DE3543982A1 - INDOLDER DERIVATIVES, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME - Google Patents

Description

The invention relates to indole derivatives and processes for their Manufacture, pharmaceutical preparations containing them and their medical use. She concerns especially compounds and preparations that can be used in the treatment of migraines.

The migraine pain is associated with excessive dilation of the cranial vasculature. Known treatments for migraines include the administration of compounds with vasoconstricting properties, such as ergotamine. Ergotamine, however, is a non-selective vasoconstrictor Agent that narrows the blood vessels inside the body and has undesirable and dangerous side effects having. Migraines can also be resolved by giving an analgesic, usually together treated with an anti-emetic. However, such treatments are of limited value.

There is a need for a safe and effective drug for treating migraines which either can be used prophylactically or to relieve an existing headache. A connection with selective vasoconstricting activity would serve such a role.

There was now a group of Indo! Derivatives with potent and selective vasoconstricting activity found.

The invention relates to an indole of the general formula

(D

^R i ^R r ^rn ™ _; .:.,. ·,. = -. Cho, NR, R,

N H

1 in which

R _{1 is} a hydrogen atom, a C ^ g -alkyl, C- * y-cycloalkyl or C, g-alkenyl group or a phenyl or PHeHyI- (C ₁ _ ^) - alkyl group in which the phenyl ring is unsubstituted or may be substituted by one or two substituents, selected from C _1- ^ - AlkOXy, hydroxy, halogen, a group RcRgNCO-, where Rc and Rg (which can be the same or different) each represent a hydrogen atom or a C ₁ ^ - Alkyl group, or a group RyRoN-, wherein Ry and Rg (which can be the same or different) each represent a hydrogen atom or a C ₁ , -alkyl group or RyRgN- represents a saturated, monocyclic, 5- to 7-membered ring; Rp means a what s he st off atom or a C ,, / - alkyl group; or

R ₁ and R ₂ together with the nitrogen atom to which they are attached form a saturated, monocyclic, 5- to 7-membered ring;

R- * and R ^, which can be the same or different, each a hydrogen atom, a C ^^ - alkyl group or represent a 2-propenyl group; and

η is an integer from 2 to 5; as well as their physiologically acceptable salts and solvates

25 (e.g. hydrates).

The invention embraces all optical isomers of compounds of formula (I) and their mixtures, including their racemic mixtures. All geometric isomers of compounds of general formula (I) are also Subject of the present invention.

With reference to the general formula (I), the alkyl groups can be straight chain or branched chain alkyl groups be like methyl, ethyl or isopropyl

groups. The cycloalkyl group can be, for example, a cyclopentyl or cyclohexyl group. Alkenyl groups that can be represented by R ₁ include propenyl and butenyl groups. It is evident that the double bond in such alkenyl groups will not be adjacent to the nitrogen atom.

If R _{1 is} a substituted phenyl or substituted phenyl (C _1- Zf) -alkyl group, a C _1- ^ -AlkOXy substituent can be, for example, methoxy and a halogen substituent can be, for example, fluorine, chlorine or bromine. Substituents of the formula RcRgNCO- include N-methylcarbamoyl and examples of substituents RyRgN- are amino, dimethylamino and pyrrolidino. The substituent can be in the ortho, meta or para position.

The alkyl moiety of phenyl (C ₁ _ ^) - alkyl group is a methyl or Ethylmolekülteil may for example be.

A preferred class of compounds of general formula (I) is that wherein R ₁ is a hydrogen atom, a C _1-> g-alkyl or C, g-alkenyl group or a phenyl or phenyl (C ₁ _4 _) - älkylgruppe- , in which the phenyl ring may be substituted, as previously described, means.

It is preferred that in the compounds of the general formula (I) one of the radicals R ₁ and Rg denotes a hydrogen atom.

Another preferred class of compounds is that wherein R _? and R ^ (which can be the same or different) each represent a hydrogen atom or a C 1 -C alkyl group.

In a further, preferred class of compounds according to the invention, η is 2 or 3.

If R _{1 is} a substituted phenyl or substituted phenyl (C ^^ - alkyl group, preferred substituents include C ₁ ^ -alkoxy (eg methoxy), halogen (eg chlorine), a group RcRgNCO- or a group RyRgN- in the case of the substituent around a group RcRgNCO-, it is particularly preferred that Rc and Rg independently represent a hydrogen atom or a methyl group a methyl group or together form a pyrrolidino ring.

A particularly preferred class of compounds falling under the general formula (I) is those in which R _{1 is} a C _1- ^ alkyl group (e.g. methyl), a C 1-6 alkenyl group (e.g. 2-propenyl) or a phenyl - (C- ^) "denotes an alkyl group in which the phenyl ring, as previously described, can be unsubstituted or substituted; R _{2 represents} a hydrogen atom; R, and R ^ (which can be the same or different) each represent a hydrogen atom or a methyl or ethyl group; and η is 2 or 3; and their physiologically acceptable salts and solvates (e.g. hydrates).

Preferred inventions according to the invention include:

3- (2-aminoethyl) -N- (phenylmethyl) -iH-indole-5-propanamide;

3- (2-Aminoethyl) - N - [[4- (I-pyrrolidinyl) phenyl] methyl ] -iH-indo1-5-propanamide;

3-C2- (Dimethylamine) -ethyl] -N - [(4-methoxyphenyl) -methyl] -iH-indole-5-propanamide;

3- (2-aminoethyl) -N- (2-propenyl) -1H-indole-5-propanamide;

BATH

3- (2-Aminoethyl) -N - [(4-methoxyphenyl) -methyl] -IH-indole-5-propanamide;

as well as their physiologically acceptable salts and solvates (e.g. hydrates).

Suitable physiologically acceptable salts of the indoles of general formula (I). are acid addition salts that are formed with inorganic or organic acids, for example the hydrochlorides, hydrobromides, sulfates, nitrates, oxalates, phosphates, tartrates, citrates, fumarates, Maleates, succinates and sulfonates, e.g. mesylates. Other salts may be useful in preparing the compounds of formula (I), e.g. Creatinine Sulphate Adducts.

The invention also relates to the other physiologically acceptable equivalents of compounds according to the invention, i.e., physiologically acceptable compounds which are converted to the parent compound in vivo. Examples of such Equivalents are physiologically acceptable, meta-

20 bolically labile N-Acy1 derivatives.

The compounds according to the invention selectively narrow the carotid arterial layers of the anesthetized dog, while they have negligible effect on blood pressure. The selective vasoconstricting effect the compounds of the invention have been demonstrated in vitro.

The compounds of the invention are for treatment useful of pain caused by dilation of the cranial Vessels, particularly migraines and cluster headache.

The invention thus also relates to a pharmaceutical one Preparation for use in human medicine that

BATH ORIGINAL

at least one compound of formula (I) or one of its physiologically acceptable salts or solvates (e.g. the hydrate) and is formulated so as to be suitable for administration by any conventional route is. Such preparations can be pharmaceutical in a manner known per se using one or more acceptable carriers or diluents.

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

For oral administration, the preparations according to the invention can be in the form of, for example, tablets or Capsules are present, according to known methods with pharmaceutically acceptable diluents, such as Binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl cellulose); Fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); Lubricants (e.g. magnesium stearate, talc or silicon dioxide); Disintegrants (e.g.

Potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulfate). The tablets can be prepared according to methods well known per se be coated. Liquid preparations for oral administration can be in the form of, for example Solutions, syrups or suspensions can be present or can be used as a dry product for constitution with water or other suitable vehicle prior to use. Such liquid preparations can after methods known per se using pharmaceutically acceptable additives such as suspending agents

BATH ORIGINAL

■ 1 (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible Fats); Emulsifiers (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters of Ethy! Alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbic acid) will. The liquid preparations can also be known per se buffers, flavorings, colors and Contains sweeteners as required.

For buccal administration, the preparations can be in the form of tablets or lozenges, which be formulated in a manner known per se.

The compounds of the invention can be used for parenteral administration by injection or continuous Infusion to be prepared. Preparations for injection may be in unit dosage form, e.g., in ampoules or in multi-dose containers with one added Preservatives.

The preparations can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles are present and preparation auxiliaries, such as suspending agents, Stabilizers and / or dispersants and / or agents for adjusting the tonicity of the Solution included. Alternatively, the active ingredient can be in powder form for constitution with a suitable one Carriers, e.g., sterile, pyrogen-free water, are presented before use.

The compounds according to the invention can also be used in In the form of rectal preparations, such as suppositories or retention enema, which, for example, knew suppository raw materials like cocoa butter or

35 other glycerides.

BAD OBSGlHAL

For administration by inhalation are those according to the invention Compounds expediently dispensed in the form of an aerosol spray from pressurized containers, using suitable propellants, e.g. dichlorodifluoromethane, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or another suitable gas, used. You can also use a nebulizer use. In the case of a pressurized aerosol, the unit dose can be determined by provides a valve that releases a metered amount. Capsules and cartridges made from, for example, gelatine for use in an inhalation or insufflation device can be formulated to be a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A suitable dose of the compounds of the invention for oral, parenteral, buccal or rectal administration in people (average body weight around 70 kg) for the treatment of migraines 0.1 to 100 mg of active ingredient per unit dose, up to 8 times a day, normally 1 to 4 times a day, can be administered. It may · be necessary to make routine variations with the dose to be performed, depending on the age and weight of the patient as well as the severity of the condition being treated.

For oral administration, the unit dose is preferably about 0.5 to 50 mg, e.g., 2 to 10 mg, of active Part included. A unit dose for parenteral administration is preferably 0.2 to 5 mg active ingredient included.

BATH

Aerosol formulations are preferably prepared so that any metered dose or "burst" of is dispensed from the pressurized aerosol container, contains 0.2 to 2 mg of a compound of the invention, and any dose that is via capsules or cartridges in one Inhalation or insufflation device dispensed contains 0.2 to 20 mg. The total daily dose by inhalation will range from 1 mg to 100 mg. Administration can be several times a day, for example 2 to 8 times, for example 1, 2 or 3 doses being administered each time.

The compounds according to the invention can optionally together with one or more other therapists Agents such as analgesics, anti-inflammatory agents, and anti-emetics can be administered.

The invention further relates to a process for the preparation of the compounds according to the invention in general Formula (I) and its physiologically acceptable salts or solvates (e.g. hydrates). In the following General procedures listed have R ^ -, R £> R ,, R ^ and η those given in the general formula (I) Meaning unless otherwise stated.

According to a general process (A), a compound of the general formula (I) is prepared by condensation of an amine of the formula R ^ R ₂ NH with an acid of the general formula (II)

HO-, CC CH-O (PH \ MR D

7 η

• ·

• N

BAD ORiGINAL

or a corresponding acylating agent or a Salt ("for example an organic or inorganic acid addition salt, such as the hydrochloride, hydrobromide, Sulfate or maleate salt or the creatinine sulfate adduct) or a protected derivative thereof.

The reaction, which comprises the condensation of the amine HNR-Rp with the acid of the general formula (II), is preferably carried out in the presence of a coupling agent, for example carbonyldiimidazole or carbodiimide, such as N, N'-dicyclohexylcarbodiimide. The condensation reaction can be in a suitable reaction medium, preferably an anhydrous medium, conveniently serving lent at a temperature of -50 to +50 ⁰ C, preferably -5 to +30 ⁰ C, are performed. Suitable solvents are halogenated hydrocarbons, for example dichloromethane; Nitriles, for example acetonitrile; Amides, for example Ν, Ν-dimethylformamide; and ethers; for example tetrahydrofuran, and mixtures of two or more such solvents. The reaction can also be carried out in the absence of a coupling agent in a suitable reaction medium, such as a hydrocarbon (for example toluene or xylene), expediently at a temperature of 50 to 120 ^° C.

25 take place.

Acylating agents which correspond to the acid of the general formula (II) and for the preparation of the compounds of the formula (I) can be used include acid halides, e.g. acid chlorides. Such acylating agents can be obtained by reacting an acid of the general Formula (II) or a salt or protected derivative of which with a halogenating agent such as phosphorus pentachloride, Thionyl chloride or oxalyl chloride. Other suitable acylating agents that can be used to prepare

BATH ORIGINAL

Position of compounds of the formula (I) can be used are alkyl esters such as the methyl esters, activated esters [e.g. the 2- (1-methylpyridinyl) ester] and mixed anhydrides (e.g. formed with pivaloyl chloride, a sulfonyl halide such as methanesulfonyl chloride, or a haloformate such as lower alkyl haloformate). Acids of the formula (II) .self can, for example by cyclizing a suitable hydrazine compound in a manner analogous to the process described below (B) can be produced.

When using an acid of general formula (II) corresponding acylating agent, the condensation process in aqueous or nonaqueous reaction media and conveniently be carried out at a temperature of -70 to +150 ⁰ C. Thus, the condensation reaction can be carried out using an acid halide, anhydride or activated ester in a suitable reaction medium, such as an amide, for example Ν, Ν-dimethylformamide; an ether, for example tetrahydrofuran or diethyl ether; a nitrile, for example acetonitrile; a halogen Erten hydrocarbon!, eg dichloromethane, or mixtures thereof, optionally effected in the presence of a base such as a tertiary amine, for example triethylamine or pyridine, and preferably at a temperature of -5 to +25 ⁰ C. The condensation reaction using an alkyl ester can be carried out in a suitable reaction medium such as an alcohol such as methanol; an amide, for example dimethylformamide; an ether, e.g.

Tetrahydrofuran or diethyl ether; or mixtures thereof, and conveniently carried out at a temperature of from 0 to 100 ° C. In some cases, the amine R ₂ itself can serve as the reaction solvent.

_BATH

If it is desired to prepare a compound of the formula (I) in which R ₁ and R _{2 are} both hydrogen, the condensation can be carried out using ammonia, for example in the form of aqueous ammonia or in a solvent such as methanol can.

Compounds of the general formula (II) and the acylating agents corresponding to them, such as the alkyl esters, are new compounds and also a subject of the present invention.

According to a further, general process (B), compounds of the general formula (I) can be obtained by cyclization a compound of the general formula (III)

R ₁ R ₉ NCO (CH ₀ )

²ⁿ V

20 35

V \ (in)

• -NHN = CH (CH ₂ ) ₃ Q W / *

wherein Q is the group NR, R λ (or a protected derivative thereof) or a leaving group such as a halogen atom (e.g. chlorine or bromine) or an acyloxy group (e.g. a carboxylic acid or sulfonic acid acyloxy group, such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methane sulf onyloxy), means to be produced.

The reaction can expediently be carried out in an aqueous or non-aqueous reaction medium and at temperatures from 20 to 20 <
leads to be.

from 20 to 200 ° ", preferably 50 to 125 ° - ~, through

BATH

Particularly preferred embodiments are described below of the procedure.

Q means the group NR, Rj- (or a protected derivative thereof), the process is preferably carried out in the presence of a polyphosphate ester in a reaction medium carried out, which may include one or more organic solvents, preferably halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, dichlorodifluoromethane or mixtures thereof. at the polyphosphate ester is a mixture of esters composed of phosphorus pentoxide, diethyl ether and Chloroform according to the in "Reagents for Organic Synthesis" (Fieser and Fieser, John Wiley and Sons 1967) procedures described can be produced.

Alternatively, the cyclization in an aqueous or non-aqueous reaction medium can be carried out in the presence of an acidic catalyst. Becomes a watery one When medium is used, it 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) and a mixture such solvent. The acidic catalyst can, for example, be an inorganic one Acid, such as concentrated hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid, Act. (In some cases, the acid catalyst can also act as a reaction solvent.) In a non-aqueous reaction medium comprising one or more May comprise ethers (e.g. those previously described) or esters (e.g. ethyl acetate), the acidic catalyst will generally be a Lewis acid such as boron trifluoride, Zinc chloride or magnesium chloride.

ORIGINAL BATHROOM

If Q is a leaving group such as a chlorine or bromine atom, the reaction can be carried out in an aqueous, organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous ether (e.g. dioxane or tetrahydrofuran), in the absence of an acidic one Catalyst and expediently at a temperature of 20 to 200 ⁰ C, preferably 50 to 125 ° C, carried out. This process results in the formation of a compound of formula (I) in which FU and R ^ are both hydrogen atoms.

According to a special embodiment of this process, compounds of the formula (I) can be converted directly a compound of the general formula (IV)

¹⁵ R ₁ R ₂ NCO (CHJ

^{12 2 n} \ // \

or a salt thereof with a compound of the formula (V)

OHC (CH ₂ KQ (V)

(wherein Q is as defined above) or a salt or a protected derivative thereof (such as an acetal or ketal, for example, with a suitable alkyl-o-formate or diol or formed as a bisulfite addition complex is) using suitable conditions, as described above for the cyclization of compounds of the general formula (III) have been described. It should be noted that in this embodiment of the cyclization process (B) a compound of the general formula (III) as an intermediate is formed and reacted in situ to form the desired compound of the general formula (I) can.

BATH ORIGINAL

Compounds of the general formula (III) can, if desired, be isolated as intermediates during the process for the preparation of compounds of the formula (i), wherein a compound of the formula (IV) or a salt or protected derivative thereof with a compound of the formula (V) or a salt or protected derivative thereof is reacted in a suitable solvent such as an aqueous alcohol (zBMethanol), at a temperature of, for example, 20 to 30 ⁰ C. If an acetal or ketal of a compound of the formula (V) is used, it may be necessary to carry out the reaction in the presence of an acid (for example acetic or hydrochloric acid).

Compounds of the general formula (IV) can, for example can be prepared from the corresponding nitro compounds using processes known per se.

Another general process (C) for the preparation of compounds of general formula (I) includes Implementation of a compound of the general formula (VI)

_{χ //} . _{χ /} (CH ₂ ). ₂ Y

25 yrs

• · · ■ ■ -

• N H

(where Y is an easily exchangeable group) or a protected derivative thereof with an amine of the formula R ^ R

The exchange reaction can expediently be carried out on compounds of the formula (VI) in which. the substituent group Y is a halogen atom (e.g. chlorine,

BATH ORIGINAL

Bromine or iodine) or a group ORg, in which ORg means, for example, an acyloxy group which can be derived from a carboxylic acid or sulfonic acid, such as an acetoxy, chloroacetoxy, dichloroacetoxy, Trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy group.

The exchange reaction can expediently be carried out in an inert, organic solvent (if appropriate in the presence of water), for example alcohols such as ethanol; cyclic ethers such as dioxane or tetrahydrofuran; acyIic Ethers such as diethyl ether; Esters such as ethyl acetate; Amides, e.g., N, N-dimethylformamide; and ketones, such as acetone or methyl ethyl ketone, at one temperature

of 10

will.

from -10 to +150 ⁰ C, preferably 20 to 50 ⁰ C, effected

The compounds of the general formula (VI) in which Y represents a halogen atom can be prepared by Reaction of a hydrazine of the general formula (IV) with an aldehyde or ketone (or a protected Derivative thereof) of formula (V), wherein Q is a halogen atom means in an aqueous alkanol (e.g. methanol) that contains an acid (e.g. acetic or hydrochloric acid). Compounds of the formula (VI) in which Y denotes the group ORq can be selected from the corresponding compound, wherein Y represents a hydroxyl group, activated by acylation or sulfonylation with the appropriate one Species (e.g. anhydride or sulfonyl chloride) under

30 turn of known techniques can be obtained. Of the

Intermediate alcohol may be prepared by cyclising a compound of formula (III), wherein "2 represents a Ιΐ / dr oxy group,! (Or _IU se availed derivative thereof) produced v / ground under standard conditions.

Compounds of the formula (I) can also be prepared by a further general process (D). This includes the reduction of a compound of the general formula (VII)

/ ^w evil)

• N 10 H

[where W is a group _{which can be reduced to form the required - (CH 2} ) ,, NR-xR ^ group or to form a protected derivative of - (CHg) gNR, R ^, and A is the group - (CHo) _n - * as previously defined, or a group _{which can be reduced to - (CHg) n} -] or a salt or protected derivative thereof.

The required - (CHg) ₂ - u * ¹⁰ -NR ^ R ^ groups in 3-

Position can be obtained through reduction stages, which run separately or together in any suitable manner.

Groups A, forming the desired group

- Can be reduced, include corresponding unsaturated groups, such as Cg ^ c-alkenyl groups.

Examples of groups represented by the Substltuenten W include - (CH ₂ J ₂ NO _2; -CH = _CHNO2; ': - (CHg) ₂ N _3, -CH ₂ CN -CH ₂ CHO; -COCH ₂ Z; -CH ₂ CH = NOH; and -CH (OH) CHgNR-s R ^ (where 2 is an azido group or the group -NR ^ R ^ or a protected derivative thereof ) .
. ■ - '■. ■ -

BATH

Groups which can be reduced to the - (CH ₂ ) ₂ moiety in the 3-position include the corresponding unsaturated group and corresponding groups which contain a hydroxyl group or a carbonyl function. 5

Groups which can be reduced to the group -NIUR ^, where R- * and R ^ are both hydrogen, include nitro, azido, hydroxyimino and nitrile groups. In the latter case, the reduction gives the group -CH ₂ NH ₂ and a methylene group of the - (CH ₂ ) ₂ moiety is obtained.

The required -NR _x R, group, in which R- and / or R _{L have} a meaning other than hydrogen, can be obtained by reducing a nitrile -CH ₂ CN or an aldehyde -CH ₂ CHO in the presence of an amine, R ^ R ^ NH, to be produced.

A particularly suitable process for the preparation of a compound of formula (I) wherein R ^ and / or R ^ are have a meaning other than hydrogen, includes the reductive alkylation of the corresponding compound, wherein R, and / or R ^ are hydrogen, with a suitable aldehyde or ketone (e.g. formaldehyde or acetone) in the presence of a suitable reducing agent. In some cases [e.g. for the introduction of the group (s) R-, and / or R /, if these are methyl] the aldehyde (e.g. formaldehyde) can be condensed with the amine and the intermediate product thus formed can then be reduced using a suitable reducing agent.

It is obvious that the choice of reducing agent and reaction conditions depend on the nature the group W as well as the other groups already present in the molecule.

BATH ORIGINAL

Suitable reducing agents which are used in the above process for reducing compounds of the formula (VII) in which W is, for example, for the groups - (CH ₂ ) 2 ^N0 2 * -CH = CHNO ₂ , - (CH ₂ ) ₂ N ,, -CH ₂ CN, -CH ₂ CH = NOH or -CH (OH) CH ₂ NR: * R ^ can be used include 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 carriers, for example they can contain activated carbon, kieselguhr or aluminum oxide. In the case of Raney nickel, hydrazine can also be used as a hydrogen source. This process can conveniently be carried out in a solvent such as an alcohol, e.g. ethanol, an ether, e.g. dioxane or tetrahydrofuran ·, an amide, e.g. dimethylformamide, or an ester, ζ. B. ethyl acetate, and at a temperature of -10 to +50 ⁰ C, preferably -5 to +30 ⁰ C, are carried out.

The reduction process can also be carried out on compounds of the formula (VIl) in which W is e.g. B. the groups - (CH ₂ J ₂ NO ₂ , -CH = CHNO ₂ , - (CHg) ₂ IT ₅ , -CH (OH) CH ₂ -NR ₃ R ^ or -COCH ₂ Z (where Z is as before using an alkali metal or alkaline earth metal borohydride or cyanoborohydride, e.g. 10 to TOO ⁰ C, preferably 50 to 100 ⁰ C. In some cases, the reduction can be carried out using a borohydride in the presence of cobalt (II) chloride.

The reductive alkylation of a compound of the formula (VII) can be carried out using a

BATH ORIGINAL

Alkali metal or alkaline earth metal borohydrides or cyanoborohydrides. The reaction takes place in an aqueous or non-aqueous reaction medium, expediently an alcohol (for example methanol or ethanol) or an ether (for example dioxane or tetrahydrofuran), optionally in the presence of water. The reaction may conveniently be effected at a temperature in the range of 0 to 100 ° C, preferably 5 to 50 ⁰ C are performed.

A particular embodiment of the general process (D) comprises the reduction of a compound of the formula (VII) in which W is the --CH ₂ CN group, for example by catalytic reduction with hydrogen in the presence of a catalyst such as palladium on activated carbon or rhodium on -Aluminium oxide, optionally in the presence of an amine, HNR ^ R ^. The reduction can be effected in a suitable solvent such as an alcohol, e.g. methanol or ethanol.

A compound of the general formula (I) wherein R ^ means a hydrogen atom, can also by hydrogenolysis a corresponding compound in which R ^ is a benzyl group, for example with hydrogen in the presence of a catalyst, e.g. 10% palladium

25 on-charcoal.

Suitable reducing agents that can be used in the group A reduction are hydrogen in the presence of a metal catalyst. Suitable metal catalysts and conditions for the reduction process are described for the reduction of group ^r ; I.

The starting materials or intermediate compounds of the formula (VII) in which W is - (CHp) ₂ NO ₂ , -CH = CHNO ₂ , -CHpCN or -COCH ₀ Z can be used analogously to the

BATH ORIGINAL

driving are produced as they are published in the GB patent application 2035310 and in "A Chemistry of Heterocyclic Compounds - Indoles Part II", Chapter VI, edited by W.J. Houlihan (1972), Wiley Interscience,

5 New York, ".

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

The intermediate compound of formula (VII) wherein W represents the group - (CH ₂ ) 2% can be prepared from a compound of formula (VI) wherein Y represents a halogen atom using standard methods.

Standard reducing agents, such as sodium borohydride, can be used to prepare a compound of the formula (VII) in which W is the group -CH (OH) CH ₂ NR ₃ R ^, from the corresponding compound of the formula (VII) in which W is the

25 group -COCH ₂ NR ^ R r can be used.

The intermediate compounds of the formula (VII) in which A is a C ₂ c -alkenyl group can be prepared by reacting a compound of the general formula (VIII) 30

• N

35 H.

BATH ORIGINAL

[.Where W is given in the general formula (VII) Has meaning and ρ stands for 0 or an integer from 1 to J5] with, for example, a suitable phosphonium salt using standard conditions

5 can be produced.

Compounds in which R «j. and R _{2 are} both hydrogen atoms, can be prepared according to a further, general process (E) which involves the reaction of a nitrile of the general formula (IX)

15 · N

^ib H

or a salt or protected derivative thereof with a suitable oxygen-containing compound includes. For example, a nitrile of the general Formula (IX) can be hydrolyzed with an acid or an alkali under controlled conditions. Acids and alkalis that can be used in this process are concentrated sulfuric acid; concentrated Hydrochloric acid; a mixture of

25 centered sulfuric acid, acetic acid and water

(1: 1: 1); Polyphosphoric acid; Sodium tert-butoxide in refluxing tert-butanol; Sodium hydroxide in aqueous ethanol in the presence of hydrogen peroxide; a base in the form of a resin; or boron trifluoride in acetic acid. The reaction is expediently carried out at a temperature of -10 to 100 ^° C.

Compounds of the general formula (IX) themselves can be prepared by cyclization of the appropriate hydrazone in a manner analogous to process (E).

BATH ORIGINAL

■■■■: 29 ■■ "" ■ "* ■

ι According to a further, general procedure (F; Can a compound of formula (I) according to the invention or converting a salt or protected derivative thereof into another compound using conventional methods

5 of the formula (I) can be converted.

For example, a compound of the general formula (I) in which one or more of the radicals R ^, Rp, R * and R ^ are alkyl groups, from the corresponding compounds of the formula (I) in which one or more of the radicals R ^, R ₂ , Rz and R ^ represent hydrogen atoms, by reaction with a suitable alkylating agent, such as a compound of the formula R _x L (where R _{x represents} the desired R «.- ·, R ₂ -, R * or R ^ group and L denotes a leaving group, such as a halogen atom or a tosylate group) or a sulfate (R _x ) 2 ^S0 4>. Therefore, the alkylating agent can, for example, be an alkyl halide (e.g. methyl or ethyl iodide), alkyl tosylate (e.g. methyl tosylate) or di-

20 alkyl sulfate (e.g. dimethyl sulfate).

The alkylation reaction can expediently be carried out in an inert, organic solvent such as an amide (eg dimethylformamide), an ether (eg tetrahydrofuran) or an aromatic hydrocarbon (eg toluene), preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides, such as sodium or potassium hydride; Alkali metal amides such as sodium amide; Alkali metal carbonates such as sodium carbonate; Alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or tert-butoxide; and tetra butylammonium fluoride. If an alkyl halide is used as the alkylating agent, the reaction can also be carried out in the presence of an acid scavenger, such as propylene oxide or ethylene oxide. The reaction is expediently carried out at a temperature of -20 to 100 ^° C.

BATH ORIGINAL

Compounds of the formula (I) in which R _{1 is} a cycloalkyl, alkenyl or PhenylaIkylgruppe and / or one or both radicals R, and R ^ are propenyl, can in a similar manner using a suitable compound of the formula R _x L or ( ^R _x ) 2 ^S0 4 can be produced.

According to a further, general process (G), a compound of the general formula (i) according to the invention or a salt thereof can be prepared by using a protected derivative of the general formula (I) or a salt thereof is subjected to a reaction to remove the protective group (s).

Thus, at an early stage in the sequence of reactions in the preparation of a compound, the general Formula (I) or a salt thereof may be required or desired, one or more sensitive Protect groups in the molecule to avoid undesirable side reactions. For example, it may be required be the group NR, R ^, wherein R- * and / or R ^ stand for hydrogen, by protonation or with to protect a group that can be easily removed at the end of the reaction sequence. Such groups can, for example, aralkyl groups such as benzyl, dipheny! methyl or triphenylmethyl; or acyl groups such as N-benzyloxycarbonyl or tert-butoxycarbonyl or Phthaloyi, be.

In some cases it may also be desirable to use the indolitrogen with, for example, an Aralky! group,

like benzyl, to protect.

The subsequent cleavage of the protective group or groups can be carried out by processes known per se.

BATH ORIGINAL

31 ■ '* "*

For example, an aralky group, such as benzyl, can through hydrogenolysis in the presence of a catalyst (e.g. palladium on activated carbon) or of sodium and liquid ammonia be split off; an acyl group such as N-benzyloxycarbonyl can by hydrolysis with, for example, hydrogen bromide in acetic acid or by reduction, = for example by catalytic hydrogenation. The phthaloyl group can be purified by hydrazinolysis (e.g. by treatment with hydrazine hydrate) or by treatment with a primary amine (e.g. methylamine) will.

Obviously, with some of the previously described Process (A) to (F) may be necessary or desirable to identify any sensitive groups in the Protect molecule as just described. So can a reaction stage, which the cleavage of protective groups in the case of a protected derivative of the general formula (!) or a salt thereof, followed by any of the above-described processes (A) to (F) can be carried out.

According to a further aspect of the invention can thus the following reactions in any suitable sequence if necessary and / or desired following any of procedures (A) through (F) be performed:

(i) removal of any protecting groups; and (ii) conversion of a compound of the general Formula (I) or a salt thereof into a physiologically acceptable salt or solvate (e.g. hydrate) thereof.

If desired, a compound of the invention as a salt, e.g. as an acid addition salt, this can be done by treating the free base of the

BATH

general formula (I) with a suitable acid · is preferred with an equivalent amount, or with creatinine sulfate in a suitable solvent (e.g. aqueous ethanol).

The starting materials or intermediate compounds for the preparation of the compounds of the invention can be by processes analogous to those described in the published GB patent application 2035310 will.

The general processes given above for the preparation of the compounds according to the invention can be used as the last Main stage in the preparative sequence. However, you can also go for the introduction of the desired groups can be used at an intermediate stage in the preparation of the desired compound. For example, the desired group in the 5-position can be used before or after cyclization for formation of the indole nucleus. In such a multi-step process, the reaction sequence should be as follows be chosen so that the reaction conditions the groups present in the molecule, which are also in the end product should be present, not affect.

The following examples illustrate the invention. All temperatures are in ⁰ C.

The chromatography is carried out either in a manner known per se using silica gel (Merck, Kiese Igel 60, Art.773 ^ or 774-7) or by flash chromatography (W.C. Still, M. Kahn and A.Mitra, J.Org.Chem. 1973, 43, 293?) On silicon dioxide (Merck 9385), and thin layer chromatography (TLC) is carried out on silicon dioxide (Macherly-Magel, Polygram), unless otherwise

BATH ORIGINAL

ι specified. The following abbreviations define ³ aas for chromatography and TLC eluent used.
A) dichloromethane-ethanol-0.88 ammonia 50: 8: 1

B) dichloromethane-ethanol-0.88 ammonia 35: 8: 1

C) Dichloromethane-Sthano1-0.88 ammonia 25: 8: 1

D) dichloromethane-ethanol-0.88 ammonia 40: 8: 1

E) dichloromethane-ethanol-0.88 ammonia 20: 8: 1

F) dichloromethane-ethanol-0.88 ammonia 100: 8: 1 G) dichloromethane-ethanol-0.88 ammonia 75: 8: 1

H) ethyl acetate-cyclohexane-acetic acid 2: 4: 1

I) Ethyl acetate-ethanol-water-0.88 ammonia 25: 15: 1: 1

J) Ethyl acetate-ethanol-water-0.88 ammonia 25: 15: 8: 2

K) toluene-ethanol-0.88 ammonia 78: 20: 2

L) dichloromethane-ethanol-0.88 ammonia 78: 20: 2

M) dichloromethane-ethanol-0.88 ammonia 200: 8: 1

N) toluene-ethanol-0.88 ammonia 39: 10: 1

The intermediates are routinely checked for purity tested according to TLC, using UV light for the detection and spray reagents such as potassium permanganate (KMnOr). Indolian intermediates are also used detected by spraying with an aqueous cerium (IV) sulfate solution (CeIV). Tryptamines will be proven by spraying with a solution of iodoplatinic acid (JPA) or cerium (IV) sulfate »

Proton (H) nuclear magnetic resonance (NMR) spectra are recorded either at 90 MHz using a Varian EM-390 instrument or at 250 MHz using a Bruker ΛΜ or \ vM-250 instrument; s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet and br = broad «The values are given in Ί .

BATH ORIGINAL

34 - * -

* d e / ο η ο ^

"Reactivials" are 4 ml ampoules with a thick glass wall and a screw cap and Teflon-coated sealing washer manufactured by Pierce and Warriner (UK) Ltd. are available.

The following abbreviations are used in Tables 1 and 2 :.

TEA - triethylamine

PC - pivaloyl chloride 10 EtOH - ethanol

MeOH - methanol

IPA - isopropanol

EtOAc-ethyl acetate

IPAC - isopropyl acetate 15 CH- cyclohexane

BU - butan-2-one

AC - acetone

HH - hydrazine hydrate.

20 intermediate 1

4-hydrazinobenzene propanoic acid hydrochloride To a stirred suspension of 3.30 g of 4-aminobenzene propanoic acid in 25 concentrated hydrochloric acid is added a solution of 1.45 g of sodium nitrite in 10 ml of water at such a rate that the temperature does not exceed + 3 °. After the addition is complete, the solution is stirred at 0 ° for 10 min. The mixture is added to a stirred solution of 22.5 g of tin (II) chloride dihydrate in 15 ml of concentrated hydrochloric acid at -10 ° at such a rate that the temperature does not exceed -5 °. The resulting suspension is allowed to warm to room temperature over 1 hour. The solid is collected by filtration, washed with 50 ml of ethanol and 100 ml of ether and dried in vacuo. 3.9 g of the title compound are obtained as a powder, melting point 205-2O6 ° (decomp.)

Crystallization from 2-propanol gives an analytisc pure sample, m.p. 209 to 210 ° (dec.).

Intermediate 2

3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -ethyl] -1H -indole-5-propanoic acid

A mixture of is heated under reflux for 2 hours 5.8 g of intermediate 1 and 7.79 g of 2- (4,4-diethoxybutyl) -1H-isoindole-1,3 (2H) -dione in 150 ml of water with a content of 50 ml of acetic acid. The cooled suspension is extracted with 2 × 150 ml of ethyl acetate and the combined organic extracts are washed with 100 ml of water and 100 ml of brine. Evaporation of the Solvent gives a gum which is dissolved in ethyl acetate and adsorbed onto 30 g of silica. This is added to a column of silica and eluted (H). The appropriate fractions provide a powder, which crystallizes from 100 ml of ethyl acetate-cyclohexane (1: 1) and gives 5.0 g of the title compound as a powder,

20 mp 171-172 °.

Intermediate 3

4-hydrazinobenzenebutanoic acid hydrochloride

To a stirred suspension of 5.37 g of 4-aminobenzenebutanoic acid in 37.5 ml conc. Hydrochloric acid M- ^ b gives a solution of 2.18 g of sodium nitrite in 15 ml of water at such a rate that the temperature + 2 ° does not exceed. After the addition is complete, the mixture is stirred for 10 min and then at -10 ° to one stirred solution of 33.75 g of tin (II) chloride dihydrate in 25 ml of concentrated hydrochloric acid added at such a rate that the temperature is not -5 ° exceeds. After stirring the resulting suspension for 30 minutes, the solid is collected by filtration, washed with 100 ml of ether and dried. Crime

BATH ORIGINAL

1 installation from 100 ml of ethanol and 100 ml of isop

acetate gives 3.13 g of the title compound as a powder, melting point 199 ° to 201 °.

5 intermediate 4

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

1H-indole-5-butanoic acid

A mixture of 2.305 g of 4-hydrazinobenzenebutanoic acid and 2.91 g of 2- (4,4-diethoxybutyl) -1H-insoindole-1,3 (2H) -dione is in 112.5 ml of water and 37.5 ml of acetic acid for 1 h Heated to reflux. The suspension is poured into 150 ml of ethyl acetate and the phases are separated. The organic Phase is washed with 50 ml of brine, dried over Na ^ SO ^ and under reduced pressure evaporated to form a gum. This is dissolved in 30 ml of tetrahydrofuran and added to 20 g of silicon dioxide adsorbed. The dried material is placed on a silica column and eluted (H). Suitable Eluates are collected and evaporated under reduced pressure. Trituration of the residue with cyclohexane gives 2.35 g of the title compound as a powder, melting point i60 up to 162 °.

Intermediate 5

(E) -Methyl 3- [4- [2- [2- (2-oxo-3-piperidinylidene)] hydrazino j-phenyl] -2-propenoate

To a suspension of 10.68 g of (E) -methyl-3, (4-aminophenyl) -2-propenoate in 150 ml of water and 12.5 ml of conc. Hydrochloric acid is added to a solution at 0 ° to 2 ° from 3.9 g of sodium nitrite in 12.5 ml of water. The mixture is stirred for 0.25 h and a solution of 3-carbethoxy-2-piperidone (prepared from S, 55 g of 3-carbethoxy-2-piperi ~ doη and 3.0g of potassium hydroxide in 100 ml of water, whereby the constituents were left to stand at 5 ° for 72 h) were added. The reaction mixture is made with sodium acetate

SAD ORIGINAL

adjusted to pH 4 to 5, allowed to warm to room temperature and stirred for 18 h. The precipitated Collect solid, wash with ethanol and ether and dried at 60 ° in vacuo. 13.0 g of the title compound are obtained as a solid, melting point 208 ° to 209 °. ■

Intermediate 6 ,

(E) -Methyl-3- (1,2,3,4-tetrahydro-1-oxo-9H-pyrido [3.4-b] -

indol-6-yl) «- 2-pro-penoat ________________

0.5 g of intermediate product 5 is heated under reflux for 2 hours in 85% strength aqueous formic acid and allowed to come to room temperature cooling down. The mixture is filtered and gives 0.22 g of the title compound as a crystalline solid, 258-259 °.

Intermediate 7

(E) -3- (2-aminoethyl) -5- (2-carboxyl-1-etheny 2-carboxylic acid

2.0 g of intermediate 6 in a mixture of 45 ml of 60% ethanol and 7.5 g of potassium hydroxide are added for 4 h Heated to 60 °. The solution is cooled to 0 ° and washed dropwise with 20% hydrochloric acid until Treated reaching pH 5. The precipitate is filtered, washed with water, ethanol and ether and dried. 1.7 g of the title compound are obtained as a solid, melting point 292 ° to 295 ° (decomp.).

Intermediate 8

3- (2-aminoethyl) -5- (2-carboxyethyl) -1H-indole-2-carbon-

acid _ \ .

1.5 g of intermediate 7, 200 mg of 1OS palladium oxide on carbon and 50 ml of acetic acid are hydrogenated for 5.5 h at atmospheric pressure (V / hydrogen uptake = .148 ml). The reaction mixture is filtered, evaporated to dryness and crystallized from methanol / ether. 1.1 g are obtained Title compound as a crystalline solid, melting point 230-232 °.

BATH

¹ Intermediate 9

3- (2-Minoethyl) -1H-indole-5-nropanoic acid 0.9 g of intermediate 8 are heated for 60 hours at 100 ° in a mixture of 27 ml of acetic acid and 20% strength aqueous hydrochloric acid. Evaporation to dryness gives 0.9 g of the title compound as a crystalline solid, which is used in the next step without purification.

Intermediate 10

Ethyl 3- (2-aminoethyl) -1H-indole-5-propanoate hydrochloride 0.85 g of intermediate 9 are added under nitrogen to a mixture of 10 ml of thionyl chloride in 40 ml of ethanol. The reaction mixture is refluxed for 4 h, cooled to 50 ° and treated with 200 ml of ether. Filtration and evaporation of the mother liquors to dryness gives an oil which is chromatographed on silica gel. Elution (i) provides the tryptamine which is converted to the hydrochloride salt in a mixture of ethanol and ether. 0.4 g of the title compound is obtained as a crystalline solid,

20 m.p. 182 to 185 °.

Intermediate 11

(E) - and (Z) -Methyl-3- [3- [2- (dimethylamino) -ethyl] -1H-

indol-5-yl] -2-propenoate

2.14 g of 5-BrOm-N, N-dimethyl-1H-indole-3-ethanamine become 17 h at 100 ° in an autoclave with 0.90 ml methyl acrylate, 18 mg palladium (ll) acetate and 49 mg tri- (οίο IyI) -phosphine heated in 4 ml of dry triethylamine. Another 18 mg of palladium acetate, 100 mg of tri- (otolyl) -phosphine are added, 0.9 ml of methyl acrylate and 1.5 ml of triethylamine are added and the mixture is heated at 100 ° for a further 16 h. The mixture between 20 ml of water and 20 ml of ethyl acetate divided up. The aqueous layer is diluted with 2 × 20 ml Extracted ethyl acetate. The organic layers are washed with 2 κ 15 ml of brine, dried over MgSO ^

BATH ORIGINAL

^ E / <5Q QJ

dries and evaporated. 2.30 g of the title compound are obtained as oil contaminated with raw material. This material can be found in the US without further purification used next level.

Intermediate 12

Methyl 5- [2- (dimethylamine) ethyl] -1H-indole-5-propanoate 2.08 g of intermediate product 11 in 100 ml of ethanol containing 5 ml of 2N hydrochloric acid are dissolved at room temperature and pressure above 10% palladium oxide Activated charcoal (50% paste with water, 0.4 g) is hydrogenated until the hydrogen is absorbed (28 h; further 400 mg portions of catalyst are added after 2 h, 20 min and after 17 h). After filtering the catalyst, the solvent is evaporated, the residue is made basic with 40 ml of 8% aqueous sodium bicarbonate and extracted with 4 × 50 ml of ethyl acetate. The organic layers are washed with brine, dried over MgSO ^ and evaporated. 1.69 g of the title compound is obtained as

20 oil. TLC (SiO ₂ ) K Rf 0.35; UV / JPA.

Intermediate 13

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

TH-indole-5-carboxaldehyde hydrated acid

About 2 g of Raney nickel are added to a stirred solution of 4.98 g of 3- [2- (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) -ethyl] -1H-indole- 5-carbonitrile and 10.06 g of sodium hypophosphite in 100 ml of pyridine, 50 ml of water and 50 ml Acetic acid. The mixture is heated to approx. 50 for 6 h, periodically further Raney nickel (5 x about 2g) is added. After cooling, the mixture is filtered, the Fil-entered with 1250 ml of water and diluted with 3 x 500 ml of ethyl acetate extracted. The combined organic extracts are mixed with 2 × 500 ml of 2N hydrochloric acid washed, dried over magnesium sulfate

BATH ORIGINAL

? r / q Q O 9 Ö1UO1

azeotropically distilled. 4.6 g of title aldehyde are obtained as a solid. A sample (0.53 g) is analyzed by chromatography Purified on a silica column, eluting with ethyl acetate, to give 0.49 g of pure title aldehyde as a solid, mp 202 ° to 203 °.

Intermediate 14

(E) - and (Z) -6- [3- [2- (i, 3-dihydro-1,3-dioxo-2H-isoindol- 2-yl) ethyl] -1H-indol-5-yl] -5-hexenoic acid hydrate (4: 5) A solution of 4.39 g of (4-carboxybutyl) triphenylphosphonium bromide in 40 ml of dry dimethylformamide (DMF) is added dropwise over 3 minutes under nitrogen to a stirred suspension of 2.23 g of potassium -tert-butoxide in 50 ml of DMF. The resulting suspension is stirred for 15 min at room temperature, a solution of 2.36 g of intermediate 13 in 50 ml of DMF is added and the resulting solution is heated at 100 ° for 44 h. After the emulsion has cooled, it is partitioned between 1000 ml of 2N hydrochloric acid saturated with sodium chloride and extracted with 3 × 500 ml of ethyl acetate. The combined organic extract is washed with 4 × 500 ml of water and 500 ml of salt solution, dried over magnesium sulfate and evaporated in vacuo. 5.98 g of a foam are obtained which is purified by flash chromatography on silica, eluting successively with chloroform-methanol 49/1 (9000 ml), 19/1 (1000 ml), 9/1 (1000 ml). The title acids are obtained as a foam which collapses to a gum (0.55 g)

Analysis: for C ₂₄ H ₂₂ N ₂ O ₄ .1.25H ₂ O

Calculated: C 67.8 $ H 5.3% N 6.6? S found: 63.2 5.3 6.1.

Intermediate 15

3- [2- (1,3-Dihydro-i, 3-dioxo-2H-isoindol-2-yl) -ethyl] - 1H-indole-5-hexanoic acid compound: with ethanol (2: 1)

BATH ORIGINAL

A solution of 1.30 g of intermediate 14 in 170 ml Ethanol is poured over prereduced 10So palladium oxide on activated carbon (50% strength) at room temperature and pressure aqueous paste; 0.95 g) 1 h Ms to end the hydrogen uptake (69 ml) hydrogenated. The catalyst is filtered off and the filtrate is evaporated in vacuo. Man receives 1.08 g of the title acid as a solid, melting point 176 bis 178 °.

10 intermediate 16

3- (Cyanomethyl) -N- [4- (methoxyphenyl) -methyl] -1H-indole-

5-propenamide

A mixture of 1.63 g of N - [(4-methoxyphenyl) methyl] acrylamide, 2 g of 5-bromo-3- (cyanomethyl) -1H-indole, 37 mg of palladium acetate, 109 mg of tri- (o-tolyl) -phosphine and 2 ml Triethylamine in 3 ml of acetonitrile is heated in a "Reactivial" at 100 ° for 72 hours. The cooled mixture is distributed between 3 x 25 ml of ethyl acetate and 25 ml of water and the extracts are dried over MgSO ^ and evaporated. The residue is washed with dichloromethane-ethanol-ammonia solution (250: 8: 1) rubbed. 1.4 g of the title compound are obtained as a powder, melting point 108 ° to 110 °.

B e i s ρ i el 1

3- (2-Aminoethyl) -N - [(4-methoxyphenyl) -methyl] -1H-indole- 5-propanamide hemisuccinate (4: 1) -

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

Nf (4-methoxyphenyl ·) -methyl] -1H-indole-5-propanamide A solution of 1.0 g of Zv; ischenproduct 2 in 25 ml of anhydrous THF containing 0.42 ml of triethylamine is mixed with 0.37 ml of pivaloyl chloride treated and stirred at 0 ° for 1 h. A solution of 0.337 g of 4-methoxybenzenemethanamine in 10 ml of anhydrous THF is added and the mixture is stirred at room temperature for 2.5 hours. The suspension is filtered and the filtrate is

Evaporated to dryness ι tem pressure. The residue will Triturated between 30 ml of water and mixed with 2 × 50 ml of ethyl acetate extracted. The combined organic extracts are evaporated under reduced pressure and deliver approx. 2.0 g of solid. Trituration with ether gives 0.8 g of powder which crystallizes from butan-2-one / cyclohexane will. 0.49 g of the title compound is obtained as a powder, melting point 196 ° to 199 °.

(ii) 3- (2-Aminoethyl) -N - [(4-methoxyphenyl) methyl] -1H-

indole-5-propanamide hemisuccinate (4: 1) A stirred suspension of 0.48 g of the product from step (i) in 10 ml of ethanol containing 0.1 ml of hydrazine hydrate is refluxed for 3 hours. 0.05 ml of hydrazine hydrate are added and the solution is refluxed for a further hour. After cooling, the solution is evaporated to dryness under reduced pressure. The residue is mixed with 60 ml of 2N sodium carbonate solution and extracted with 100 ml of methylene chloride. The extract is washed with 2 × 60 ml of 2N sodium carbonate solution, _{dried over MgSO 4} and evaporated to a gum (0.25 g) under reduced pressure. This material is chromatographed on a silica column (eluents A and B). Evaporation of the appropriate fractions gives 0.204 g of the free base as a gum. A solution of this material in 2 ml of hot isopropanol is treated with a hot solution of 0.0343 g of succinic acid in 2 ml of isopropanol. The title compound crystallizes out as a powder on cooling

30 (0.189 g), m.p. 185-187 °.

Analysis: for C ₂₁ H ₂₅ N ₃ O ₂ .0.5C ₄ H ₅ O ₄ .0.25H ₂ O.

calculated: C 6ό.5 Η β.9% II 10.150 found: 66.6 7.0 10.0

NMR (250 MHz: DMSO-dg): 2.86-3.00 (6H, m, CH ₂ CH ₂ CO and CH ₅ CHpNHo), 3.76 (3H, s, OCH,), 4.22 (2H , d,

BATHROOM OBlGINAL

ο π / q ο θ j

₂ 6.96-7.10 (3Η, m, H-6 and aromatic

Groups), 8.30 (1H, brt, NHCO) and 10.84 (1H, brs, indole WH).

The following compounds are made using similar ones Procedures as described in Example 1 were prepared with the appropriate amine starting material. the Reaction conditions in steps (i) and (ii) are in Table 1 and 2 below. 10

Example 2 . (i) 3- [2- (i, 3-Dihydro-i, 3-dioxo-2H-isoindol-2-yl) -ethyl ] -

N- Γ4- (1-pyrrolidinyl) -phenyl] -1H-indole-5-propanamide m.p. 197-199 °.

(ii) 3- (2-Aminoethyl) -N- [4- (1-pyrrolidinyl) -phenyl] -1H-

indole-5-propanamide theaisuccinate m.p. 222-223 °.

Analysis: _{Calculated for C 23} H ₂₈ N 1 O * 0.5 C 1 HgO ₄ 20: C 68.9% H 7.2% N 12.9% found: 68.8 7.1 12.6

NMR (90 MHz; DMSO-dg): 1.90 (4H _{, m, pyrrolidine-CH 2} CH ₂ N), 2.50-2.75 (2H, m, CH ₂ CH ₂ CO), 2.78- 3.05 (6H, m, CH ₂ CH ₂ CO and CH ₂ CH ₂ IiH ₂ ), 5.80 (2H, br, NH ₂ ), 7.10-7.50 (5H, m, arom gr. ), 9.65 (1H, brs, NHCO) and 10.70 (1H, brs, indole NH).

Example 3

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-.isoindol-2-yl) -ethyl] - N- (phenylmethyl) -1H-indole-5-propanamide, m.p. 142 up to 143 °.

(ii) 3- (2-Aminoethyl) -N- (phenylinethyl) -IH-indole-5-propane

amide hydrochloride
35 m.p. 205 Ms 206 °.

BAD ORiGINAL

NMR (90 MHz; DMSO-dg): 2.80-3.10 (6H, m, CH ₂ CH ₂ CO and CH ₂ CH ₂ NH ₂ ), 4.27 (2H, d, CH ₂ Ph), 8 , 45 (1H, brt, NHCO) and 10.90 (1H, brs, indole NH).

5 Example 4

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

N- (pheny! Methyl) -IH-indole-5-butanamide, mp 166-167 °.

(ii) 3- (2-Aminoethyl) -N- (phenylmethyl) -1H-indole-5-butane

amide hydrochloride mp 195 Ms 198 °.

NMR (90 MHz; DMSO-dg): 1.80 (2H, m, CH ₂ CH ₂ CH ₂ ), 3.00 (4H, s, CH ₂ CH ₂ NH ₂ ), 4.30 (2H, d, Cg ₂ Ph) ", 7.1-7.40 (8H, m, arom.Gr.), 8.40 (1H, t, NHCO) and 10.90 (1H, brd, indole NH).

Example 5

(i) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) -ethyl ] -N- (4-methoxyphenyl) -IH -indole-5-propanainide

Mp 184-186 °.

(ii) 3- (2-Aminoethyl) -N- (4-methoxyphenyl) -1H-indole

propanamide hydrochloride 25 m.p. 264-266 °.

NMR (90 MHz; DMSO-dg): 2.80-3.10 (6H, m, CH ₂ CH ₂ CO and CH ₂ CH ₂ NH ₂ ), 3.70 (3H, s, OCH ₃ ), 7, 2-7.70 (5H, m, CONH and arom. Group) »8.20 (2H, br, NH ₂ ) and 10.90 (1H, d, indole IiH).

Example 6

(i) N - [(4-chlorophenyl) methyl] -3- [2- (1,3-dihydro-1,3- dioxo-2H-i5.oindol-2-yl) -ef.hyl j-1H -indo 1 - S-

Mp 199.5 to 202 °.

BATH ORIGINAL

(ii) 3- (2-Aminoethyl) -N - [(4 ~ chlorophenyl) -methyl] -1H-

indole-5-propanamide hemisuccinate hydrate (4: 1) mp 188-192 °.

Analysis: for C ₂₀ H ₂₂ ClN ₃ O'0.5C ₄ H ₅ O ₄ .O, 25H ₂ O Calculated: C 63.0% H 6.1% N 10.2% found: 63.1 6.05 9.8 NMR (250 MHz; DMSO-dg): 2.90 (6H, m, CH ₂ CH ₂ CO and CH ₂ CH ₂ NH ₂ ), 4.25 (2H, d, CH ₂ Ph), 7, 0-7.40 (7H, m, arom. Group), 8.40 (1H, t, NHCO) and 10.80 (1H, brs, indole NH).

Example 7

(i) 3- [2- (1,3-Qihydro-1,3-dioxo-2H-isoindol-2-yl) ethyl] -

N-Ohenyl-IH-indole-S-butanamide 15 m.p. 152-153 °.

(ii) 3 ~ (2-Aminoethyl) -N-phenyl-1H-indole-5-butanamide-

hydro chloride _; ; -

Mp 222-224 °.

NMR (90 MHz; DMSO-dg): 2.0 (2H, m, CH ₂ CH ₂ CH ₂ ), 3.00 (4H, s, CH ₂ CH ₂ rra ₂ ), 6.90-7.70 ( 9H, m, arom. Group), 10.10 (IH, brs, NHCO) and 10.90 (1H, brs, indole NH).

For hall 8
(i) N- (4-chlorophenyl) -3- [2- (1,3-dihydro-i, 3-dioxo-2H-

isoindol-2-yl) -ethyl 1-1H-indol-5-propanamide m.p. 200-203 °.

(ii) 3- (2-Aminoethyl) -N- (4-chlorophenyl) -1H-indole-5- propanamide hemisuccinate

Mp.2i6 to 218 °
Änsilvcii = * · "Tut * f * H Cl ^ TO» O ^ r ₁ K-Or calculated: C 62 ^ 9% ^ H 5.3% N 1Ο, 5? 0 found: 62.6 5.8 10, 2

BAD OHiGiNAL

NMR (250 MHz; DMSO-dg): 2.80-3.10 (βΗ, m, COCH ₂ CH ₂ and CH ₂ CH ₂ NH ₂ ), 7.35-7.50 (3H, m, arom. Gr .), 10.20 (1H, brs, NHCO) and 10.80 (1H, brs, indole NH).

Example 9

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

N- r ^ -Caminocarbonyl) -phenyl 1-1H-indole-5-propanamide m.p. 238-240 °.

(ii) N- [4- (aminocarbonyl) phenyl] -3- [2- (aminoethyl)] - 1H-indole-5-propanamide compound with creatinine, sulfuric acid and water (1: 1: 1: 1, 5) Mp. 205-208 °

Analysis: for C ₂₁ H ₂₄ N ₄ O ₂ .C ₄ H ₇ N ₃ OH ₂ SO ₄ .1.5H ₂ O 15 calculated: C 49.8% H 6.0% N 16.3% found: 49, 8 6.0 16.3 NMR (250 MHz; DMSO-dg): 2.90-3.20 (9H, m and s,

CH ₂ CH ₂ CO and CH ₂ CH ₂ NH ₂ ), 4.30 (2H, d, CH ₂ NHCO), 7.20-8.00 (9H, m, arom.gr. and CONH ₂ ), 8, 40 (1H, t, NHCO) and 10.90 (1H, brs, indole NH).

Example 10

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

N- [[4- (1-pyrrolidinyl) -phenylj-methyl] -1H-indole-5- propanamide
M.p. 121 to 123 °.

(ii) 3- (2-Aminoethyl) -N - [[4- (1-pyrrolidinyl) -phenyl] -me-

ethyl] -1H-indole-5-propanamide hemi succinate 30 m.p. 206-208 °

Analysis: for C ₂₄ H ₃₀ N ₄ OO ^ C ₄ H ₅ O ₄

calculated: C 69.5? S H 7.45 ^ N 12.55-ά found: 69.3 7.4 12.3

NMR (250 MHz; DMSO-dg): 2.00 (4H, m, pyrrolidine-CH ₂ CH ₂ N), 2.80-3.00 (6H, m, CHpCH ₂ CO and CH ₂ CH ₂ ITO ₂ ) , 3.20

BATH ORIGINAL

OE / OQ Θ J.

(4H, m, pyrrolidine -CH ₂ CH ₂ N), 4.15 (2H, d, CH ₂ NH-CO), 6.40-7.00 (5H, m, arom.gr. and H-6) , 8.20 (1H ₁ t, NHCO) and 10.90 (1H, brs, Inddl NH).

5 Example 11

(i) 3-C2- (i _f 3-dihydro-1,3-dioxo-2H-isoindal-2-yl) -ethyl.] r

(2-propenvl) -1H-indole ~ 5-T> ropanamide m.p. 268 to 269 °.

(ii) 3- (2-Aminoethyl) -N- (2-propenyl) * 1H-indole-5-propane.

amide hydrochloride pp. 230 to 231 °. Analysis: _{Calculated for C 16} H ₂₁ N ₃ O ₄ HCl: C 62.4% H 7.2% N 13.7% 15 found: 62.3 7.3 13.5

NMR (250 MHz; D ₂ O): 3.10 (2H, t, CH ₂ CH ₂ CO), 3.35 (2H, t, CH ₂ CH ₂ NH ₂ ), 3.70 (2H, m, NHCH ₂ CH =), 4.90 (-, m, CH = CH ₂ ) and 5.70 (1H, m, CH ₂ CH = CH ₂ ). v.

ω
cn Example
Mr. ω
ο TEA
(ml) to
cn Time to
O Tabel ι— ·
cn
1 Time Temp.
⁰ C - RT O Cn Stress
te
(G) CO 1 ■ ι ^; 0.42 10 min Acylation 2h - - Kristallisa
solution solution
middle 0.98 543982 3 i i Ί activation 0.42 Pc
(ml) 10 in i η Arain
(G) 15 minutes RT EtOH 1.0 4ί ι i Indole
(G) 0.42 0.37 20 min 0.45 20 min - IPAC / CH 0.84 5 (1 i 1.0 0.63 0.37 10 min 0.29 1.5h RT MeOH / IPAC l.l 6 (i) in 0.42 0.57 lh
+ 0.5h 0.29 20h RT IPAC / MeOH 0.47 7ί ι < 1 .04 0.42 0.56 20 min 0.51 10h RT BU / CH (x2) 0.7B ΗΊ) 1.5 0.63 0.37
+0.0 57 lh 0.39 20h (2h RT
(2h (reflux) IPAC 0.81 9 ·., Ι '} 1.0 0.63 0.37 10 min 0.25ml 1Bh A BOOK 0.49 10 (i) 1 .04 0.63 0.55 2 h 0.52 2 h AC / IPA 0.6 1 1 ί ι ') 1 .5 0.42 η. 56 10 min 0.54 rtOAC 0.R9 1.5 0.55 0.72 IPA / 1PAC 1.5 0.37 0.16 1.0

to σι

to

ο table 2

σι

σι

Ex.
No. Indole
(G) HH
(ml) Time
(H) onsrait
tel Salt formation base
'(g) Acid solvent
(g) tel Crystalline
sation solution
solvent - Stress 2Ui) 0.75 0.8. H C. - Succinic acid,
MeOH
(0.176) IPA / IPAC
(1: 1) te
Cg) } (ii) 0.9 0.2 2 - - HCl / MeOH (2N, 2ml) IPA / IPAC
(1: 1) 0.49 4 (i i) o.n. 0.2
+0.2 1 .5
+2 D. - HCl / F.tOH (3.1N, 0.6ml) IPA / IPAC
(1: 1) 0.48 5 (ii) 1.0 0.43 3 C. 0.25 HCl / EtOH (T.IN, 0.3ml) MeOH / IPAC
(1: 2) 0.53 6 C ii)
7 (ii)
8 (ii) 0.59
0.75
0.79 0.12
0.25
0.16
+0.08 2.5
2
2
+2 A + R
E.
F, G + C 0.152
0.49 Bernsteins., IPA
(0.025)
ItC I / Et OH - (3.1N, 0.6ml)
Amber
acid, IPA
(0.085) MeOH
IPAC - 0.205 9 (ii) 0.22 0.07 3 C. 0.115 Creatinine + H ₂ SO ₁₁
aq. OH 0.125
0.48
0.345 10 (i i) 0.4 0.12 3 C. 0.3 Bernsteins., IPA
(0.09) EtOH / IPAC
(1: 1) 0.119 ll (ii) 0.85 0.20 1 - - HCl / MeOH (2N, 2ml)
EtOH 0.25 0.57

1 example 12

3- (2 ~ Aminoethyl) ~ 1H-indole-5-propanamide, compound with creatinine sulfate, sulfuric acid and water (1: 1: 1: 1 «25) 0.3 g of ethyl 3- (2-aminoethyl) -1H- indol-5-propanoate are heated 24 h in 20 ml of 0.880 ammonia at 38 ⁰ C d.

Evaporation to dryness gives the crude amide which is purified by chromatography (eluent J) to give 130 mg of oil. This is dissolved in ethanol and a 1 molar aqueous solution in sulfuric acid, and 0.28 ml of creatinine is added. Addition of acetone to the hot (80 °) creatinine sulfate solution until it becomes cloudy gives 120 mg of the title compound as a solid, mp 218 ° to 220 ° (decomp.).
Analysis: for C ₁₃ H ₁₇ N ₃ O.04H ₇ N ₃ OH ₂ SO ₄ .1.25H ₂ O

15 calculated: C 44.1% H 6.2% N 18.1% found: 44.4 6.05 17.7.

Example 13
3 ~ (2-Aminoethyl) -N-methyl-1H-indole-5-propanaraidhydro-

20 chloride

0.37 ml of pivaloyl chloride are added at 0 ° to a solution of 1.0 g of intermediate 2 in 25 ml of dry tetrahydrofuran containing 0.42 ml of triethylamine. After stirring for 10 minutes, the suspension is filtered and the filtrate is evaporated under reduced pressure. 20 ml of 33% ethanolic methylamine are added to the oily residue. The resulting solution is stirred for 18 hours. Evaporation of the solvent gives a solid which is partitioned between 10 ml of 2N hydrochloric acid and 25 ml of ethyl acetate. The organic phase is separated off and extracted again with 10 ml of 2N hydrochloric acid. The combined aqueous extracts ^i, \ rerden saturated with laliumcartonat and extracted with 4 χ 50 ml ethyl acetate. Evaporation of the dried (Na ₂ SO ₄ ), combined extracts gives a solid,

BATH ORIGINAL

that in 10 ml of 2N methanolic hydrochloric acid is dissolved and evaporated again to dryness. Crystallization of the residue from propan-2-ol and isopropyl acetate (2/1). (10 ml) gives 0.27 g of the title compound, m.p. 224-226 °.

Analysis: _{Calculated for C 14} H ₁₉ N ₃ O ^ Cl: C 59.7% H 7.2% N 14.9% found: 59.3 7.2 14.6

NMR (90 MHz, DMSO-dg): 2.90 (2H, m, CH ₂ CH ₂ CO), 3.10 (4H, brs, CH ₂ CH ₂ NH ₂ ), 7.10-7.50 (3H , m, arom.Gr.), 7.80 (1H, q, NHCH ₃ ), 8.20 (2H, br, NH ₂ ) and 11.00 (1Ή, brs, indole NH).

EXAMPLE 14

3- [2- (Dimethylamino) -ethyl] -N - [(4-methoxyphenyl) -methyl] -I -indole-5-propanaaidhrochloride To a stirred solution of 0.2 g of the product from Example 1 (ii) in 5 ml 0.26 ml of 37-40% strength formaldehyde solution (aqueous) is added to n-propanol at 0 ° and the mixture is stirred for 15 minutes. 0.11 g of sodium borohydride is added in portions over the course of 5 minutes and the temperature is maintained at 0 ° . After 30 minutes the mixture is acidified with 5 ml of 2N hydrochloric acid and diluted with 25 ml of water. The solution is washed with 2 × 10 ml of ethyl acetate and then made basic with 8 ml of 2N sodium carbonate. The cloudy solution is extracted with 3 × 25 ml of ethyl acetate and the extracts are evaporated under reduced pressure. The residue (0.2 g) is chromatographed on silica (G) and gives 45 mg of an oil. This oil is dissolved in 2 ml of absolute ethanol and mixed with 5 ml of ethereal hydrogen chloride solution. Then 15 ml of ethyl acetate are added. The solid obtained is collected and dried, giving 37 mg of the title compound as a powder, mp 94 ° to 96 °.

BATH ORIGINAL

Analysis: for C ₂₃ H ₂₉ N ₃ O ₂ .HCl.O.6CH ₃ CH ₂ O ₂ CH ₃ calcd: C 64.5% H 7.6% N 9.1% found: 64.2 7.3 9.1

NMR (250 MHz; DMSO-dg): 2.80 (6H, s, NMe ₂ ), 2.95 (2H, t, CH ₂ CH ₂ CO), 3.00-3.30 (4H, m, CH ₂ CH ₂ NMe ₂ ), 3.70 (3H, s, OCH ₃ ), 4.20 (2H, d, CH ₂ NHCO), 7.0-7.50 (6H, m, arom. Gr.), 8.30 (1H, t, NHCO) and 10.90 (1H, brs, indole NH).

¹⁰ Example 15

3- [2- (Dimethylamine ») -ethyl] -1 H-indole-5-propanamidoxalate 1.54 g of intermediate 12 are heated in a screwed glass bottle with 1 ml of 880 ammonia and 1.2 ml of methanol at 75 ° for 26 h. Some of the methanol is evaporated, a further 880 ammonia (1 ml) are added and the mixture is heated at 75 ° for a further 24 h. Evaporation of the solvent gives 1.32 g of a foam which is purified by flash chromatography (eluent L). 0.507 g of an oil is obtained. A portion (481 mg) of this oil is dissolved in 2 ml of methanol, and 175 mg of oxalic acid in methanol are added. Addition of dry ether gives a gummy precipitate which is triturated with dry ether. 0.401 g of the title compound is obtained as a solid, melting point 139 ° to 142 °.

25 Analysis: for C ₁₅ H ₂₁ N ₃ CC ₂ H ₂ O ₄

Calculated: C, 58.4%, H, 6.6%, N, 12.0% found: 58.1, 6.8, 11.7 NMR (90 MHz; DMSO-dg); 2.7-3.40 (12H, m, CH ₂ CH ₂ CO, CHoCH ^ NHo and NMe ₀ ), 6.70 (1H, brs, CONHH), 7.10-7.50 (4H, m, arom .Gr. and CONHH) and 10.90 (1H, brs, indole NH).

Example 16

3- [2- (Dimethylamino) ethyl] -M, N-dimethyl-1H-indole-5- propanamide succinate

BATH ORIGINAL

A mixture of 4 ml of dimethylamine in ethanol (33% w / v) and 0.75 g of intermediate 12 is heated in a "Reactavial" at 100 ° for 24 hours. The solution is then evaporated under reduced pressure and the residue is chromatographed on silica (F and G). 0.112 g of an oil is obtained which, dissolved in hot isopropanol (2 ml), is treated with a solution of succinic acid (46 mg) in hot isopropanol. Isopropyl acetate is added dropwise to the hot mixture until a cloudy solution is obtained. After cooling, the solid obtained is recrystallized from isopropanol and yields 75 mg of the title compound as a powder, melting point 131 ° to 133 °. NMR (90 MHz; DMSO-dg): 2.40, 2.7-3.40 (12H, m, CH ₂ CH ₂ CO, CH ₂ CH ₂ IiH ₂ and NMe ₂ ), 6.70 (1H, brs , CONHH), 7.10-7.50 (4H, m, arom.Gr. and CONHH), and 10.90

(1H, brs, indole NH).

Analysis: _{Calculated for C 1} ^ ₂₅ N ₃ OC ^ HgO ^ .O, 25H ₂ O: C 61.5% H 7.7% N 10.2% found: 61.4 8.0 9.8

NMR (250 MHz; DMSO-dg): 2.80-3.00 (14H, m, NMe ₂ , CONMe ₂ and CH ₂ CH ₂ CO), 3.00-3.40 (4H, m, CH ₂ CH ₂ NMe ₂ ) and 10.90 (1H, brs, indole NH).

Example 17

3- [2- (Dimethylamino) -ethyl} -N-methyl-1H-indole-5-propane amide hydrochloride

A mixture of methylamine in ethanol (33% w / v,

4 ml) and 0.56 g of intermediate 12 is 24 h at 75 ° heated in a "Reactavial". The cooled solution is evaporated under reduced pressure and the residue chromatographed on silica (M and F) to give 220 mg of an oil. This oil is in

Dissolved 5 ml of ethanolic hydrogen chloride and the solution evaporated under reduced pressure to a gum.

Trituration of the gum with approx. 15 ml of ethyl acetate results

a solid which is collected and dried (0.18 g), m.p. 73-75 °.
Analysis: for C ₁ ^ H ₂₃ N ₃ O.HCl.H ₂ O
Calculated: C 58.6%, H 7.9%, N 12.8% found: 58.4 7.9 12.4

MR (250 MHz; DMSO-dg): 2.60 (3H, d, NHCH ₃ ), 2.85 (6H, s, NMe ₂ ), 2.90 (2H, t, CH ₂ CH ₂ CO), 3 , 10-3.40 (4H, m, CH ₂ CH ₂ Me ₂ ), 7.90 (1H, brq, NHCH ₃ ) and 10.90 (1H, brs, indole NH).

Example 18

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

1H-indole-5-hexanamide
0.38 ml of pivaloyl chloride are added to a solution of 1.31 g of intermediate 15 and 0.43 ml of triethylamine in 100 ml of dry tetrahydrofuran, the mixture is stirred for 1 hour at room temperature and, after 40 minutes, a further 0.10 ml of triethylamine and 0.05 are added ml of pivaloyl chloride. A saturated solution of ammonia in tetrahydrofuran (60 ml) is added and the mixture is stirred in a sealed flask at room temperature for 3.5 hours. The mixture is filtered and evaporated in vacuo. An oil is obtained which is partitioned between 150 ml of 2N sodium carbonate solution and 3 × 100 ml of ethyl acetate. The combined organic extract is dried over magnesium sulfate and evaporated in vacuo. 0.99 g of a solid is obtained which is partially purified by flash chromatography, eluting with ethyl acetate-methanol (19: 1), to give 0.84 g of a solid. A sample of this material (0.117 g) is suspended in 10 ml v / water at 90 ° for 1 hour. The precipitate is filtered off, washed with 5 ml of boiling water and dried at 50 in vacuo. 0.075 g of the title compound is obtained as a solid, melting point 177 bis

BATH ORIGINAL

(ii) 3- (2-Aminoethyl) -1H-indole-5-hexanamide, compound with creatinine, sulfuric acid, water and ethanol

(10: 10: 10: 5: 2)

A mixture of 0.59 g of the product from step (i), 1.5 ml of hydrazine hydrate and 50 ml of ethanol is refluxed for 1.75 hours, then cooled and evaporated to dryness. The solid obtained is azeotropically distilled with 2 × 50 ml of absolute ethanol and then partitioned between 50 ml of 2N sodium carbonate and 3 × 50 ml of ethyl acetate. The combined organic extract is dried over magnesium sulfate and evaporated in vacuo, 0.43 g of the title base being obtained as an oil. This oil is dissolved in a hot mixture of 48 ml of ethanol and 6 ml of water and treated with an aqueous solution of creatinine and sulfuric acid (1: 1; 2M; 0.75 ml). On cooling, the title compound (0.49 g) crystallizes out as a solid. M.p. 188 to 193 ° (dec.). Analysis: Calculated _{for C 16} H ₉₃ N ₃ OC ₄ H ₇ N ₃ OH ₂ SO _{4 .0.5H 2} O.0.2C ₂ HgO: C 48.7%, H 6.9%, N 16.7% found : 49.0 7.1 16.8 NMR (90 MHz; DMSO-dg): 1.20-1.80 (6H, m, -CH ₂ (CHg) ₃ -

CH ₂ -), 2.10 (2H, t, CH ₂ CH ₂ CO), 2.90 (3H, 3, NCH ₃ ), 3.00 (4H, brs, CH ₂ CH ₂ NH ₂ I and 10, 90 (1H, brs, indole NH).
25th

B e i s ρ i el 19

3- [2- (Dimethylamine) -ethyl] -N- (2-propenyl) -1H-indole-5-

propane amide oxalate

A mixture of 0.75 g of intermediate 12 and 3.5 ml Allylamine in 1.5 ml of methanol is stirred in a "Reactivial" at room temperature for 96 hours. The solvent is evaporated under reduced pressure and: the residue is chromatographed on silicon dioxide (eluent M). Appropriate fractions are collected and evaporated under reduced pressure. 0.142 g is obtained

BATH ORIGINAL

56 - - ■

of an oil which is dissolved in 2 ml of methanol and treated with a solution of 44 mg of oxalic acid in 1 ml of methanol will. About 20 ml of ethyl acetate are added and the resulting solid is collected and dried. Man

5 receives 0.13 g of a powder, melting point 68 to 70 °. Analysis: for C ₁₈ H ₂₅ N ₃ O. (CO ₂ H) ₂ O.33EtOAc calcd: C 61.2 % H 7.1 % N 10.0% found: 60.8 7.5 10.2.

10 Example 20

(i) 3- (Cyanomethyl) -N- [4- (methoxyphenyl) -methyl] -1H-

indole-5-propanamide

A solution of 1.4 g of intermediate 16 in 50 ml of methanol becomes a pre-reduced suspension of 10% Palladium oxide on activated carbon (50% paste with water, 300 mg) in 20 ml of methanol and the mixture until the hydrogen uptake ceases (approx. 95 ml) hydrogenated. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. You get

20 1.2 g of an oil.

TLC (M) Rf 0.40, detection

(ii) 3- [2- (Ethylamino) ethyl] -N- [4- (methoxyphenyl) methyl] -iH-indole-5-propanamidoxalate salt A mixture of 0.6 g of product from step (i) and ethanolic Ethylamine solution (30 ml, 30% w / v) in 100 ml of ethanol is added to a prereduced suspension of 10% palladium oxide on activated carbon (50> oige paste with water, 0.6 g) and the mixture is added until completion the intake is hydrated. Another 0.6 g of catalyst is added and the mixture is again hydrogenated until uptake is complete. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. 0.59 g of an oil is obtained, which is dissolved in 2 ml of methanol and treated with a solution of 140 mg of oxaline

BATH ORIGINAL

acid in f? al ethyl acetate added. The solution is with diluted approx. 50 ml of ethyl acetate, the resulting solid collected, washed well with approx. 25 ml of diethyl ether and dried. 0.47 g of the title compound is obtained as a powder, melting point 104 ° to 106 °.

Analysis: for C ₂₃ H ₂₉ N ₃ O _2. (CO ₂ H) ₂ .0.5H ₂ O Calculated: C 62.8% K 6.7% N 8.8% found: 62.6 6.8 8 , 8 The water assay shows 0.4 moles of water.

The following examples illustrate pharmaceuticals according to the invention Preparations containing 3- (2-aminoethyl) -N - [(4-methoxypheny 1) -methyl] -1H-indole-5-propanamide hemisuccinate hydrate (4: 1) included as an active ingredient. Other compounds of the invention can be based on similar Way to be phrased.

Tablets for oral administration Direct compression mg / tablet

active ingredient 8.4

Calcium hydrogen phosphate B.P. 89.1

Sodium Carboxymethyl Cellulose USP 2.00

Magnesium stearate BP 0.50

Compression weight 100.00 mg

quality suitable for direct pressing

The active ingredient is sieved before use. Calcium hydrogen phosphate, sodium carboxymethyl cellulose and the active ingredient are weighed into clean polyethylene bags. The powders are under vigorous shaking. Magnesium stearate is then weighed and added to the mixture, which continues to mix will. The mixture is then made using a Manesty F3 tablet machine with 5.5 mm punch holes is provided with flattened edges, into tablets with an intake compression weight of 100 mg priced.

Tablets can also be produced by other processes known per se, such as wet granulation.

Tablets of other strengths can be made by changing the ratio of active ingredient to Lactose or the compression weight changes and appropriate punch holes are used.

The tablets can be coated with suitable film-forming materials, such as hydroxypropylmethyl cellulose, under Standard conditions are coated with a film. Alternatively, the tablets can be coated with sugar will.

Capsules mg / capsule

active ingredient 8.4

Strength 1500 (a form of a direct

compressible strength) 190.6

Magnesium stearate BP 1.00

Fill weight 200.00

The active ingredient is sifted and mixed with the diluents mixed. The mixture is packed in No. 2 hard gelatin capsules using a suitable device bottled. Other dosage levels can be made by changing the bulk weight and optionally changes the capsule size as needed.

Syrup mg; / 5nil ibsis

active ingredient 8.4

30 buffers)

Flavoring) coloring)

Preservatives) as required

Thickener) 35 sweetener)

purified water to 5.00 ml

BATH ORIGINAL

The active ingredient, the buffer, flavor, The color, preservative, thickener and sweetener are dissolved in some water, the solution becomes adjusted to volume and mixed. The hereditary

5 put syrup is clarified by filtration.

SupTDQsitorien for rectal administration

active component . 8.4 mg

Witepsol H15 ⁺ to 1.0 g

suitable quality from Adeps solidus Ph.Eur.

A suspension of the active ingredient in molten Witepsol is prepared and made using a suitable device in 1 g suppository forms filled.

Injection for intravenous administration

mg / ml

active ingredient 2.1

Sodium Chloride BP as needed

Water for Injections BP to 1.0 ml

Sodium chloride can be used to adjust the tonicity of the Solution can be added and the pH can be adjusted using be adjusted by acid or alkali so that the solution has optimal stability and / or for ease the dissolution of the active ingredient. Alternatively, suitable buffer salts can be used. The solution is made, clarified and in ampoules of appropriate size bottled, which are sealed by melting the glass »The injection is made by heating in an autoclave Sterilized using acceptable cycles. Alternatively the solution can be sterilized by filtration and filled into sterile ampoules under aseptic conditions will. The solution can be under an inert nitrogen atmosphere or other suitable gas be packed.

Claims (1)

KRAUS ■ WEISERT & PARTRER - "- ^: PAT E N TA N WA LTE AND APPROVED REPRESENTATIVES BEFORE THE EUROPEAN PATENT OFFICE DR. WALTER KRAUS DIPLOMA CHEMIST DR.-ING. DIPL.-ING. ANNEKÄTH WEISERT · DIPL.-PHYS. JOHN SPIES THOMAS-WIVMER-RING 15 D - SOOO MUNICH 22 TE LEFO N O8 9/22 73 77 TELEGRAM KRAUS PATENT · TELEX 5-212156 kpat d. FAX (089) 22 79 94 5315 AW / My GLAXO GROUP LIMITED London W1Y 8 DH, England Indole derivatives, process for their preparation and them containing pharmaceutical preparations Claims 1. Indoles of the general formula (I) ^ CO (CIL,) _r (D wherein R _{1 is} a hydrogen atom, a C ^^ - alkyl, C, ~ - cycloalkyl or C- * ^ -alkenyl group or a phenyl or phenyl- (C _Λ _ ^) -alkyl group, in which the phenyl ring is unsubstituted or can be substituted by one or two substituents selected from C-, alkoxy, hydroxy, halogen, a group R ₁ -RgNCO-, where Rj- BATH ORIGINAL and Rg (which can be the same or different) each represent a hydrogen atom or a C ^, -alkyl group, or a group RyRgN-, where Ry and Rg (which can be the same or different) each represent a hydrogen atom 5 or a C ^^ - Denote an alkyl group or where R ₇ R ₃ N- denotes a saturated, monocyclic, 5- to 7-membered ring; R2 is a hydrogen atom or a C, g-alkyl group means; or R ^ and R2 together with the nitrogen atom to which they are bound to form a saturated, monocyclic, 5- to 7-membered ring; R, and R ^, which can be the same or different, each represents a hydrogen atom, a C 1, C, alkyl group or represent a 2-propenyl group; and η is an integer from 2 to 5; as well as their physiologically acceptable salts and solvates. 2. indoles according to claim 1, characterized in that R _{1 is} a hydrogen atom, a C ^ g-alkyl or C- * £ - Alkenyl group or a phenyl or phenyl (Cj _ ^) - alkyl group, in which the phenyl ring is unsubstituted or by one or two substituents as defined in claim 1, may be substituted, means. 25th 3. indoles according to claim 1 or 2, characterized in that one of the substituents R ₁ and R £ is a hydrogen atom. 4. indoles according to any one of claims 1 to 3 »thereby characterized in that R, and R ^, which are the same or different can be, each represent a hydrogen atom or a Cji-alkyl group. 35 BATH 15-indoles according to any one of claims 1 to 4, characterized characterized in that η stands for 2 or 3. 6. indoles according to claim 1, characterized in that R _{1 is} a C ₁ , -alkyl group, a C, g-alkenyl group or a phenyl (C ₁ ^) - alkyl group in which the phenyl ring can be unsubstituted or substituted by one or two substituents as defined in claim 1; FL, represents a hydrogen atom; FU and R ^, which can be the same or different, each represent a hydrogen atom or a methyl or ethyl group; and η is 2 or 3. 7. indoles according to claim 1, selected from 3- (2-aminoethyl) -N- (pheny! Methyl) -IH-indole-5-propanamide; 3- (2-Aminoethyl) -N - [[4- (1-pyrrolidinyl) -phenyl] -methyl] -1H-indole-5-propanamide; 3- [2- (Dimethylamine) ethyl] - N - [(4-methoxyphenyl) methyl] -1H-indole-5-propanamide; 3- (2-aminoethyl) -N- (2-propenyl) -IH-indole-5-propanamide; and 3- (2-Aminoethyl) -N - [(4-methoxyphenyl) -methyl] -1H-indole-5-propanamide;
as well as their physiologically acceptable salts and solvates. 8. Pharmaceutical preparation, characterized in that it is an effective amount as the active ingredient of at least one indole of the general formula (I) according to Claim 1 or one of its physiologically acceptable salts or solvates together with one or more pharmaceutically contains acceptable carriers or diluents - Often 9. Process for the preparation of an indole of the general Formula (I) according to Claim 1 or a salt or solvate thereof, characterized in that (A) an amine of the formula R ₁ R ₂ NH (in which R ^ and R _{2 have} the meaning given in claim 1) with an acid of the general formula (II) HO ₀ C (CH _n ) ^{2 2 n} - (CH-J ₀ NR-R. ίο ¹ ^ A .. ¹ J (H) (where R ,, R ^ and η are as defined in claim 1) or a corresponding acylating agent or a Condensed salt or protected derivative thereof; or (B) a compound of the general formula (III) R ₁ R ₀ NCO (CH ₀ ) _n α (III) NKN = CH (CH ₂ ) ₃ Q (wherein R «., R ₂ and η are as defined in claim 1 and Q stands for the group MFURa, where R- * and R ^ are as defined in claim 1) or a protected derivative thereof or a leaving group cyclizes; or (C) a compound of the general formula (VI) . ^ K .LU (L ..) (CIO ₀ Y H 35 8AD ORIGINAL (wherein R ^, R ₂ and η are as defined in claim 1 and Y is an easily exchangeable group) or a protected derivative thereof with an amine of the formula R, R ^ NH, where R, and R ^ are those in claim 1 given significance 5 owning) implements; or (D) a compound of the general formula (VII) ίο ^ I (VII) [wherein R ^ and R _{2 are} as defined in claim 1 and W is a group reducible to the desired - (CHg) ₂ NRJi ^ - group or a protected derivative thereof, wherein R, and R ^ are those in claim 1 have given meaning, and A represents the group - (CH ₂ ) - or ^{group reducible to ~ (CH} ₂ ) _n , in which η has the meaning given in claim 1] or a salt or a protected derivative thereof; or (E) a nitrile of the general formula (IX) NC (CH ^) _n
- ^ V ^> rf (IX) (where R ,, R ^ and η are as defined in claim 1) or reacting a salt or protected derivative thereof with a suitable oxygen-containing compound; or (F) a compound of the general formula (I) according to claim 1 or a salt or protected derivative thereof converted into another compound of the general formula (I); or (G) a protected derivative of the general formula (I) as defined in claim 1, or a salt thereof Subjecting implementation to removal of the protecting group or groups; and optionally and / or if desired one or more additional reactions following one of processes A to F, such as (i) removal of any protecting group or groups; and (ii) Conversion of a compound of the general formula (I) or a salt thereof into one of its physiological acceptable salts or solvates. 20 25 30