DK165976B - 3-Aminoalkyl-5-sulphamoyl:alkyl-indole derivs. - useful for treating migraine (BE 7.12.83) - Google Patents

Abstract

Indole derivs. of formula (I) and their salts and solvates are new (where R1 is H, 1-6C alkyl or 3-6C alkenyl; R2 is H, 1-3C alkyl, 3-6C alkenyl, aryl, aralkyl or 5-7C cycloalkyl; R3 is H or 1-3C alkyl; R4 and R5 are H, 1-3C alkyl or propenyl, or R4+R5 is aralkylidene; A is 2-3C alkylene opt. mono- or disubstd. by 1-3C alkyl). (I) produce selective contraction of the carotid artery and are thus useful for treatment of migraine. Effective unit doses are 0.1-100 mg, e.g. given 1-4 times a day. 4 Cpds. (I) are specifically claimed including 3-(2-aminoethyl)-N-methyl-1H-indole 5-methanesulphonamide (Ia).

Description

DK 165976B

The present invention relates to pharmaceutically active ingredient derivatives.

The present invention provides 5-aminosulfonylmethylindole derivatives of the general formula I

R ^ HSO ^ fh - / IKMVa

H

wherein R 1, R 4 and R 5 are the same or different and each is hydrogen or C 1-3 alkyl; r2 is hydrogen, alkyl, C3-4 alkenyl or ar (C1_2) alkyl; and

Alk is an alkylene chain containing two or three carbon atoms and optionally substituted with not more than two C1-3 alkyl groups, and physiologically acceptable acid addition salts and solvates thereof.

All optical isomers of compounds of general formula I and mixtures thereof comprising racemic mixtures thereof are encompassed by the invention.

In the general formula I, as mentioned above, alkyl of R 1 may contain 20 to 1-3 carbon atoms. Examples of alkyl include methyl, ethyl, propyl and isopropyl. Alkenyl contains, as indicated, 3 or 4 carbon atoms, and examples thereof include propenyl and butenyl. The term aryl, used in the term aralkyl, preferably denotes phenyl. Examples of aralkyl 25 include benzyl and phenethyl.

Suitable physiologically acceptable acid addition salts of the indoles of general formula I include salts formed with organic or inorganic acids such as, for example, hydrochlorides, hydrobromides, sulfates, fumarates, maleate and

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2 succinates. Other salts may be useful in the preparation of the compounds of general formula I, e.g., creatinine sulfate adducts.

It is generally believed that the pain of migraine is of 5 vascular origin and is caused by unusually large branchation of branches of the carotid artery bed (JW Lance, Mechanisms and Management of Migraine, Butterworths, pp. 113-152 (1973)), and many various vasoconstrictor agents have been shown to relieve headaches. The compounds 10 of the invention mimic methysergide by contracting the isolated saphenaven strip from dogs (E. Apperley et al., Br. J. Pharmacol., 1980, 68 / 215-224). Methysergide and ergotamine are known to be useful in the treatment of migraines and increase carotid vascular resistance in anesthetized dogs; it has been suggested (P.R.

Saxena, Eur. J. Pharmacol, 1974, 27 / 99-105 and P.R. Saxena and G.M. De Vlaam-Schluter, Headache, 142, 1974) that this is the basis for their efficacy. The compounds of the invention that the applicants have tested selectively narrow the carotid artery bed of anesthetized dogs, and thus the compounds of the invention are potentially useful for the treatment of migraine.

DE 3,131,728 A1 discloses 5-aminocarbonylmethyl indole derivatives which are described as having anti-migraine effect. Out of a realistic assessment of the problems posed by providing compounds with selective antimigraine effect, primarily due to the very complex and specific thermodynamic requirements of a receptor agonist in that context, the compounds of formula I were according to the invention, with their selective anti-migraine effect in no way obvious.

Furthermore, as can be seen from Table 1 below, changes in the substituent in the 5-position of indole derivatives cause significant and unpredictable changes in the pharmacological properties of the compounds.

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3

Comparison of properties of compounds with different substituents at the 5-position (Otøa · NH2

N

H

5 Table 1 X Pharmacological Properties -OH All Properties of 5-Hydroxytryptamine -CH2-CONH2 Selective Anti-Migraine Effect 10 -C0NH2 Hypotensive, Anti-Migraine Effect -NHS02H Hypotensive, CNS Suppressive and Smooth Muscle Suppressant Effect No Anti-Immigrant Information have been able to predict with any certainty whether compounds with alternative 5 substituents that would exhibit selective anti-migraine action would be prepared. 1 2 3 4 5 6

Compounds of general formula I according to the invention have been tested for biological efficacy in vena saphena strips 3 from dogs. The study has concerned compounds 4 according to Examples 1-17 and 19-23. It was found that the dose needed to achieve 50% of 6 the maximum response, ED50, for all the compounds tested.

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4 ser was less than 6.8 x 10 6 mol / l. Ie all the compounds studied are very potent and have a vasoconstrictive effect which is particularly useful in the treatment of migraine.

The selective antimigraine activity of compounds of the invention was elucidated by determining the selective agonist activity of the compounds against 5-HT 1 -like receptors. This selectivity was determined in vitro by measuring the agonist potency of the compounds at 5-HT 2-like receptors mediating contraction of isolated vena saphena from dogs, and at 5-HT 2 receptors mediating contraction of isolated aorta from rabbits. as also described by PPA Humphrey et al. f Br. J. Pharmacol.

(1988), 94, pp. 1123-1132. For a number of representatives of the compounds of the invention with various substituents in the 5-position of the indole ring, Table 2 below shows the relative potency of the compounds on the two preparations relative to 5-hydroxytryptamine.

Table 2

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5

RjR2NSO2CH2 ^^ CH2CH2NH2

H

Relative potency

Dog saphenous rabbit aorta 5 Example Ri R2 5-HTi-like. 5-HT2 1 H CH3 4.4> 294 9 H Phenyl-CH2 22> 266 12 CH3 CH3 12 245 10 13 H Phenyl-CH2CH2 5.4 653 14 H CH2 = CHCH2 10.6> 633 15 H (CH3) 2CH 49 645 16 H CH3CH2 19 The invention also provides a pharmaceutical composition adapted for use in medicine comprising at least one compound of general formula I, a physiologically acceptable acid addition salt or solvate (e.g. hydrate) thereof, and formulated for administration by any convenient route together with one or more pharmaceutically acceptable carriers or excipients.

Thus, the compounds of the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may be, for example, in the form of tablets or capsules prepared on

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6 conventional manner with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be, for example, in the form of solutions, syrups or suspensions, or they may appear as a dry product for constitution with water or another suitable carrier before use. Such liquid compositions may be prepared in a conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous carriers (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 composition may be in the form of tablets or lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteral administration by injection, including the use of conventional catheterization techniques or infusion. Formulations for injection may be in unit dosage form, for example in ampoules or multi-dose containers, along with an added preservative. The compositions may, for example, be in the form of suspensions, solutions or emulsions in oily or aqueous carriers and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable carrier, e.g., sterile pyrogen-free water, before use.

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7

The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention layers, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

5 For administration by inhalation, the compounds of the invention are conveniently disclosed in the form of an aerosol spray obtained from pressurized or atomized gaskets using an appropriate propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas. . In the case of a pressurized aerosol, the dosage unit may be determined by using a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch.

A suggested dose of the compounds of the invention for oral, parenteral, rectal or buccal administration to humans for the treatment of migraine is from 0.1 to 100 mg of the 20 active ingredient per day. dose, which can be administered, for example, 1-4 times per dose. day.

Aerosol preparations are preferably arranged such that each metered dose or "breath" aerosol contains 20 Mg-1000 µg of a compound of the invention. The total daily dose of 25 with an aerosol will be in the range of 100 µg / 10 mg. Administration can be done several times per day. per day, eg 2, 3, 4 or 8 times, during administration of, for example, 1, 2 or 3 doses each time. The total daily dose and metered dose obtained from capsules and cartridges in an inhaler or insufflator may be twice the doses of aerosol preparations.

A preferred class of compounds of formula I is that wherein R 2 is hydrogen or C 1-3 alkyl and especially such compounds.

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8, wherein, in the general formula I, R 1, R 2, R 4 and R 5, which may be the same or different, are each hydrogen or methyl.

Another preferred class of compounds is that wherein R2 is alkyl or C3-4 alkenyl and R4 is hydrogen.

Preferred compounds of the invention include: 3- (2- (Methylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide, 3- (2-aminoethyl) -N, N-dimethyl-1H-indole-5-methanesulfonamide 10 and physiologically acceptable acid addition salts and solvates (e.g. hydrates) of these compounds.

A particularly preferred compound of the invention is 3- (2-aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide and the physiologically acceptable acid addition salts (e.g., hydrochlorides and succinates) and solvates (e.g., hydrates) thereof.

Compounds of general formula I and their physiologically acceptable acid addition salts and solvates (e.g. hydrates) can be prepared by the general methods described below. In the following processes, Rlr is R2, R4, R5 and Alk as defined for the general formula I unless otherwise stated.

According to a general process (A), compounds of general formula I can be prepared by cyclizing compounds of general formula II

R ^ ^ NSOjC -

kX

NHN = CH, AlkQ

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Wherein Q is the group NR 4 R 5 or a protected derivative thereof or a leaving group such as halogen (e.g. chlorine or bromine), or acyloxy such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy or p-nitrobenzoyloxy or a sulfonate group such as p-toluenesulfonate or methylsulfonate .

Particularly convenient embodiments of the method are described below.

If Q is the group NR 4 R 5 (or a protected derivative thereof), it is desirable to carry out the process in an appropriate reaction medium such as an aqueous organic solvent, e.g., an aqueous alcohol (e.g., methanol, ethanol and isopropanol) or an aqueous ether (e.g. dioxane) in the presence of an acid catalyst. (In some cases, the acid catalyst may also act as the reaction solvent). Suitable acid catalysts include inorganic acids such as sulfuric acid or hydrochloric acid or organic carboxylic acids such as acetic acid. Alternatively, the cyclization may be carried out using polyphosphate ester in a chlorinated solvent (e.g., chloroform) or using a Lewis acid such as zinc chloride in ethanol or boron trifluoride in acetic acid. The reaction may conveniently be carried out at a temperature of from 20 to 200 ° C, preferably from 50 to 125 ° C.

If Q is a leaving group such as chlorine or bromine, the reaction may 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) in the absence of an inorganic acid, conveniently at a temperature of from 20 to 200 ° C, preferably from 50 to 125 ° C. This process results in the formation of a compound of general formula I wherein R 4 and R 5 are both hydrogen atoms.

According to a particular embodiment of this process, compounds of general formula I can be prepared directly by reacting a compound of general formula III

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10 R1R2NS02CH2

I III

NHNH2

or a salt (e.g., the hydrochloride) thereof, with a compound of general formula IV

HCOCH2AlkQ IV

wherein Q is as defined above, or a salt or protected derivative thereof (such as an acetal, e.g., a dialkyl or cyclic acetal, e.g. formed with a suitable alkyl orthoformate or diol or protected as a bisulfite addition complex), using of the appropriate reaction conditions described above for cyclizing a compound of general formula II (The Fischer-Indole Synthesis, B. Robinson p. 488, Wiley 1982).

Compounds of general formula II may, if desired, be isolated as intermediates by reacting a compound of general formula III or a salt or protected derivative thereof with a compound of general formula IV or a salt or protected derivative thereof, in a suitable solvent such as an aqueous alcohol (e.g., methanol) or an aqueous ether (e.g., dioxane) and at a temperature, for example, from 20 to 30 ° C. If an acetal of a compound of general formula IV is used, it may be necessary to carry out the reaction in the presence of an acid (e.g., acetic acid or hydrochloric acid).

As shown in the following general methods (B) and (C), the aminoalkyl substituent -AlkNR4R5 can be introduced at the 3-position by various conventional techniques which may involve, for example, modification of a substituent at the 3-position 11

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or direct introduction of the aminoalkyl substituent at the 3-position.

Thus, a further general method (B) for preparing compounds of general formula I,

5 reaction of a compound of general formula V

R1R2NS02C ^ 2 ^. aLKY

XXR

H

wherein Y is a readily interchangeable group, or a protected derivative thereof, with a compound of the general formula R 4 R 5 NH.

This replacement reaction can conveniently be carried out on those compounds of general formula V wherein the substituent Y is halogen (e.g. chlorine, bromine or iodine) or a group OR wherein OR is e.g. acyloxy such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy or p -nitrobenzoyloxy or sulfonate (e.g., p-toluenesulfonate or methylsulfonate).

The above reaction is conveniently carried out in an inert organic solvent (optionally in the presence of water), and examples thereof include alcohols, for example ethanol; ethers, eg tetrahydrofuran; esters, e.g., ethyl acetate; amides, e.g., N, N-dimethylformamide; and ketones, e.g., acetone. The process can be carried out at a temperature of, for example, from -10 to + 150 ° C, preferably from 20 to 50 ° C.

The compounds of general formula V, wherein Y is halogen, can be prepared by reacting a hydrazine of general formula III with an aldehyde (or a protected derivative thereof) of general formula IV, where Q is halogen, in an aqueous alcohol (e.g., methanol) or an aqueous ether (e.g., dioxane) containing an acid (e.g., acetic or hydrochloric), or

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12 by reacting a compound of general formula V wherein Y is hydroxy with a suitable phosphorus trihalide. The intermediate alcohol where Y is hydroxy may also be used to prepare compounds of general formula V, wherein Y is a group OR, by acylation or sulfonylation with the suitably activated compound (e.g., anhydride or sulfonyl chloride) using conventional techniques.

Compounds of general formula I may also be prepared by yet another general method (C) involving -reducing a compound of general formula VI

R-R, NS0, CH2 W

XX / -

H

wherein W is a group which may be reduced to form the desired AlkNR4R5 group or a protected derivative thereof, or a salt or protected derivative thereof.

The desired groups of Alk and NR4R5 can be formed by reduction steps taking place separately or together in any suitable manner.

Examples of groups represented by the substituent W include the following: TNO 2 (where T is Alk or alkenyl corresponding to Alk); AlkN3; AlkNR4C0R5 /; -C0C0NR4R5; (CHR 6) xCHR7CN; CHR7COZ; (CHRG) xCR7 = N0H; CH (OH) CHR7NR4R5; COCHR7Z (wherein R6 and R7, which may be the same or different, each are hydrogen or C1-3 alkyl, Z is azido or NR4Rs or a protected derivative thereof, x is 0 or 1 and R5 'is part of the group R5 or the group ORc wherein Rc is alkyl or aralkyl). Groups that can be reduced to the group Alk include the equivalent 13

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the unsaturated groups and corresponding groups containing one or more hydroxyl groups or carbonyl functions.

Groups that can be reduced to the group NR 4 R 5, where R 4 and R 5 are both hydrogen, include nitro, azido, hydroxyimino and nitrile. Reduction of a nitrile group gives the group CH 2 NH 2 and thus provides a methylene group of the group Alk.

The desired group NR 4 R 5, wherein R 4 and / or R 5 is other than hydrogen, can be prepared by reduction of a nitrile (CHR 6) XCHR 7 CN or an aldehyde (CHR 6) xCHR 7 CHO (wherein R 6, R 7 10 and x are as defined above) in the presence of and an amine R 4 R 5 NH.

A particularly convenient process for preparing a compound of general formula I wherein R 4 and / or R 5 is other than hydrogen is reductive alkylation of the corresponding compound wherein R 4 and / or R 5 is hydrogen with an appropriate aldehyde. or a ketone (e.g., acetaldehyde or benzaldehyde or acetone) in the presence of a suitable reducing agent. In some cases (e.g., by introducing the group R5 where R5 is ethyl), the aldehyde (e.g., acetaldehyde) can be condensed with the primary amine and the intermediate thus formed can then be reduced using an appropriate reducing agent.

A compound of the general formula I wherein R 5 is hydrogen may also be prepared by reducing a corresponding compound of the general formula I wherein R 5 is benzyl, e.g. with hydrogen in the presence of a catalyst, e.g., 10% palladium of carbon.

The desired group NR 4 R 5, wherein R 4 and / or R 5 is other than hydrogen, may also be prepared by reducing a corresponding amide, e.g., AlkNR 4 CO R 5 '(where R 5' is as defined above).

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14

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

Suitable reducing agents which can be used in the process described above for the preparation of compounds of general formula VI wherein W is, for example, the groups TNO2, AlkN3, (CHR6) xCHR8CN, (CHRg) xCR7 = NOH, CH (OH) CHR7NR4R5 T, R4, R5, R6 and R7 and x are as defined above) comprises hydrogen in the presence of a metal catalyst, e.g., 10 Raney nickel or a noble metal catalyst such as platinum, platinum oxide, palladium or rhodium, which may be supported on e.g. or alumina. In the case of Raney nickel, hydrazine can also be used as a source of hydrogen. This process can conveniently be carried out in a solvent such as an alcohol, e.g., ethanol, an ether, e.g., dioxane or tetrahydrofuran, an amide, e.g., dimethylformamide or an ester, e.g., ethyl acetate, and at a temperature of from -10 to + 50 °. c, preferably from -5 to + 39 ° c.

The reduction process may also be carried out on compounds of general formula VI wherein W is, for example, the groups TNO2, AlkN3, CH (OH) CHR7NR4R5 or COCHR7Z (where T, R7 and Z are as defined above), using an alkali metal or alkaline earth metal borohydride or cyanoborohydride, e.g., sodium or calcium borohydride or cyanoborohydride, which process may conveniently be carried out in an alcohol such as propanol or ethanol and at a temperature of from 10 to 100 ° C, preferably from 50 to 100 ° C. In some cases, reduction using a borohydride can be carried out in the presence of cobalt chloride.

Reduction of compounds of general formula VI wherein W is, for example, the groups TNO 2, AlkN R7, Z and x are as defined above) can also be performed using a metal hydride such as lithium aluminum hydride. This process can be performed in one

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In a solvent such as an ether such as tetrahydrofuran, and suitably at a temperature of from 10 to 100 ° C, preferably from 50 to 100 ° C.

A particular embodiment of this process comprises reducing a compound of general formula VI wherein W is the group CHR 7 CN, for example by catalytic reduction with hydrogen in the presence of a catalyst such as palladium or rhodium on alumina, optionally in the presence of an amine HNR 4 R 5, or using lithium aluminum hydride.

The starting materials or intermediate compounds of general formula VI can be prepared by methods analogous to those described in British Patent Application Laid-Open No. 2,035,310 and "A Chemistry of Heterocyclic Compounds - Indoles Part II", Chapter VI, edited 15 by WJ Houlihan (1972), Wiley Interscience, New York, U.S.A.

A compound of the general formula VI, wherein W is the group AlkNHCOOR 5 ', can be prepared by acylating the corresponding unsubstituted amine using conventional techniques.

The Fischer indole cyclization process can be used to prepare in a conventional manner a compound of general formula VI wherein W is the group (CHR 6) xCHR 7 CN or CHR 6 CHR 7 NO 2.

The following reactions (D), in any suitable order, may be carried out, if necessary and / or desired, by any of the methods described above: 1) Conversion of one compound of the general formula I 30 or a salt or protected derivative thereof to another compound of general formula I;

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16 2) removal of any protecting groups present; and 3) converting a compound of general formula I or a salt thereof into a physiologically acceptable salt or solvate (e.g. hydrate) thereof.

Thus, a compound of general formula I according to the invention can be converted to another compound according to the invention using conventional methods.

For example, a compound of general formula I wherein one or more of R1 # R2, R4 and R5 is alkyl can be prepared from the corresponding compounds of general formula I wherein one or more of R1, R2, R4 and R5 is hydrogen, by reaction with a suitable alkylating agent such as an alkyl halide (e.g., methyl or ethyl iodide), alkyl tosylate (e.g., methyl tosylate) or dialkyl sulfate (e.g., dimethyl sulfate). The alkylation reaction is conveniently carried out in an inert organic solvent such as an amide (e.g., dimethylformamide), an ether (e.g., tetrahydrofuran) or an aromatic hydrocarbon (e.g., toluene), preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides such as sodium hydride, alkali metal amides such as sodium amide, alkali metal carbonates such as sodium carbonate or alkali metal alkoxides such as sodium or potassium methoxide, ethoxide or tert-butoxide.

It will be clear that in some of the aforementioned conversions, it may be necessary or desirable to protect any sensitive groups in the molecule of the present compound to avoid undesirable side reactions. For example, during any of the reaction sequences described above, it may be necessary to protect the group NR4 R5, wherein R4 and / or R5 is hydrogen, with a group readily removable at the end of the reaction sequence. Such groups may include, for example, aralkyl such as benzyl, diphenylmethyl

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17 or triphenylmethyl; or acyl such as N-benzyloxycarbonyl, tert-butoxycarbonyl or phthaloyl.

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

Subsequent cleavage of the protecting group can be achieved by conventional methods. Thus, aralkyl such as benzyl may be decomposed by hydrogenolysis in the presence of a catalyst (e.g., palladium on charcoal) or sodium and liquid ammonia; acyl such as N-benzyloxycarbonyl can be removed by hydrolysis by, for example, hydrogen bromide in acetic acid or by reduction, for example, by catalytic hydrogenation.

Phthaloyl can be removed by hydrazinolysis (e.g., by treatment with hydrazine hydrate) or by treatment with a primary amine (e.g., methylamine).

If it is desired to isolate a compound prepared by the process of the invention as a physiologically acceptable salt, e.g., an acid addition salt, it may be obtained by treating the free base of the general formula I with a suitable acid (e.g. succinic or hydrochloric acid), preferably with a 20 equivalent amount in a suitable solvent (e.g. aqueous ethanol).

The starting materials or intermediates for preparing the compounds prepared by the process of the invention can be prepared by conventional methods analogous to those described in British Patent Application Laid-Open No. 2,035,310.

In addition to being able to be used as the final step in the preparation sequence, the general methods described above for the preparation of the compounds can also be used to introduce the desired groups in an intermediate step in the preparation of the desired compound. Thus, for example, the desired group at the 5-position can be introduced either before or after cyclization to form the indole core.

18

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Therefore, it will be clear that in such multi-step processes, the order of reactions should be chosen such that the reaction conditions do not affect the groups present in the molecule desired in the final product. The invention 5 is further illustrated by the following examples. "Hyflo®" is a filter aid.

Chromatography was performed using silica gel (Merck, Kieselgel 60, Art. 7734) and thin layer chromatography on silica (Mackerly Nagel, Polygram), unless otherwise indicated. The following abbreviations define the eluent used for chromatography and thin layer chromatography.

(A) Methylene chloride / ethanol / 0.88 ammonia water 100: 8,: 1.

(B) Methylene chloride / ethanol / 0.88 ammonia water 40: 8: 1.

(C) Cyclohexane / ethyl acetate 1: 4.

(D) Ethyl acetate / toluene 1: 1.

(E) Ethyl acetate / toluene 3: 7.

(F) Methylene chloride / ethanol / 0.88 ammonia water 30: 8: 1.

(G) Methylene chloride / ethanol / 0.88 ammonia water 150: 8: 1.

(H) Methylene chloride / ethanol / 0.88 ammonia water 25: 8: 1.

(I) Chloroform / methanol 97: 3.

(J) Methylene chloride / ethanol / 0.88 ammonia water 20: 8: 1.

(K) Ether / isopropanol / water / 0.88 ammonia water 20: 20: 8: 1.

(L) Ethyl acetate / isopropanol / water / 0.88 ammonia water 25: 15: 8: 2.

(M) Methylene chloride / methanol 95: 5.

(N) Methylene chloride / ethanol / 0.88 ammonia water 50: 8: 1.

(O) Methylene chloride / ethanol / 0.88 ammonia water 10: 8: 1.

(P) Chloroform / methanol 95: 5.

(Q) Methylene chloride / ethanol / 0.88 ammonia water 200: 8: 1.

Intermediates were routinely examined for purity by thin layer chromatography (TLC) using ultraviolet light for detection and spray reagents such as DNP and potassium permanganate. In addition, indolic intermediates were detected by spraying with aqueous cerium sulfate, and tryptamines by spraying with a solution of iodoplatinic acid or cerium sulfate.

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EXAMPLE 1 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide maleate a) 4-Aroino-N-methylbenzenemethanesulfonamide hydrochloride A suspension of N-methyl-4-nitrobenzenemethanesulfonamide (30 g) in ethanol (150 ml), water (300 ml) and hydrochloric acid (2N, 65 ml) were hydrogenated over 10% palladium oxide on charcoal (7.5 g, 50% paste with water) until hydrogen uptake stopped (9.75 l ). The catalyst was removed by filtration through "Hyflo®" and the filter cake washed with water (30 ml). The filtrate was evaporated under reduced pressure to give the title compound as a pale yellow powder (28.2 g), mp 143-144 ° C.

b) 4-Hydrazino-N-methylbenzene methanesulfonamide hydrochloride A solution of sodium nitrite (13.72 g) in water (160 ml) was added slowly to a cooled stirred mixture of 4-amino-N-methylbenzenemethanesulfonamide (39.3 g) , water (240 ml) and concentrated hydrochloric acid (400 ml) so that the temperature did not exceed 0 ° C. After stirring for 15 minutes, this mixture was added slowly to a cold solution of tin (II) chloride dihydrates (221.1 g) in concentrated hydrochloric acid (400 ml), keeping the temperature again below 0 ° C. After the addition was complete, the mixture was allowed to warm to room temperature (1 hour). The solid was collected by filtration, washed thoroughly with diethyl ether (4 x 250 ml) and dried at 45 ° C to give the title compound as a white powder (31.6 g). This was analyzed by period titration to have a purity of 91.3%.

TLC (A) Rf 0.4.

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C) 3- (2-Aminomethyl) -N-methyl-1H-indole-5-methanesulfonamide maleate

A solution of 4-hydrazino-N-methylbenzemethanesulfonamide hydrochloride (10 g) and 4-chlorobutanaldimethyl acetal (6.5 g) 5 in ethanol / water (5: 1, 500 ml) was heated at reflux for 2 hours. The solution was then cooled and evaporated to dryness under reduced pressure. The orange-brown residue was purified by column chromatography (B) to give the tryptamine as an oil (3.9 g). A solution of this material (3.9 g) in ethanol (50 ml) and methanol (10 ml) was treated with a solution of maleic acid (1.7 g) in ethanol (10 ml) and the resulting solution was concentrated to a thick oil which solidified on cooling to give the title compound, mp 140-141 ° C.

Analysis:

Calc'd for 0.3038.0.0404: C 50.1 H5.5 N 11.0.

Found: C 50.1 H 5.3 N 10.6.

TLC (F) Rf 0.26.

EXAMPLE 2 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide maleate a) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindole-2 yl) ethyl] -N-methyl-1H-indole-5-methanesulfonamide

A suspension of the product of Example 1b) (7 g) and 2-25 (4,4-diethoxybutyl) -1H-isoindole-1,3 (2H) -dione (8.15 g) in dilute acetic acid (25%, 450 ml) was stirred at room temperature for 1/2 hour and then heated to reflux for 1 hour. The resulting suspension was partitioned between water (1 ml) and ethyl acetate (200 ml). The aqueous phase was extracted with more ethyl acetate (3 x 250 ml). The organic extracts were combined, washed with sat.

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21 carbonate (to pH 7) and dried over magnesium sulfate. Evaporation of the solvent gave the title compound as a yellow-orange foam (4.5 g), which was used in the next step without further purification. TLC (C) Rf 0.63, impurities at Rf 5 0.45 and 0.07.

b) Phenylmethyl [2- [5- [[(methylamino) sulfonyl] methyl] -1H-indol-3-yl] ethyl] carbamate

A hot solution of the product of step a) (4.5 g) in ethanol (70 ml) was treated with hydrazine hydrate (2.8 ml) and heated to reflux for 2 hours. The solvent was evaporated and the residual solid was suspended in sodium carbonate (2N, 50 ml) and tetrahydrofuran (20 ml) and treated with benzyl chloroformate (3.15 ml).

After 2 hours, the aqueous phase was extracted with ethyl acetate (4 x 50 ml), the extract was dried with magnesium sulfate and the solvent was evaporated. chromatography

(D) gave the title compound as a yellow foam (2.5 g) which was used in the next step without further purification. TLC

(E) Rf 0.35.

C) 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide maleate

A solution of the product of step b) (0.85 g) in methanol (10 ml) was hydrogenated over pre-reduced palladium oxide on carbon (10%, 300 mg) at room temperature and atmospheric pressure for 6 hours (hydrogen uptake 30 ml). The catalyst was filtered off (Hyflo®) and washed with methanol (100 mL). The filtrate was concentrated and the remaining white solid (0.56 g) was purified by column chromatography (F) to give the tryptamine as a white foam (0.26 g). Part of this (0.13 g) in absolute ethanol (5 ml) was treated with maleic acid (0.052 g) and the solvent was evaporated. The residual oil crystallized in tetrahydrofuran (5 ml) with a few drops of ethanol,

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22 to give the title compound as an off-white solid, mp 150-154 ° C (0.11 g).

Analysis:

Calcd for c12 H17 N3 ° 2s * c4H4 ° 4: C 50.1 H5.5 N 10.9.

5 Found; C 50.2 H 5.6 N 10.7.

TLC (F) Rf 0.26.

Example 3 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide a) 4- [2- (3-Cyanopropylidene) hydrazino] -N-roethylbenzenemethanesulfonamide

A solution of the product of Example 1 b) (2 g) and 3-cyanopropanaldimethyl acetal (1.4 g) in water (25 ml) was treated with dilute hydrochloric acid (2N; 5 drops) and stirred for 24 hours at room temperature. The resulting white solid was filtered off, washed with water (20 ml) and ether (100 ml) and dried in vacuo at 40 ° C to give the title compound (2.1 g), mp 124-125 ° C.

b) 3- (Cyanomethyl) -N-methyl-1H-indole-5-methanesulfonamide

A suspension of the product of step a) (0.7 g) in polyphosphate ester (7 g) and chloroform (14 ml) was heated at reflux for 5 minutes and then poured into ice. The resulting suspension was stirred with ice for 20 min and then extracted with chloroform (4 x 20 ml) and the extract dried, the solvent was then removed and the residue was purified by column chromatography (G). The title compound was obtained as a reddish semi-solid (0.38 g) which was impure and used directly in the next step. TLC (G) Rf 0.4 with impurities at Rf 0.44 and 0.46.

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C) 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide

A solution of the product of step b) (0.15 g) in methanolic ammonia was hydrogenated over pre-reduced rhodium on alumina (5%, 0.15 g) for 18 hours at room temperature 5 and atmospheric pressure. TLC (F) showed that the solution contained a major component of Rf 0.26 identical to Rf of 3- (2-aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide prepared by the procedure of Example 1.

Example 4 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide

To a solution of the product of Example 3b) (0.15 g) in dry tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.15 g) and the resulting suspension was heated to reflux (under nitrogen atmosphere) for 1 hour. hour.

Excess lithium aluminum hydride was destroyed by the addition of ethyl acetate (5 ml) followed by the addition of aqueous potassium carbonate (10 ml; saturated). The aqueous phase was extracted with ethanol (10 mL). The solvent was evaporated under reduced pressure, and the residual oil 20 was purified by column chromatography in (H) to give the title compound as a slightly crude oil (21 mg) shown by NMR and TLC (F) Rf 0.26. be identical to a sample prepared by the method of Example 1.

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EXAMPLE 5 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide a) N-Methyl-4- [2- (4-nitrobutylidene) hydrazino] benzene methanesulfonamide 5 To a solution of the product from Example 1b) (1g) in water (20ml) was added 4-nitrobutanal (0f5g) and an oil separated within a few minutes. The resulting suspension was extracted with dichloromethane (4x20ml), the extracts were dried over magnesium sulfate and the solvent was evaporated in vacuo to give the title compound as a thick oil (1.08 g).

Analysis:

Calcd. For C12 H18 N4 O4.0.2H2 O: C 45.6 H5.2 N 17.7.

Found: C 45.3 H 5.6 N 17.3.

TLC isopropyl acetate / cyclohexane (3: 1) Rf 0.26.

b) N-Methyl-3- (2-nitroethyl) -1H-indole-5-methanesulfonamide

A solution of the product of step a) (2 g) in chloroform (40 ml) and polyphosphate ester (20 g) was heated under reflux for 3 minutes and then poured into ice 20 (50 g) and sodium bicarbonate (8%, 20 ml). ). The mixture was stirred at room temperature for 30 minutes and extracted with chloroform (4 x 50 ml). The organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (Merck 9385) (I),

To give the title compound as an oil (0.72 g) used in the next step without further purification. TLC

(Q) Rf 0.26. NMR Spectrum: δ (ppm) = 5.2 (triplet CH

c) 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide

A solution of the product of step b) (0.13 g) in ethyl acetate (5 ml) was hydrogenated over reduced 10% palladium.

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25 dioxide on charcoal (0.2 g, 50% paste with water) for 2 hours, after which hydrogen uptake (20 ml) ceased. The catalyst was removed by filtration (Hyflo®) and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel 9385) to give the title compound (8 mg) as an oil which, by TLC (F) Rf 0.26, was shown to be identical to the product of Example 1.

Example 6 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide a) 4- [2- (4-Chlorobutylidene) hydrazino] -N-methylbenzenesethane sulfonamide

A mixture of the product of Example 1 b) (0.54 g), 4-ehlorobutanaldimethyl acetal (0.30 g), water (4 ml) and hydrochloric acid (2N; 2 drops) was stirred at room temperature for 1.5 hours. The mixture was filtered and the solid washed with water (20 ml), air dried for 1 hour and dried overnight in vacuo over phosphorus pentoxide to give the title compound as a cream solid (0.44 g), mp 77-79 ° C (decomposition).

B) 3- (2-Chloroethyl) -N-methyl-1H-indole-5-methanesulfonamide

A solution of the product of step a) (0.29 g) in chloroform (3 ml) was added to a solution of polyphosphate ester (2.92 g) in chloroform (2 ml) and the yellow solution was heated to reflux for 5 hours. minutes. The resulting brown solution was then immediately poured into ice (about 20 g), gently diluted with sodium hydrogen carbonate solution (8%; about 50 ml) until basic reaction and stirred at room temperature for 15 minutes. The mixture was then extracted with chloroform (3 x 20 ml) and the combined organic extracts were washed with brine (20 ml), dried over magnesium sulfate and evaporated in vacuo

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26 to give the crude title compound as a tan oil (0.60 g) used in the next step without further purification. TLC (I) major components Rf 0.25, 0.32, minor products Rf 0.0, 0.05, 0.43 and 0.57.

C) 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide

A solution of the product of step b) (0.60 g) in methanol (4 ml) was diluted with ammonium hydroxide (30 ml) and the suspension was stirred in an autoclave at 90 ° C for 110 minutes. The mixture was filtered and the filtrate was evaporated in vacuo to give a yellow gum which was azeotropified with absolute ethanol (2 x 30 ml) to give a sticky solid (0.46 g). This material was purified by chromatography (J) to give the title compound as a pale yellow oil (0.036 g), which by TLC (J) R f 0.23 and NMR was shown to be identical to the product of Example 1.

EXAMPLE 7 3- (2-Aminoethyl 1) -N-methyl-1H-indole-5-methanesulfonamide hydrochloride 20 To a solution of the free tryptamine base (0.267 g) prepared by the procedure described in Example 1 in ethanol (3 ml) was added 3, 1N ethanolic hydrogen chloride until the solution was just acidic. The yellow solution was heated to boiling and upon cooling, the title compound ice separated as slightly cream-colored microneedle crystals (0.26 g), mp 229-231 ° C.

Analysis:

Calcd for C 21 H 17 N 3 O 2 S * HC 3: C 47.4 H6.0 N 13.8.

Found: C 47.7 H 6.1 N 13.4.

TLC (J) Rf 0.3.

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EXAMPLE 8 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide hemisuccinate

To a hot solution of the free tryptamine base (0.267 g) prepared by the procedure described in Example 1 in ethanol (3 ml) was added a hot solution of succinic acid (0.059 g) in ethanol (3 ml). On cooling, the title compound separated as an off-white powder (0.29 g), mp 179-181 ° C.

Analysis:

Calcd for C12 N17 N3 O2 S.0.5C4HgO4: C 51.5 H 6.2 N 12.9. Found: C 51.5 H6.2 N 12.6.

TLC (J) Rf 0.30.

EXAMPLE 9 3- (2-Aminoethyl) -N- (phenylmethyl) -1H-indole-5-methanesulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1,2) a) 4-Nitro -N- (phenylmethyl) benzenmethansulfonamid

Benzylamine (0.8 ml) was added at once to a solution of 4-nitrobenzene methanesulfonyl chloride (0.6 g) in dichloromethane (50 ml) at room temperature. A white solid precipitated immediately. Stirring was continued for 1 hour, the solvent was evaporated and the residual solid was washed with water (100 ml), ether (200 ml) and dried. The title compound was obtained as a white solid (0.64 g), mp 180-181 ° C. A sample (0.2 g) was recrystallized from hot ethanol (5 ml) to give analytically pure material as an off-white solid (0.15 g), mp 182-183 ° C.

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B) 4-Amino-N- (phenylmethyl) benzenemethanesulfonamide

A suspension of the product of step a) (5 g) in methanol (150 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (1 g) at room temperature and pressure.

5 Hydrogen uptake was complete in 20 minutes after absorbing l / l 1. The catalyst was filtered off (Hyflo®), washed with more methanol (500 ml) and the solvent was evaporated. The product was obtained as an off-white solid (3.75 g), mp 116-117 ° C. A small sample (0.15 g) was recrystallized from hot ethanol (3 ml) and a few drops of ether to give the title compound (0.1 g), mp 117-118 ° C.

c) 4-Hydrazino-N- (phenylmethyl) benzene methanesulfonamide hydrochloride A thick suspension of the product of step b) (3.68 g) in concentrated hydrochloric acid (50 ml) was stirred at -5 ° C while a solution of sodium nitrite ( 0.9 g) in water (10 ml) was added dropwise so that the temperature did not exceed 0 ° C. Stirring continued for 30 minutes. The resulting suspension was filtered to remove starting material and in a few portions the filtrate was added to a solution of tin (II) chloride dihydrate (13.5 g) in hydrochloric acid (15 ml) at -20 ° C and heated to room temperature. The precipitated solid was filtered off and recrystallized from hot methanol (100 ml) to give the title compound as white plates (0.39 g), mp 192-193 ° C. The mother liquors gave another portion (0.52 g).

d) 3- (2-Aminoethyl) -N- (phenylmethyl-1H-indole-5-methanesulfonamide, compound with creatinine, sulfuric acid and water (1: 1: 1: 1.2)

A solution of the product of step c) (0.47 g) and 4-chloro-butanaldimethyl acetal (0.24 g) in ethanol (50 ml) and water

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29 (10 ml) was heated to reflux for 4 hours. The solvent was evaporated and the residual oil was purified by column chromatography (F) to give the tryptamine as a weak crude oil (0.34 g). Yet another chromatography (K) gave pure free base as an oil (0.1 g), which was taken up in hot ethanol (8 ml) and water (1 ml) and treated with a solution of creatinine and sulfuric acid ( 1: 1, 2N, 0.15 ml). The salt which crystallized on cooling was filtered off, dried in vacuo at 60 ° C (16 hours) and the title compound was obtained as an off-white powder (0.125 g), mp 230-231 ° C.

Analysis:

Calcd. For C18 H21 N3 ° 2 ^ C4H7N3 ° H2 H2 ° 4: C 45.7 H 5.3 N 14'2 · 15 Found: C 45.9 H 5.7 N 14.6.

TLC (K) Rf 0.41. IN

EXAMPLE 10 3- (2-Aminoethyl) -N, N-dimethyl-1H-indole-5-methanesulfonamide maleate a) 4-Amino-N, N-dimethylbenzenemethanesulfonamide

A suspension of N, N-dimethyl-4-nitrobenzene methanesulfonamide (4.2 g) in methanol (300 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (1 g) at atmospheric pressure and room temperature. The hydrogen uptake was completed in 1 hour. The catalyst was filtered off (Hyflo®), washed with ethyl acetate (400 ml), the solvent was evaporated and the title compound was obtained as a cream solid (3.3 g), mp 151-152 ° C.

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B) 4-Hydrazino-N, N-dimethylbenzene methanesulfonamide hydrochloride

To a stirred suspension of the product of step a) (3.2 g) in concentrated hydrochloric acid (35 ml) and water (17 ml) at -5 ° C (ice / salt bath) was added a solution of sodium nitrite (1.1 g) in water (3 ml) at such a rate that the temperature does not exceed 0 ° C. After stirring for 10 minutes, the yellow solution was added to a solution of tin (II) chloride dihydrate (17 g) in concentrated hydrochloric acid (40 ml) at -10 ° C at such a rate that the temperature did not exceed 0 ° C. Stirring was continued for one hour at room temperature and the solid collected by filtration, washed with ether (500 ml) and dried in vacuo at room temperature. The crude product (2.95 g) was recrystallized from hot ethanol (40 ml) and methanol (20 ml) to give the title compound as a white solid (1.6 g), mp 155-156 ° C.

c) 3- (2-Aminoethyl-N, N-dimethyl-1H-indole-5-methanesulfonamide maleate

A solution of the product of step b) (1 g) and 4-chlorobutanal-dimethyl acetal (0.7 g) in ethanol / water (5: 1, 50 ml) was heated to reflux for 1 hour and 40 minutes. The cooled solution was evaporated to dryness under reduced pressure. The reddish brown residue was purified by column chromatography (B) to give the tryptamine as an oil 25 (0.13 g). A solution of this in ethanol (5 ml) was treated with maleic acid (0.054 g) and then concentrated to a foam which was triturated with ether and dried in vacuo at 80 ° C to give the title compound as a hygroscopic solid (0 , 06 g).

Analysis:

Calcd for C 13 H 19 N 3 ° 2S, C 4 H 4 ° 4: C 51.4 H 5.8 N 10.6.

Found: C 51.6 H 6.0 N 10.1.

TLC (F) Rf 0.34.

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31 In another experiment, a hot solution of the tryptamine (0.07 g) in ethanol / water (8: 1, 6 ml) was treated with a solution of creatinine and sulfuric acid (1: 1.0 125 ml, 2N). added at once, and upon cooling, the title compound crystallized as the creatinine sulfate adduct (85 mg), mp 197-198 ° C, dried at 60 ° C.

Analysis:

Calculated for C 13 H 19 N 3 ° 2S * C 4 H 7 N 3 ° .H 2 SO 4 .H 2 O: C 40.0 H 5.9 N 16.5.

Found: C 40.3 H 5.7 N 16.1.

EXAMPLE 11 3- (2-Aminoethyl) -N- (2-phenylethyl) -1H-indole-5-methanesulfonamide hydrochloride, 1/4 hydrate a) 4-Nitro-N- (2-phenylethyl) benzenemethanesulfonamide In a process similar to that described in Example 9 (a), 4-nitrobenzene methanesulfonyl chloride (6.0 g) was condensed with 2-phenylethylamine (8 ml) to give the title compound as a light brown solid (7.5 g), m.p. -103 "C.

B) 4-Amino-N- (2-phenylethyl) benzenemethanesulfonamide

By a process similar to that described in Example 9 b), the product of step a) (7.0 g) was hydrogenated in ethanol to give the title compound as a white solid (6.0 g), mp 123-125 ° C (of ethanol).

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C) 4-Hydrazino-N- (2-phenylethyl) benzenemethanesulfonamide hydrochloride

By a procedure similar to that described in Example 9 (c), the product of step b) (4 g) was diazotized and reduced to give the title compound (3.0 g), mp 160-163 ° C (of ethanol).

d) 3- (2-Aminoethyl) -N- (2-phenylethyl) -1H-indole-5-methanesulfonamide hydrochloride, 1/4 hydrate

By a procedure similar to that described in Example 9 d), the product of step c) (2.0 g) was condensed with 4-chlorobutanal dimethyl acetal (1.0 g) and flash chromatographed (silica gel 9385) to give the tryptamine as a yellow oil. The oil was dissolved in methanol (10 ml), acidified with ethanolic hydrogen chloride (about 2 ml) and diluted with ether (200 ml). The ether was decanted from the resulting rubber and replaced with more dry ether (200 ml). Scratching allowed the rubber to crystallize and the resulting solid was filtered off and dried in vacuo to give the title compound as a cream colored solid (0.65 g), mp 115-119 ° C.

Analysis:

Calc'd for C 19 H 23 N 3 ° 1 * HCl 0.25 H 2 °: C 57.3 H 6.2 N 10/5

Found: C 57.25 H 6.2 N 10.3.

TLC (J) Rf 0.4.

3- (2-Aminoethyl) -N- (2-propenyl) -1H-indole-5-methanesulfonamide hydrochloride

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EXAMPLE 12 a) 4-Nitro-N- (2-propenyl) benzene methanesulfonamide 4 4-Nitrophenylmethanesulfonyl chloride (5.0 g) was added dropwise to dry dichloromethane (50 ml) to a stirred solution of allylamine (3.3 ml). dry dichloromethane (50 ml) at room temperature under nitrogen over 15 minutes. Stirring was continued for 45 minutes. The mixture was washed with water 10 (3 x 50 ml) and dried over magnesium sulfate and the solvent evaporated to give a very pale yellow solid (5.22 g). A sample (0.26 g) was recrystallized from ethanol to give the title compound as very pale yellow needle crystals (0.182 g), mp 118-120.5 ° C.

B) 4-Amino-N- (2-propenyl) benzenemethanesulfonamide hydrochloride

Sodium borohydride (0.37 g) in ethanol (120 ml) was added dropwise over 30 minutes to a stirred solution of the product of step a) (5.0 g) and tin (II) chloride dihydrate 20 (22 g) in ethanol (400 ml) at 65 ° C under nitrogen. After stirring at 65 ° C for an additional 30 minutes, the mixture was cooled in an ice bath and ice water (400 ml) was added followed by 5N sodium hydroxide (40 ml, to pH 8) to give a milky emulsion. The ethanol was evaporated at reduced pressure, more 5N sodium hydroxide (110 ml) was added and the mixture was extracted with ethyl acetate (3 x 250 ml). The organic phases were washed with brine, dried over magnesium sulfate and evaporated to give a yellow solid (4.96 g). A sample (0.3 g) was dissolved in ethanol (1.5 mL) and ethanolic hydrogen chloride (about 3M, 0.6 mL) was added to give a pale yellow precipitate which was filtered off and dried in vacuo at 45 ° C to give the title compound.

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34 compound as pale yellow crystals (0.239 g), mp 153.5-155 ° C.

c) 4-Hydrazino-N- (2-propenyl) benzene methanesulfonamide hydrochloride 5 A solution of sodium nitrite (1.06 g) in water (2.5 ml) was added dropwise to a stirred suspension of the product of step b) (3.5 g) in 5N hydrochloric acid (28 ml) at between -8 ° C and -3 ° C under nitrogen and stirring was continued at ca. -3 ° C for 80 minutes. The mixture was filtered and the clear yellow 10 filtrate was added dropwise from an ice-cooled, dropwise dropping funnel to a stirred solution of tin (II) chloride dihydrate (17.5 g) in concentrated hydrochloric acid (17.5 ml ) at between -2 ° C and + 1 ° C over 35 minutes. After heating to 10 ° C over 15 minutes, the mixture was filtered and the residue washed with concentrated hydrochloric acid (4 x 5 ml) and dry ether (4 x 30 ml) and dried to give the title compound as a very pale yellow solid. substance (2.44 g), mp 163-166 ° C, containing 5% inorganic material.

D) 3- (2-Aminoethyl) -N- (2-propenyl) -1H-indole-5-methanesulfonamide hydrochloride

The product of step c) (1.5 g) was heated under reflux with 4-chlorobutanol-dimethyl acetal (0.83 g) in 5: 1 ethanol / water (75 ml) with stirring in a nitrogen atmosphere for 1.5 hours. The mixture was poured into 8% aqueous sodium hydrogen carbonate (25 mL) and the ethanol was evaporated off at room temperature (vacuum pump). The mixture was extracted with ethyl acetate (4 x 40 ml) and the organic phases were washed with brine, dried over magnesium sulfate and evaporated to give a brown oil (1.62 g). Further extraction of the aqueous phases with butanone (3 x 40 ml), drying over magnesium sulfate and evaporation gave an additional amount of brown oil (0.3 g).

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35

The combined crude products were purified by flash chromatography (silica gel 9385, H) to give a pale yellow foam (0.55 g). The foam was dissolved in absolute ethanol (2 ml) and ethanolic hydrogen chloride (about 3M, 0.6 ml) was added to give a clear solution (pH 3). Addition of ethyl acetate (10 ml) followed by dry ether (60 ml) gave a white precipitate which was triturated with dry ether (3 x 70 ml), filtered off and dried in vacuo at room temperature to give the title compound as a powdery white 10 solid (0.484 g), m.p. 90-150 ° C, which was dried at 75 ° C. TLC (L) Rf 0.45.

Analysis:

Calcd. For C 14 H 19 N 3 O 2 S.HCl: C 51.0 H6, N N 12.7.

Found: C, 50.7; H, 5.9; N, 12.3.

EXAMPLE 13 3- (2-Aminoethyl) -N- (1-methylethyl) -1H-indole-5-methanesulfonamide, compound with maleic acid (2: 3) a) N- (1-Methylethyl) -4 -nitrobenz and methanesulfonamide

In a process similar to that described in Example 9 (a), 4-nitrobenzene methanesulfonyl chloride (5 g) was reacted with isopropylamine (5.63 ml) to give the title compound (4.14 g), m.p. 146-147 ° C ( ethanol).

b) 4-Amino-N- (1-methylethyl) benzenemethanesulfonamide

By a process similar to that described in Example 9 b), the product of step a) was hydrogenated in ethanol to give the title compound (2.45 g), mp 105-107 ° C (of isopropanol).

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C) 4-Hydrazino-N- (1-methylethyl) benzenemethanesulfonamide hydrochloride

By a method similar to that described in Example 9 (c), the product of step b) was diazotized and reduced to give the title compound as a white powder (1.5 g), purity 79% by period titration. TLC (A) Rf 0.36.

d) 3- (2-Aminoethyl) -N- (1-methylethyl) -1H-indole-5-methanesulfonamide, compound with maleic acid (2: 3) A mixture of the product of step c) (1.5 g ) and 4-chloro-butanal-dimethyl acetal (0.7 g) in a mixture of ethanol (35 ml) and water (5 ml) were heated to 50 ° C for 30 minutes. Ammonium acetate (0.97 g) was added and the mixture was heated at reflux for 4 hours. The suspension 15 was then diluted with water (200 ml) and the solid removed by filtration. The filtrate was washed with ethyl acetate (3 x 50 ml) and the wash phases discarded. The aqueous phase was made basic by the addition of solid potassium carbonate (30 g) and the mixture was extracted with 20 ethyl acetate (4 x 50 ml) and the extracts were dried over sodium sulfate and evaporated under reduced pressure. The residual oil was chromatographed (B) and the tryptamine (0.2 g) was dissolved in ethanol (5 ml), maleic acid (78.5 mg) in ethanol (5 ml) was added and the solution was evaporated. to dryness, yielding a slightly brown rubber. Trituration with isopropanol (3 x 5 ml) gave the title compound as a pale brown powder (0.21 g), mp 150-152 ° C.

Analysis:

Calculated for C 14 H 21 N 3 O 2 S, 1.5 C 4 H 4 O 4: C, 51.2 H5.8, N9.0.

Found: C 50.9 H 5.9 N 8.6.

TLC (H) Rf 0.30.

3- (2-Aminoethyl) -N-ethyl-1H-indole-5-methanesulfonamide malate, hemihydrate compound with diethyl ether (10: 10: 5: 1) 37

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Example 14 a) 4-Amino-N-ethylbenzene methanesulfonamide A solution of N-ethyl-4-nitrobenzene methanesulfonamide (4.35 g) in hot ethanol (125 ml) was added to 10% palladium oxide on carbon (0.75 g , 50% aqueous paste) reduced in ethanol (25 ml) and hydrogenated at atmospheric pressure. Hydrogen uptake (1400 ml) stopped after 20 minutes.

The suspension was filtered and the catalyst was washed with methanol (100 ml) and ethanol (100 ml). Evaporation of the combined filtrates and washing phases gave a gray solid (2.0 g) which was recrystallized from isopropanol (120 ml) to give the title compound as cream-colored microneedles 15 (1.48 g), mp 161-164 ° C.

b) N-Ethyl-4-hydrazinobenzene methanesulfonamide hydrochloride

Sodium nitrite (1.01 g) in water (12 ml) was slowly added at -5 ° C to a stirred suspension of the finely ground product of step a) (3.14 g) in concentrated hydrochloric acid (30 ml), with the temperature was kept below 0 ° C. The resulting mixture was stirred at -5 ° C for 15 minutes and then slowly added to a cold (-5 ° C) stirred solution of tin (II) chlorine (16.52 g) in concentrated hydrochloric acid (30 ml), the solution was kept below 0 ° C.

After allowing the mixture to warm to room temperature over 1 hour, the suspension was filtered and the solid washed with ether to give the title compound as a white solid (2.06 g), m.p. 170 "C.

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C) 3- (2-Aminoethyl) -N-ethyl-1H-indole-5-methanesulfonamide maleate, hemihydrate compound with diethyl ether (10: 10: 5: 1)

A solution of the product of step b) (0.425 g) and 4-chloro-butanal-dimethyl acetal (0.244 g) in ethanol / water (5: 1) (20 ml) was stirred at 50 ° C for 40 minutes. Ammonium acetate (0.7394 g) was added and the pH of the solution was then adjusted to 4 by hydrochloric acid. The resulting solution was heated at reflux for 2 hours.

The slightly brown mixture was diluted with water (200 ml) and washed with ethyl acetate (3 x 100 ml). The aqueous solution was basified with potassium carbonate (solid) and then extracted with ethyl acetate (4 x 100 mL). Subsequent evaporation of the organic extracts dried with magnesium sulfate gave a brown foam (0.38 g) which was purified by chromatography in (N) to give the tryptamine as a pale brown gum (0.1435 g).

A solution of the base (0.1435 g) in methanol (2 ml) was treated with maleic acid (0.05916 g) in methanol (2 ml). Subsequent evaporation of the clear solution under reduced pressure gave a slightly brown gum, which became one with anhydrous diethyl ether to give the title compound as a cream powder (0.09 g), mp 139-142 ° C. TLC

(H) Rf 0.4.

Calcd. For C 13 H 19 N 3 O 2 S.c4H404.0.5H2O.0, C4H10O: C 50.5 H 6.1 N 10.2. Found: C 50.1 H 5.8 N 9.4.

3- (2-Aminoethyl) -1H-indole-5-methanesulfonamide hydrochloride 39

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Example 15 a) 4-Aminobenzene methanesulfonamide

A suspension of 4-nitrobenzene methanesulfonamide (7.11 g) and 5% palladium oxide on charcoal (1.4 g) in ethanol (1.1 l) was hydrogenated at room temperature and pressure. The reaction was completed after 2.5 L of hydrogen had been absorbed and the catalyst was removed by filtration. The filtrate was concentrated to give the title compound as a solid (4.72 g). Recrystallization of a sample of ethanol gave analytically pure material, m.p. 166 ° C (bubbles).

b) 4-Hydrazinobenzene methanesulfonamide hydrochloride

A solution of sodium nitrite (1.12 g) in water (10 ml) was added dropwise over 10 minutes and with stirring to a paste of the product of step a) (3.0 g) in concentrated hydrochloric acid (4.8 ml) at from 0 to 5 ° C. The mixture was cooled to -5 ° C and over 10 minutes was added portionwise to a vigorously stirred solution of sodium sulfite (5.02 g) and sodium acetate (5 g) in water (40 ml) at 0 to -5 ° C.

After 20 minutes, the mixture was allowed to warm to room temperature over 1 hour and then heated to 75-85 ° C for 1 hour. The solution was filtered and acidified with concentrated hydrochloric acid (5.2 ml) and heated to 80-85 ° C, then more concentrated hydrochloric acid (28 ml) was added.

The solution was then cooled and the title compound separated as a cream-colored solid (2.15 g) used in the next step without further purification. TLC methanol-ethyl acetate, (1: 4) Rf 0.6, 0.9 (minor component).

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C) 3- [2- (1,3-Dihydro-1,3-dioxo-2H-isoindo-1-2-yl) ethyl] -1H-indole-5-methanesulfonamide

A mixture of 2- (4,4-diethoxybutyl) -1H-isoindole-1,3 (2H) -dione (0.58 g), the product of step b) (0.51 g) and 50% water 5 µg of acetic acid (20 ml) was heated to give a yellow solution, which was then boiled in a nitrogen atmosphere for 2 hours. The mixture was cooled and extracted with ethyl acetate (5 x 25 mL). The extracts were washed with water (3 x 30 ml), dried over sodium sulfate and concentrated to give a gum which, upon trituration with ether, gave a cream-colored solid (0.57 g). This was chromatographed by eluting with ethyl acetate to give the product as a gum which solidified by trituration with ether. This material (0.29 g) was absorbed from acetone on a PLC plate (Merck 15 silica gel 60 F254, 20 x 20 cm) and eluted twice with ethyl acetate / cyclohexane (1: 1). The pure indole was isolated from the stationary phase by Soxhlet extraction with ether over one day.

Removal of the solvent gave a gum which, upon trituration with ethyl acetate, gave the title compound as a cream colored solid, mp 186-188 ° C (32 mg).

d) 3- (2-Aminoethyl) -1H-indole-5-methanesulfonamide hydrochloride

The product of step c) (0.3 g) was taken up in a solution of methylamine in ethanol (38%, 8 ml) to give a clear yellow solution which was kept at room temperature for 3 hours. The solvent was removed in vacuo and the residual gum was re-evaporated with ethanol (2x8 ml) and then taken up in methanol (5 ml) and filtered. The filtrate 30 was treated with ethereal hydrogen chloride and diluted with ethyl acetate (50 ml). A rubbery solid separated which was absorbed from ethanol on a PLC plate (Merck silica gel 60, 20 x 20 cm) and eluted in ethyl acetate / isopropanol / water / 0.88 ammonia water (25: 15: 8: 2 ). The sulfonamide became

DK 165976B

41 extracted from the stationary phase with methanol (6 x 10 ml). The methanol solution was filtered and concentrated to a gum. This was taken up in ethyl acetate and filtered to remove silica and then treated with ethereal hydrogen chloride. The title compound separated as a cream-colored solid (25 mg), mp 237-239 ° C (dec.).

Analysis:

Calcd for c ^ h ^ NsC2SHCl: c 45.6 H 5.6 N 14.5.

Found: C 45.5 H 5.6 N 13.5.

TLC (L) Rf 0.37.

EXAMPLE 16 3- (2-Aminoethyl) -1H-indole-5-methanesulfonamide maleate a) Phenylmethyl [2- [5 - [(aminosulfonyl) methyl] -1H-indol-3-15 yl] ethyl] carbamate

A solution of the product of Example 15 c) (1.38 g) and hydrazine hydrate (0.72 ml) in ethanol (80 ml) and ethyl acetate (20 ml) was heated at reflux for 2 hours. The mixture was cooled to room temperature and the resulting 20 yellow solids filtered off. The filtrate was washed with saturated potassium carbonate (2 x 30 ml), the solvent was evaporated and the crude free base identical to the product of Example 15 d) was used in the next step without further purification.

A suspension of the base in dilute sodium carbonate (2N; 50 ml) was treated with benzyl chloroformate (1 ml) and stirred at room temperature for 1 hour. The resulting suspension was extracted with ethyl acetate (4 x 30 mL), the organic phase was dried over magnesium sulfate, the solvent was evaporated and the crude product, a black oil (1.7 g), was purified by column chromatography ( M), which

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42 gave an oil (0.6 g). Recrystallization of chloroform (40 ml) afforded the title compound as a white solid (0.4 g), mp 74-75 ° C.

b) 3- (2-Aminoethyl) -1H-indole-5-methanesulfonamide maleate The product of step a) (0.14 g) was hydrogenated in methanol (10 mL) and over-reduced 10% palladium oxide on carbon (0.08 g) until hydrogen uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by chromatography (F) to give the tryptamine as an oil (0.057 g) treated with maleic acid (0.026 g) in ethanol (5 ml) and methanol (1 ml). The solvent was evaporated and the residual oil was recrystallized from absolute ethanol (2 ml) to give the title compound as a light brown solid (0.03 g), mp 174-175 ° C.

Analysis:

Calcd for C 11 H 15 N 3 ° 2 S * C 4 H 4 O 4: C 48 H 8 5.2 N 11.4.

Found: C 48.6 H 5.2 N 10.7.

TLC (L) Rf 0.37.

EXAMPLE 17 3- [2- (Methylamino) ethyl] -1H-indole-5-methanesulfonamide maleate a) 4- (2- (3-Cyanoprolidene) hydrazino] benzene methanesulfonamide

A thick suspension of the product of Example 15 b) (0.32 g) in water (2 ml) was stirred at room temperature and a solution of 3-cyanopropanal dimethyl acetal (0.26 g) in methanol (1 ml) was added. added followed by addition of hydrochloric acid (2N; 5 drops). Stirring was continued for 3 hours. The resulting off-white solid was filtered off and

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43 dried in vacuo at 20 ° C to give the title compound (0.31 g), mp 175-176 ° C.

b) 3- (Cyanomethyl) -1H-indole-5-methanesulfonamide

A suspension of the product of step a) (3.1 g) and polyphosphate ester (30 g) in chloroform (60 ml) was heated at reflux for 10 minutes and then poured into ice and extracted with chloroform (4 x 20). ml). The combined organic extracts were dried, the solvent was evaporated and the resulting oil was purified by chromatography (G) to give the title compound as a yellow solid (0.32 g), mp 184-185 ° C.

c) 3- [2- (Methylamino) ethyl] -1H-indole-5-methanesulfonamide maleate

A solution of the product of step b) (0.21 g) in ethanolic 15 methylamine (20 ml; 30% v / v) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (0.4 g) (as a 50% aqueous paste) in ethanol (10 ml) at room temperature and atmospheric pressure for 3 hours. The catalyst was removed by filtration (Hyflo®) and the filtrate was concentrated to an oil.

Chroma tograf in (N) and (0) gave the free base as a white solid (0.18 g). This was diluted in hot ethanol (10 ml) and a solution of maleic acid (0.1 g) in ethanol (3 ml) was added.

25 ether (10 ml) was added until a cloudy solution was obtained. On cooling, the title compound precipitated as a cream-colored powder (75 mg), mp 153-154 ° C.

Analysis:

Calcd. For C12 H17 N3 O2 S.C4 H4 O4: C 50.4 H5.0 N 11.0.

Found: C 50.0 H 5.4 N 10.8.

TLC (O) Rf 0.27.

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Example 18 3- [2- (Ethylamino) ethyl] -1H-indole-5-methanesulfonamide hydrochloride, hemihydrate, compound with ethanol (5: 5: 2.5: 1)

A solution of the product of Example 17 b) (0.32 g) in 5-ethanolic ethylamine (30 ml; 33% v / v) was hydrogenated over reduced 10% palladium oxide on charcoal (0.4 g, 50% aqueous paste). ) in ethanol (10 ml) at room temperature and atmospheric pressure overnight. The catalyst was removed by filtration (Hyflo®) and the filtrate was concentrated to an oil (0.30 g). Chromatography (0) gave the free base as a foam (0.28 g). A solution of the tryptamine (0.28 g) in absolute ethanol (10 ml) and methanol (10 ml) was treated with ethanolic hydrogen chloride (ice-cooling) to pH 1, ether (20 ml) was added and the resulting suspension was added. 15 was standing in the fridge overnight. The title compound was filtered off as a white powder (0.24 g), mp 143-144 ° C.

Analysis:

Calculated for C 20HH19 ^ · 30₂S · HCl · 0.5H₂O · 0.2 · C₂H₂O: C 47.9 H 6.7 N 12.5.

Found: C 48.1 H 6.3 N 12.4.

TLC (O) Rf 0.48.

Example 19 3- [2- (Dimethylamino) ethyl] -1H-indole-5-methanesulfonamide hydrochloride, compound with isopropanol (10: 10: 1.5)

A solution of the product of Example 17 b) (0.2 g) in methanolic dimethylamine (1: 1, 20 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (0.4 g, 50% aqueous paste) in methanol (10 ml) at room temperature and

DK 165976 B

45 atmospheric pressure for 5 hours. The catalyst was removed by filtration (Hyflo®) and the filtrate was concentrated to an oil. Chromatography (B) gave the tryptamine as a white foam (0.16 g). Ethanolic hydrogen chloride was added dropwise to a cold solution (ice bath) of the free base in isopropanol (4 ml) (up to pH 4) and the title compound precipitated as a white powder (0.14 g), mp 237-239 ° C .

Analysis:

Calcd for 10 C 13 H 19 N 3 O 2 S * HCl + 15 C 3 H 80: c 49'4 H 6'5 N 12.9.

Found: C 49.1 H 6.5 N 12.6.

TLC (B) Rf 0.23.

Example 20 N-Methyl-3- [2- (methylamino) ethyl] -1H-indole-5-methanesulfonamide, compound with maleic acid and ethanol (10: 10: 1)

A solution of the product of Example 2b) (0.9 g) in dry tetrahydrofuran (20 ml) was added to a suspension of lithium aluminum hydride (0.9 g) in dry tetrahydrofuran (100 ml) and heated for 2 hours at reflux. . The resulting suspension was cooled, treated with a saturated solution of potassium carbonate (ice-cooling) and extracted with methanol (3 x 25 mL) and the extract was concentrated. The residual oil was purified by column chromatography (K) to give the tryptamine as an oil (0.37 g). This was dissolved in absolute ethanol (5 ml) and treated with ethanolic maleic acid (0.5M; 2.6 ml). A sticky precipitate separated. Methanol was added dropwise until a clear solution was obtained, which was then concentrated under reduced pressure to ca. 1 ml and the title compound was crystallized from as an off-white solid (0.2 g), mp 123-124 ° C.

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46

Analysis:

Calcd for C 13 H 19 N 3 O 2 S * C 4 H 4 O 4 * 0.1 C 2 H 6 O: C 51.4 H 5.9 N 10.45.

Found: C, 51.0; H, 5.8; N, 10.1.

EXAMPLE 21 N-Methyl-3- [2- (methylamino) ethyl] -1H-indole-5-methanesulfonamide a) 3- (2-Chloroethyl) -N-methyl-1H-indole-methanesulfonamide

A solution of the product of Example 6 a) (0.25 g) in 10 chloroform (3 ml) was added to a solution of polyphosphate ester (2.5 g) in chloroform (2 ml) and the solution was heated at reflux with stirring for 5 minutes. The solution turned dark yellow. It was then cooled and poured into ice (20 g) and chloroform (5 ml) and stirred. The aqueous phase was brought to pH 8 by the addition of sodium hydrogen carbonate and the organic phase was collected. The aqueous phase was extracted with chloroform (4 x 20 ml) and the extracts were dried over sodium sulfate. Removal of the solvent in vacuo gave the crude 3-chloroethylindole as a light brown viscous oil (0.677 g) used in the next experiment without further purification.

TLC (P) Rf 0.58 (main component), Rf 0.64 (bicomponent).

b) N-Methyl-3- [2- (methylamino) ethyl] -1H-indole-5-methanesulfonamide The product of step a) (0.677 g) was taken up in 33% methylamine in ethanol (25 ml ) and heated in a steel autoclave at 89-90 ° C for 16 hours. The dark yellow solution was concentrated to a light brown oil (1.25 g) and chromatographed (J) to give the title compound (0.039 g)

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47 as a pale yellow glass, shown by NMR and TLC (L) R f 0.4 to be identical to the product of Example 20.

EXAMPLE 22 3- (2-Aminoethyl) -1H-indole-5-methanesulfonamide hemisuccinate A mixture of the product of Example 15 step b) (10.0 g) and 4-chlorobutanaldimethyl acetal (6.23 g) in ethanol (260 ml) and water (53 ml) were stirred at 50 ° C for 1.5 hours. Ammonium acetate (8.69 g) was then added and the resulting milk mixture was heated to reflux and stirred for 3.5 hours. The mixture was then cooled and reduced in volume in vacuo to ca. 30 ml. The orange residue was partitioned between 5N potassium carbonate (800 ml) and ethyl acetate (3 x 500 ml). The combined organic extracts were then washed with 5N potassium carbonate (200 ml) and water (200 ml). The organic solution was then dried over sodium sulfate and concentrated in vacuo. The residual brown oil was chromatographed (J) to give a brown oil which slowly crystallized (2.12 g).

A portion of this material (1.0 g) was dissolved in boiling ethanol (25 ml) and added to a hot solution of succinic acid (0.22 g) in ethanol (15 ml). The solid which crystallized on cooling was filtered off, washed with ethanol (3 x 10 ml) and dried in vacuo at 35 ° C for 6 hours to give the title sulfonamide as light brown microcrystals 25 (1.18 g), m.p. 231.5 ° C (foam). This product was shown by NMR and TLC (J, Rf 0.17) to be identical to the product of Example 15 d).

EXAMPLE 23 48

DK 165976B

3- [2- (Methylamino) ethyl] -N-methyl 1 - 1H-indo 1- 5 -methanesulfonamide maleate 1/4 hydrate.

a) 3- [2- (Formylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide

A mixture of the product of Example 1 c) as the free base (0.534 g) and N-formylimidazole (0.211 g) was stirred in dry tetrahydrofuran (30 ml) for 30 minutes. After removal of the solvent by evaporation under reduced pressure, the residue was partitioned between chloroform and (50 ml) and 2N hydrochloric acid (50 ml). The aqueous phase was made basic using 2N sodium hydroxide (to pH 9) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over sodium sulfate and evaporated under reduced pressure to give a pale yellow gum. This was chromatographed (J) to give the title compound as a colorless gum (0.35 g).

TLC (J) Rf 0.81.

b) 3- [2- (Methylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide maleate, 1/4 hydrate

To a stirred suspension of lithium aluminum hydride (0.77 g) in dry tetrahydrofuran (5 ml) under a stream of nitrogen was added a solution of the product of step a) (0.3 g) in dry tetrahydrofuran (10 ml). The suspension was heated at reflux for 5 hours. To the ice-cold mixture was added water (1 ml) in tetrahydrofuran (9 ml) and the suspension was filtered through a cake of Hyflo®. Evaporation of the filtrate gave a pale yellow gum which was chromatographed (J) to give the tryptamine as a colorless gum 30 (0.15 g). This was dissolved in hot 2-propanol (2 ml) and a solution of maleic acid (0.062 g) in ethanol (1 ml) was added. After cooling, the title compound deposited

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49 as an off-white powder (0.18 g), m.p. 122-124 ° C, identical to the product of Example 20.

Example 24 3- [2- (Ethylamino) ethyl] -N-methyl-1H-indole-5-methanesulfonamide, compound with creatinine and sulfuric acid (1: 1: 1)

A mixture of the product of Example 7 (0.2 g) and acetaldehyde (0.044 g) was stirred in methanol (10 ml) for 15 minutes. To the pale yellow solution was added sodium cyanoborohydride (0.062 g) and the mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid (2 ml) was added and the volume of the solution was reduced to approx. 2 ml by evaporation under reduced pressure. Water (20 ml) was added and the solution was washed with ethyl acetate (25 ml).

The phases were separated and potassium carbonate (5 g) was added to the aqueous phase, which was then extracted with ethyl acetate (2 x 25 ml). Evaporation of the combined organic extracts dried over sodium sulfate gave a pale yellow gum which was chromatographed (J) to give the product as a colorless gum (0.08 g). This was dissolved in ethanol 20 (4 ml) containing water (0.5 ml) and an aqueous solution of creatinine and sulfuric acid (1: 1, 2M, 0.14 ml) was added.

After cooling, the title compound precipitated as a white powder (0.089 g), mp 197-198 ° C.

Calculated for C 14 H 21 N 3 ° 2S, C 4 H 7 N 3 ° H 2 SO 4: C 42'7 H 6 '° N 16/6 ·

Found: C 42.6 H 5.9 N 16.5.

TLC (J) Rf 0.37.

EXAMPLE 25 50

DK 165976B

3- (3-Aminopropyl) -N-methyl 1- 1H-indo-1-methanesulfonamide, compound with hydrogen chloride, water and ether (100: 100: 85: 11).

A) 2- (5,5-Dimethoxypentyl) -1H-isoindole-1,3 (2H) dione

A mixture of ka lumphthalimide (0.48 g) and 5-bromopentanal dimethyl acetal (0.50 g) in dry dimethylformamide (3 ml) was stirred at 90 ° C for 5 hours and then allowed to cool. The resulting yellow suspension was partitioned between water 10 (30 ml) and ethyl acetate (3 x 30 ml). The combined organic extracts were then dried over sodium sulfate and concentrated in vacuo.

The residual pale yellow oil was purified by flash chromatography (silica gel 9385, ether) to give the title compound as a white solid (0.33 g), mp 34.5-37 ° C.

b) 3- (3- (1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) propyl) -N-methyl-1H-indole-5-methanesulfonamide

A suspension of the product of step a) (2.55 g) and the product of Example 1b) (2.50 g) in 10% aqueous acetic acid (200 ml) was stirred at room temperature for 1/2 hour and then at reflux for 1 1/4 hour. The yellow rubbery suspension was allowed to cool and then extracted with ethyl acetate (3 x 200 ml), dried over sodium sulfate 25 and concentrated in vacuo to give an orange foam (3.59 g). This material was used in step c). A portion of this foam (0.50 g) was chromatographed (G) to give the crude title sulfonamide as an orange foam which could not be recrystallized from conventional organic solvents (0.14 g), m.p. 58-66 ° C.

TLC Rf 0.37 (Q).

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(C) 3- (3-Aminopropyl) -N-methyl-1H-indole-5-methanesulfonamide, compound with hydrogen chloride, water and ether (100: 100: 85: 11)

Hydrazine hydrate (3.0 ml) was added to a stirred refluxing suspension of the product of step b) (2.90 g) in ethanol (90 ml) and stirring was continued for 3 hours. The cooled yellow suspension was evaporated in vacuo and the remaining yellow solid was partitioned between 2N sodium hydrogen carbonate (150 ml) and ethyl acetate (3 x 150 ml). The 10 combined organic solutions were then dried over sodium sulfate and evaporated in vacuo.

The remaining yellow foam (1.06 g) was chromatographed (J) to give an orange gum (0.45 g).

A portion of this gum (0.39 g) was dissolved in absolute ethanol (5 ml) and ethanolic hydrogen chloride (1 ml) was added. The stirred solution was diluted with dry ether (about 80 ml) and the precipitated solid was filtered off, washed with dry ether (4 x 15 ml) and dried.

The solid was re-precipitated three times by absolute ethanol (about 15 mL) to give the title salt as a hygroscopic brown solid (0.085 g), mp 212-215ec which slowly became a gum.

Analysis:

Calculated for 25 C3HigN3O2S.HCl. 0.85H2O.0.11C4H1 () 0: C 47.3 H 6.7 N 12.3.

Found: C 47.8 H 6.7 N 12.3.

TLC (J) Rf 0.2.

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EXAMPLE 26 (Intermediate) 52

Phenylmethyl [2- [5 - [[(methylamino) sulfonyl] methyl] -1H-indol-3-yl] ethyl] carbamate

Sodium hydride (80% in oil, 13 mg) was added to a stirred 5 ice-cooled solution of the product of Example 16 step a) (150 mg) in dry dimethylformamide (3 ml) under a nitrogen atmosphere. The suspension was stirred at room temperature for 1/2 hour and then cooled in ice. Methyl iodide (0.03 ml) was added and the solution was stirred at room temperature for 7 hours, with additional methyl iodide (0.03 ml) added after 3 hours. The solution was partitioned between water (30 ml) and ethyl acetate (4 x 20 ml). The combined organic extracts were then washed with water (4 x 20 ml), dried over sodium sulfate and concentrated in vacuo. The remaining 15 brown oil (140 mg) was chromatographed (E) to give the title carbamate as a brown oil (16 mg). This product was shown by NMR and TLC (E, Rf 0.35) to be identical to the product of Example 2 b).

EXAMPLE 27 3- (2-Aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide

To a solution of the product of Example 5 b) (0.1 g) and cobalt chloride hexahydrate (0.19 g) in ethanol (5 ml) was added sodium borohydride (0.15 g) and the resulting suspension was heated to reflux for 1 hour. It was then poured into dilute hydrochloric acid (2N, 10 ml). TLC (F) showed that the solution contained a component Rf 0.26 identical to a sample of the product of Example 1 c).

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53

Pharmaceutical Examples Tablets

These can be prepared by normal methods such as wet granulation or direct pressing.

5 A. Direct pressing mg / tablet

Active ingredient 10 f0

Microcrystalline cellulose USP 188.5

Magnesium stearate BP 1.5 10 -

Pressure weight 200.0

The active ingredient is sieved through a suitable sieve, mixed with the excipients and pressed using pistons 7 mm in diameter.

Tablets with other strengths can be made by changing the press weight and using appropriate pistons.

B. Wet granulation mg / tablet

Active ingredient 10.0 Lactose BP 143.5

Starch BP 30.0

Pregelatinized corn starch BP 15.0

Magnesium stearate BP 1.5 25 Pressure weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate amounts of pure water are added and the powders are granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then pressed

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54 for tablets using pistons 7 mm in diameter.

C. For buccal administration mg / tablet Active ingredient 10.0

Lactose BP 86.8

Sucrose BP 86.7

Hydroxypropyl methyl cellulose 15.0

Magnesium stearate BP 1.5 10 -

Pressure weight 200.0

The active ingredient is sieved through a suitable sieve and mixed with the lactose, sucrose and hydroxypropylmethyl cellulose. Appropriate amounts of pure water are added and the 15 powders are granulated. After drying, the granules are sieved and mixed with the magnesium stearate. The granules are then pressed into tablets using appropriate pistons.

The tablets may be film coated with suitable film-forming materials such as hydroxypropyl methyl cellulose using standard techniques. Alternatively, the tablets may be sugar coated.

Capsules mg / capsule

Active ingredient 10.0 25 * Starch 1500 89.0

Magnesium stearate BP 1.0 Filling weight 100.0 * A form of direct compressible starch.

The active ingredient is sieved and mixed with the excipients. The mixture is filled into hard gelatin capsules of size no.

2 using appropriate apparatus. Other doses may

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55 is made by changing the filling weight and if necessary changing the capsule size accordingly.

Syrup mg / 5 ml 5 dose

Active ingredient 10.0

Sucrose BP 2750.0

Glycerin BP 500.0

Buffer 10 Flavor as needed

Color

Preservatives1

Distilled water up to 5.0 ml

The active ingredient, buffer, flavor, color and preservative are dissolved in some of the water and the glycerine is added. The rest of the water is heated to dissolve the saccharose, and then cooled.

The two solutions are combined, volume adjusted and mixed. The prepared syrup is clarified by filtration.

20 Suppositories

Active ingredient 10.0 mg * Witepsol H15 up to 1.0 g * A proprietary quality of Adeps Solidus Ph. Eur.

A suspension of the active ingredient in molten Witepsol 25 is prepared and filled using appropriate apparatus in size 1 g suppository forms.

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56

Injection for intravenous administration% w / v

Active ingredient 0.2

Sodium chloride BP as needed 5 Water for injection BP up to 100.00

Sodium chloride can be added to adjust the tonicity of the solution and the pH can be adjusted by acid or base to pH for optimum stability and / or to facilitate dissolution of the active ingredient. Alternatively, suitable buffer salts may be used.

The solution is prepared, clarified and filled into ampoules of appropriate size and sealed by melting the glass. The injection preparation is sterilized by heating in an autoclave using one of the acceptable cycles.

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

Inhalation cartridges 20 mg / cartridge

Active ingredient, micronized 1.0

Lactose BP 39.0

The active ingredient is micronized (Microniser® is a registered trademark) in a fluid energy mill to a fine particle size range before mixing with normal tableting quality lactose in a high energy mixer. The powder mixture is filled into hard gelatin capsules # 3 on a suitable sealing machine. The contents of the cartridges are administered using a powder inhaler such as Glaxo Rotahaler®.

Claims (10)

Alk is an alkylene chain containing two or three carbon atoms and optionally substituted with not more than two C1-3 alkyl groups, and physiologically acceptable acid addition salts and solvates thereof. A compound according to claim 1, characterized in that R 2 is -alkyl or C 3-4 alkenyl; and R 4 is hydrogen. A compound according to claim 1, characterized in that R 2 is hydrogen or C 1-3 alkyl. A compound according to claim 1 or 3, characterized in that R1, R2, R4 and R5 are the same or different and each is hydrogen or methyl. A compound according to any one of claims 1-4, characterized in that Alk is - (CH 2) 2 Compound according to claim 1, characterized in that it is selected from 3- (2- (methylamino) ethyl) -N-methyl-1H-indole-5-methanesulfonamide, 3- (2-aminoethyl) -N , N-dimethyl-1H-indole-5-methanesulfonamide and physiologically acceptable acid addition salts and solvates thereof. A compound according to claim 1, characterized in that it is selected from 3- (2-30 aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide and physiologically acceptable acid addition salts and solvates thereof. DK 165976B 59 A compound according to any one of claims 1-7, characterized in that the physiologically acceptable acid addition salt is a hydrochloride, hydrobromide, sulfate, fumarate, maleate or succinate. A compound according to claim 1, characterized in that it is selected from 3- (2-aminoethyl) -N-methyl-1H-indole-5-methanesulfonamide hydrochloride and 3- (2-aminoethyl) -N-methyl -lH-indol-5-methanesulfonyl-benzenesulfonamide hemisuccinate. Pharmaceutical composition, characterized in that it contains at least one compound of the general formula X as defined in claim 1 or a physiologically acceptable acid addition salt or solvate thereof together with one or more physiologically acceptable carriers or excipients.