuric acid (1: 1, 2 M, 0.56 ml) is added. On cooling, the title salt crystallizes out (0.43 g), mp 212 to 214 °. N. mr: δ (DMSO-d ₆ ): 2.6-3.2 (14H, m, CH ₂ CH ₂ CH ₂ , NHSO ₂ Me, CH ₂ CH ₂ NH ₂ and creatinine N-Me); 6.8-7.5 (4H, m, aromatics); and 10.9 (1H, d, indole-1).

Example 4 N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] acetamide, Combination with creatinine, sulfuric acid and water (10: 12: 11: 20) (i) N- [2- [3- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] - 1H-indol-5-yl] ethyl] acetamide, 1/4 hydrate

A solution of intermediate 4 (0.3 g) in pyridine (10 ml) is cooled in an ice bath and treated dropwise with acetic anhydride (0.3 ml) with stirring. The solution is stirred at room temperature for 1 h, diluted with water (15 ml) and stirred for 15 min. The resulting solution is poured into hydrochloric acid (2N, 50 ml) and extracted with ethyl acetate (2 × 50 ml). The combined extracts are washed with 2N hydrochloric acid (50 ml), 2N Na ₂ CO ₃ (50 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a foam which is purified by chromatography (C) , whereby the title compound is obtained as a solid (0.125 g), mp. 165 to 168 °.

(ii) N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] acetamide, Compounds with creatinine, sulfuric acid and water (10: 12: 11: 20)

A solution of the product of step (i) (0.5 g) in ethanol (100 ml) containing hydrazine hydrate (1.0 ml) is heated at reflux for 3 h, cooled, evaporated in vacuo and again with ethanol ( 2 × 20 ml) evaporated. The resulting solid is partitioned between Na ₂ CO ₃ solution (2 N, 100 ml) and ethyl acetate (2 × 100 ml). The combined organic extracts are dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an oil which is dissolved in a hot mixture of ethanol (16 ml) and water (2 ml) and with an aqueous solution of creatinine and sulfuric acid (1: 1, 2 M, 0.5 ml) is treated. When cooling, the title salt crystallizes out (0.3 g), mp. 211 to 214 °.
N. mr: δ (D ₂ O): 2.95 (3H, s, NHCOMe); and 2.7-3.6 (11H, m, CH ₂ CH ₂ NHCO, CH ₂ CH ₂ NH ₂ and creatinine N-Me).

Example 5 N- [2- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] ethyl] - acetamide oxalate

Intermediate 10 (0.4 g) is added at room temperature to a stirred solution of triethylamine (0.55 ml) in dry tetrahydrofuran (15 ml) under nitrogen and then stirred at room temperature for a further 5 min. The mixture is cooled to 0 °, acetic anhydride (0.15 ml) is added and the mixture is then stirred for a further 4 h between 0 ° and 10 °. The mixture is partitioned between saturated Na ₂ CO ₃ solution (65 ml) and butanone (3 × 50 ml). The organic layers are washed with brine, dried (MgSO ₄ ) and evaporated to give an oil (0.64 g). Purification by flash chromatography (B and D) gives an oil (139 mg) which is dissolved in methanol (2 ml) and combined with another sample (57 mg) which has been prepared in a similar manner. Oxalic acid (77 mg) in methanol (0.5 mg) is added. When dry ether is added, a precipitate is obtained which is filtered off, washed with dry ether and dried, the title compound being obtained as a solid (205 mg), mp. 85 to 93 ° (foams).
N. mr: δ (DMSO): 1.81 (3H, s, NHCOMe); 2.7-3.0 (8H, m, NMe ₂ and CONHCH ₂ CH ₂ ); 3.08 (2H, t, CH ₂ CH ₂ NMe _2); 7.98 (1H, t, CONH) and 10.9 (1H, d, indole-1).

Example 6 N- [2- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] ethyl] - methanesulfonamide oxalate

Intermediate 10 (0.905 g) is added to a stirred solution of triethylamine (1.26 ml) in dry CH ₂ Cl ₂ (50 ml) at room temperature under nitrogen. The mixture is stirred at room temperature for 5 min. Methanesulfonyl chloride (0.282 ml) is added while cooling to 0 ° and the mixture is allowed to warm to room temperature by stirring for 5 hours. The mixture is poured into 2N Na ₂ CO ₃ solution (60 ml) and extracted with CH ₂ Cl ₂ (3 × 50 ml). The organic layers are dried (MgSO ₄ ) and evaporated to give a gum (0.85 g). Purification by chromatography on a short route (B, D, I, J and K) gives an oil (65 mg) which is dissolved in methanol (1 ml). Oxalic acid (25 mg) in methanol (0.5 ml) is added. The addition of dry ether gives a precipitate, which is washed with dry ether and dried. The title salt is obtained as a solid (38 mg), mp. 159 to 165 ° (foams).
N. mr: δ (DMSO): 2.9-3.0 (11H, m, NMe ₂ and MeSO ₂ NHCH ₂ CH ₂ ); 3.0-3.4 (6H, m, CH ₂ CH ₂ NMe ₂ and SO ₂ NHCH ₂ ); 7.15 (1H, t, SO ₂ NH) and 10.93 (1H, d, indole-1).

Example 7 N [2- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] ethyl] - benzamide oxalate

Benzoyl chloride (0.53 ml) is added to a stirred solution of intermediate 9 as free base (0.95 g) and triethylamine (0.7 ml) in dry CH ₂ Cl ₂ (40 ml) at room temperature under nitrogen. The mixture is stirred at room temperature for 1 h 40 min. The mixture is washed with 8% aqueous NaHCO ₃ (20 ml) and water (2 × 20 ml), dried (MgSO ₄ ) and the solvent is evaporated. The resulting oil (1.47 g) is combined with another portion that was prepared in a similar manner and purified by flash chromatography (B and L) to give a foam which is dissolved in methanol (2 ml) . A solution of oxalic acid (230 mg) in methanol (1 ml) is added. The addition of dry ether (80 ml) gives a precipitate which is washed with dry ether and dried to give the title salt as a solid (0.873 g), mp. 158 to 160 °.
N. mr: δ (DMSO): 2.80 (6H, s, NMe ₂ ), 2.95 (2H, t, CONHCH ₂ CH ₂ ); 3.06 (2H, m, CH ₂ CH ₂ NMe); 3.55 (2H, q, CONHCH ₂ CH _2); 7.44-7.6 (4H, m, phenyl, (m and p) and indole-4); 8.63 (1H, t, CONH) and 10.95 (1H, d, indole-1).

Example 8 N- [2- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] ethyl] benzenesulfonamide oxalate

Benzenesulfonyl chloride (0.61 ml) is added to a stirred solution of intermediate 9 as free base (0.98 g) and triethylamine (0.72 ml) in dry CH ₂ Cl ₂ (40 ml) at room temperature under nitrogen, and then stirring is continued at room temperature for 1 h 40 min. The mixture is washed with 8% aqueous NaHCO ₃ (20 ml) and water (2 x 20 ml), dried (MgSO ₄ ) and evaporated to give a foam (0.90 g). This is combined with a similarly prepared material and the combined samples are purified by chromatography (M and N). The resulting foam (0.607 g) is dissolved in methanol (2 ml) and oxalic acid (154 g) in methanol (1 ml) is added. The addition of dry ether (80 ml) gives a precipitate which is washed by decanting with dry ether. The precipitate is filtered off and dried. The title compound is obtained as a solid (0.702 g), mp. About 80 to 90 ° (foams).
N. mr: δ (DMSO): 2.7-2.85 (8H, m, NMe ₂ and SO ₂ NHCH ₂ CH ₂ ); 2.95-3.1 (4H, m, SO ₂ NHCH ₂ CH ₂ and CH ₂ CH ₂ NMe ₂ ); 7.37 (1H, brs, SO ₂ NH); 7.55-7.7 (4H, m, Ph (m and p) and indole-4); and 10.9 (1H, s, indole-1).

Example 9 (i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) - ethyl] -1H-indol-5-yl] ethyl] benzamide, compound with Ethyl acetate (2: 1)

A solution of thionyl chloride (1.72 ml) in dry tetrahydrofuran (20 ml) is added dropwise under nitrogen to a stirred, ice-cooled solution of benzoic acid (1.41 g) in a mixture of triethylamine (8.00 ml) and dry tetrahydrofuran ( 80 ml). The solution is stirred in ice for 1 h and intermediate 4 (2.13 g) is added and then stirring is continued for 0.75 h. The resulting suspension is partitioned between 2 N Na ₂ CO ₃ (250 ml) and ethyl acetate (2 × 250 ml). The combined organic extracts are washed with water (2 × 250 ml) and 2N Na ₂ CO ₃ (250 ml), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining oil (3.1 g) is chromatographed (E). The required fractions are combined and concentrated in vacuo to give the title compound as a foam (0.92 g), mp 75-83 °.

(ii) N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] benzamide, Connection with creatinine, sulfuric acid and water (1: 1: 1: 1)

A solution of hydrazine hydrate (0.90 ml) and the product of step (i) (0.67 g) in ethanol (25 ml) is stirred at reflux for 3.5 h and left to cool. The resulting suspension is concentrated in vacuo and the remaining solid is partitioned between 2N Na ₂ CO ₃ (50 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts are then dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining gum (0.47 g) is dissolved in a hot mixture of ethanol (40 ml) and water (5 ml) and an aqueous solution of creatinine and sulfuric acid (1: 1, 2 M, 0.76 ml) becomes admitted. The solid, which crystallizes on cooling, is filtered off, washed successively with a mixture of ethanol and water (8: 1, 27 ml) and ethanol (10 ml) and dried at 60 ° for 8 h, the title compound as a solid ( 0.60 g), mp 228-229.5 °.
N. mr: δ (D ₂ O): 3.0-3.25 (9H, m, CONHCH ₂ CH ₂ , CH ₂ CH ₂ NH ₂ and creatinine NMe); 3.68 (2H, t, CH ₂ CH ₂ NHCO); and 7.4-7.64 (7H, m, phenyl, indole-4 and indole-7).

Example 10 (i) N- [2- [3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) - ethyl] -1H-indol-5-yl] ethyl] benzenesulfonamide

A solution of benzenesulfonyl chloride (1.38 ml) in dry dimethylformamide (25 ml) is added dropwise under nitrogen to a stirred, ice-cooled suspension of intermediate 4 (2.0 g) in a mixture of triethylamine (3.0 ml), dry tetrahydrofuran (50 ml) and dry dimethylformamide (25 ml), and then stirring is continued for 2.75 h. The suspension is left at room temperature overnight and partitioned between 2N Na ₂ CO ₃ (500 ml) and ethyl acetate (2 x 500 ml). The combined organic extracts are washed with water (2 × 500 ml) and 2N Na ₂ CO ₃ (500 ml), dried Na ₂ SO ₄ ) and concentrated in vacuo. The remaining foam (2.41 g) is chromatographed (E). The required fractions are combined and concentrated in vacuo to give the title compound as a solid (0.73 g), mp. 183 to 184 °.

(ii) N- [2- [3- (2-aminoethyl) -1H-indol-5-yl] ethyl] benzenesulfonamide, compounds with creatinine, sulfuric acid and Water (1: 1: 1: 1)

A suspension of the product of step (i) (0.60 g) and hydrazine hydrate (0.75 ml) in ethanol (30 ml) is stirred at reflux for 4.25 h. The resulting suspension is evaporated in vacuo and the remaining solid is partitioned between 2N Na ₂ CO ₃ (25 ml) and ethyl acetate (3 x 25 ml). The combined organic extracts are dried (Na ₂ SO ₄ ) and concentrated in vacuo. The remaining gum (0.46 g) is dissolved in a hot mixture of ethanol (36 ml) and water (4.5 ml), and an aqueous solution of creatinine and sulfuric acid (1: 1, 2 M, 0.68 ml ) is added. The solid, which crystallizes on cooling, is filtered off, washed with a mixture of ethanol and water (8: 1, 2 × 5 ml) and ethanol (2 × 5 ml) and then dried in vacuo at 60 ° for 6 h, during which time the title compound is obtained as a solid (0.48 g), mp. 216 to 217.5 °.
N. mr: δ (DMSO): 2.78 (2H, t, SO ₂ NHCH ₂ CH ₂ ); 2.85-3.2 (9H, m, SO ₂ NHCH ₂ , CH ₂ CH ₂ NH ₂ and creatinine N-Me); 7.2-7.4 (3H, m, indole-2, indole-7 and SO ₂ NH); 7.5-8.0 (6H, m, phenyl and indole-4) and 10.9 (1H, s, indole-1).

The following examples illustrate pharmaceutical pharmaceuticals according to the invention Preparations containing 4- (acetylamino) -N- [2- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] ethylbenzene acetamide oxalate included as an active ingredient. Others according to the invention Connections can be formulated in a similar way.

Tablets for oral administration

Direct pressing

mg / tablet Active ingredient 2.4 Calcium hydrogen phosphate 95.10 BP (a quality that is suitable for direct compression)
Croscarmellose sodium USP 2.00 magnesium stearate, BP 0.50 compression weight 100 mg

The active ingredient is sieved before use. The Calcium hydrogen phosphate, croscarmellose sodium and the Active ingredient are in a clean polyethene bag weighed. The powder is mixed by vigorously shakes, then the magnesium stearate is weighed out and added to the mixture, which is further mixed. The mixture is then used to use a Manesty F3 Tablet machine, beveled with 5.5 mm flat Is equipped to make tablets with a punch Target compression weight of 100 mg pressed.

The tablets can also be made according to others known per se Processes as prepared by wet granulation will.

Tablets with other strengths can be made by looking at the ratio of active ingredient Lactose or the compression weight changes and corresponding Cutting dies used.

The tablets can be coated with suitable film-forming materials, as with hydroxypropylmethyl cellulose, under Coated using standard methods. Alternatively the tablets can be coated with sugar.

Injection for intravenous administration

mg / ml

Active ingredient 0.6 mg

Sodium chloride BP as required

Water for BP injection up to 1.0 ml

The sodium chloride can be used to adjust the tonicity of the Solution can be added and the pH can be adjusted using an acid or alkali can be adjusted so that the optimal stability is maintained and / or Dissolution of the active ingredient is facilitated. Alternatively you can use suitable buffer salts.

The solution is prepared, clarified and more suitable in ampoules Bottled size and by melting the glass sealed. The injection is made by heating in one Autoclaves using one of the acceptable ones Cycles sterilized. Alternatively, the solution can be sterilized be filtered and placed in sterile ampoules bottled aseptic conditions. The solution can be found below an inert atmosphere of nitrogen or another suitable gas can be filled.

Claims (11)

1. Compounds of the general formula (I): wherein
R _{1 represents} a hydrogen atom, a C _1-6 alkyl or C _3-7 cycloalkyl group or a phenyl or phenyl (C _1-4 ) alkyl group;
R _{2 represents} a hydrogen atom or a C _1-3 alkyl group;
R _{3 represents} a hydrogen atom or a C _1-3 alkyl group;
R ₄ and R ₅ , which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl group or a 2-propenyl group;
A represents -CO- or -SO ₂ -;
and n is an integer from 2 to 5 (with the proviso that R _{1 is} not hydrogen when A is -SO ₂ -), and their physiologically acceptable salts and solvates. 2. Compounds according to claim 1, characterized in that in the general formula (I) R _{1 is} a C _1-6 alkyl, phenyl or phenyl (C _1-4 ) alkyl group. 3. Compounds according to claim 2, characterized in that in the general formula (I) R _{1 represents} a methyl or phenyl group. 4. Compounds according to any one of claims 1 to 3, characterized in that in the general formula (I) n is the integer 2. 5. Compounds according to any one of claims 1 to 4, characterized in that in the general formula (I) R _{2 represents} a hydrogen atom. 6. Compounds according to any one of claims 1 to 5, characterized in that in the general formula (I) R _{3 represents} a hydrogen atom. 7. Compounds according to any one of claims 1 to 6, characterized in that in the general formula (I) R ₄ and R ₅ , which may be the same or different, each represent a hydrogen atom or a methyl or ethyl group. 8. N- [2- [3- [2- (methylamino) ethyl] -1H-indol-5-yl] ethyl] methanesulfonamide and its physiologically acceptable salts. 9. Pharmaceutical preparation, characterized in that they have at least one general connection Formula (I) or one of its physiologically acceptable salts or Solvate together with one or more physiologically acceptable excipients or Contains diluents. 10. A process for the preparation of a compound of general formula (I) according to claim 1 or one of its physiologically acceptable salts or solvates, characterized in that:

• (A) a compound of the general formula (II): (wherein R ₂ , R ₃ , R ₄ , R ₅ and n have the definitions given in claim 1)
  or one of its salts or one of its N-silyl derivatives or one of its protected derivatives with a reagent which serves to introduce the group R ₁ A (in which R ₁ and A have the definitions given in claim 1); or
• (B) a compound of the general formula (III): (wherein R ₁ , R ₂ , R ₃ , A and n have the definitions given in claim 1)
  and Q represents the group NR ₄ R ₅ (in which R ₄ and R _{5 have} the meanings given in claim 1)
  or represents a protected derivative thereof or a substituted atom or group, cyclizes; or
• (C) a compound of the general formula (VI): (wherein R ₁ , R ₂ , R ₃ , A, Y and n have the definitions given in claim 1 and Y represents an easily substitutable atom or group)
  or a protected derivative thereof with an amine of the formula R ₄ R ₅ -NH (in which R ₄ and R _{5 have} the definitions given in claim 1); or
• (D) a compound of the general formula (VII): (wherein R ₁ , R ₂ , R ₃ and A have the definitions given in claim 1 and W is a group which can be reduced to the desired - (CH ₂ ) ₂ NR ₄ R ₅ group, where R ₄ and R _{5 have} the definitions given in claim 1, or a protected derivative of - (CH ₂ ) ₂ NR ₄ R ₅ , and B means the group - (CH ₂ ) _n -, wherein n has the definition given in claim 1, or a Group which can be reduced to -CH ₂ ) _n -, or a salt or protected derivative thereof; or
• (E) for the preparation of a compound of general formula (I) according to claim 1 or one of its physiologically acceptable salts or solvates, subjecting another compound of general formula (I) or one of its salts or solvates to an interconversion reaction; or
• (F) subjecting a protected derivative of the general formula (I) or one of its salts to a reaction to remove the protective group or groups; and
  optionally or if desired, subjecting the compound obtained in any one of processes (A) to (E) to one or two further reactions as follows:
  • (i) removal of any protecting groups; and
  • (ii) converting a compound of general formula (I) or one of its salts into a physiologically acceptable salt or solvate thereof.

11. Compounds of the general formula (II): wherein
R _{2 represents} a hydrogen atom or a C _1-3 alkyl group;
R _{3 represents} a hydrogen atom or a C _1-3 alkyl group;
R ₄ and R ₅ , which may be the same or different, each represent a hydrogen atom, a C _1-3 alkyl group or a 2-propenyl group; and
n is an integer from 2 to 5,
and their salts.