JPS6322068A - Indole derivative - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

BACKGROUND OF THE INVENTION The present invention relates to indole derivatives, processes for their preparation, pharmaceutical compositions containing them and their medical uses, and in particular to compounds and compositions for the treatment of migraine. .

Migraine pain is associated with excessive dilation of blood vessels in the head, and known treatments for migraine include administering vasoconstricting compounds such as ergotamine. However, ergotamine is a non-selective vasoconstrictor that constricts blood vessels throughout the body and has undesirable and dangerous side effects. Migraines can also be treated with analgesics, usually along with antiemetics, but these treatments are of limited value.

Therefore, there is a need for safe and effective drugs for the treatment of migraine that can be used prophylactically or to alleviate inertia headache, and compounds with selective vasoconstrictor activity may satisfy such a role. Will.

Several compounds with selective vasoconstrictor activity have been disclosed.

British Patent No. 2 CD5310 discloses various 5-carboxamide and thioamide substituted indole derivatives. The compounds are described as having antihypertensive activity, and it is disclosed that certain compounds of the invention can also be used for migraine treatment.

GB 2,082,175 describes various 5-acetamide and 5-thioamide substituted indole derivatives with selective vasoconstrictor activity. British patent number 2
As shown in No. 082175, these compounds selectively constrict the carotid bed in anesthetized dogs and can therefore be used to treat migraine headaches.

[Summary of the invention]

The inventors have discovered novel indole derivatives with effective and selective vasoconstrictor activity.

Compounds of the present invention are indoles of the general formula (1): 1 group RRNSO(CH2), - or group RSo NH(CH2), - (R5 and R6
may be the same or different, and each hydrogen atom or C1
-3 represents an alkyl group, or R5 and R6 together with the nitrogen atom to which they are bonded form a saturated monocyclic 5- to 7-membered ring. R7 represents a C alkyl group. p is 0 or 1). R2 represents a hydrogen atom or a C1-3 alkyl group. R and R4 may be the same or different and each represents a hydrogen atom, a C1-3 alkyl group or a 2-propenyl group. m is O or an integer of 1-4.

n is O or 1 (provided that m and n are not both 0)] and physiologically acceptable salts and solvates (eg, hydrates) thereof.

The present invention includes within its scope all optical isomers of the compound of formula (1) and mixtures thereof, including racemic U compounds thereof. All geometric isomers of the compounds of general formula (I) are also included within the scope of the invention.

It is to be understood that in compounds of formula (1) the substituent R1 may be present in the ortho, meta or para position.

In general formula (1), the alkyl group is a straight chain or branched alkyl group such as a methyl, ethyl or isopropyl group. Substituent R1 may be present in the ortho, meta or para position.

Preferred compounds represented by general formula (1) include R2, R
3, R4, m and n have the abovementioned meanings, and R1 is a group Rc
, R6N-1 ROC(CH2), -・R5R6NCO(CH2)p-1 R5CONH(CH2)p-・R5R6N502(CH2)p- or group R7502NH
(CH2)p (R5 and R6 may be the same or different and each represents a hydrogen atom or a C1-3 alkyl group, and R7 and p have the above meanings).

A preferred group of compounds represented by general formula (1) are compounds in which R2 represents a hydrogen atom or a methyl group.

In the compound of general formula (1), m is 0 or an integer of 1 to 4, preferably 2.

Other preferred compound groups of general formula (I) include R3 and R4
may be the same or different, each hydrogen atom or Cl
-3 A compound representing an alkyl group, for example a methyl or ethyl group.

General formula (I) in which R1 represents R5R6N-.
), R5 and R6 may be the same or different, and each preferably represents a hydrogen atom or a methyl group. When R and R6 together form a saturated monocyclic 5- to 7-membered ring, this is preferably a pyrrolidino ring.

General formula in which R represents a group RSo NH(CH2), - (
In the compound 1), R7 preferably represents a methyl group.

Suitable substituents R1 in compounds of general formula (I) include, for example, the group H2NCOCH2-5CHSo NH-
1H2NCO-1 (CH3)2N-1CH302C-, pyrrolidino and C
There is H3NHSOCH.

In the compound of general formula (I), the substituent R1 is preferably present at the meta or para position.

A particularly preferred group of compounds falling within the scope of general formula (1) is one in which R represents a hydrogen atom, R3 and R4 may be the same or different and each represents a hydrogen atom or a methyl group, and m represents 2; R1 is a group HNC0CH-1CH3S
O2NH-1CHC0NH-1H2NCO-1 (CH) N-1CH302C-1 CHNHSO2CH2-1 or pyrrolidino ring,
This is a compound in which the substituent R1 on the phenyl ring is present at the meta or para position.

Particularly preferred compounds of general formula (I) belonging to this group are:
R is a group (CH3)2N-1 CHOC-1HNCOCH2- or CHC0NH
- represents a compound in which the group R1 is present at the para position.

Preferred compounds of the present invention include 3-(2-aminoethyl)-N-(2-(4-(dimethylamino)phenyl)ethyl)-1H-indole-
5-carboxamide, 4-(2-(((3-(2-aminoethyl)-1H
-indru-5-yl]carbonyl]amino]ethyl
Methyl benzoate and its physiologically acceptable salts and solvates (eg, hydrates).

Suitable physiologically acceptable salts for the indoles of general formula (1) include acid addition salts formed from inorganic or organic acids, such as hydrochloride, hydrobromide, sulfate, nitrate, oxalic acid. salts, phosphates, tartrates, citrates, fumarates, maleates, succinates, and sulfonates such as mesylate. Other salts, such as creatinine sulfate adduct, can be used in the preparation of compounds of formula (I).

It is noted that the invention extends to other physiologically acceptable equivalents of the compounds of the invention, ie, physiologically acceptable compounds that are converted in vivo to the crude compounds. Examples of such equivalents are physiologically acceptable and metabolically unstable N-acyl derivatives.

Uses of the Compounds The compounds of the invention selectively constrict the carotid bed of anesthetized dogs, but produce negligible effects on blood pressure. The selective vasoconstrictor effect of the compounds of the invention was also demonstrated in vitro.

The compounds of the invention are used in the treatment of pain due to dilation of the blood vessels of the head, in particular migraine and cluster headache.

Thus, the present invention provides at least one compound of formula (1) or a physiologically acceptable salt or solvate thereof (
Also provided are pharmaceutical compositions containing (eg, hydrates) suitable for human medical applications and formulated for administration by a convenient route. Such compositions can be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.

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 composition may take the form of a tablet or capsule, for example, and may contain pharmaceutically acceptable excipients, such as binders (
(e.g. corn starch before gelatinization, polyvinylpyrrolidone or hydroxypropyl methylcellulose), fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g. magnesium stearate, talc or silica), disintegrants (e.g. (e.g. potato starch or sodium starch glycolate), or wetting agents (e.g. sodium lauryl sulfate)
manufactured by conventional means. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be prepared as dry preparations for constitution with water or other suitable vehicle before use. Such liquid formulations are prepared by conventional means including pharmaceutically acceptable excipients such as suspending agents (e.g. sorbitol syrup, methylcellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or gum arabic), non-aqueous vehicles. (e.g. almond oil, oily esters or ethanol) and preservatives (e.g. methyl or propyl p-hydroxybenzoate or sorbic acid). Liquid preparations may contain, as appropriate, conventional buffering agents, flavoring, coloring and sweetening agents.

For oral or vaginal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of the invention may also be formulated for parenteral administration by injection or continuous infusion. Injectable formulations are prepared in unit form, eg, in ampoules or in multi-dose containers, with an added preservative.

The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, including suspending agents, stabilizing agents, and/or emulsions.
Alternatively, it may contain formulation agents such as dispersants and/or agents to adjust the tonicity of the solution. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

The compounds of the invention may also be formulated as rectal compositions, such as flattened or retentive complete bowel preparations, containing conventional buffering agents such as cocoa butter or other glycerides.

For administration by inhalation, the compounds of the invention can be formulated into an aerosol spray from a pressurized device or nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It is convenient to release it in the form of In the case of pressurized aerosols, the dosage unit can be metered by providing a valve to dispense a metered amount. Capsules and cartridges, such as gelatin, for inhalation or insufflation are formulated containing a powder mix of a compound of the invention and a suitable powder base, such as lactose or starch.

The suggested dosage for the compounds of the invention when administered orally, parenterally, buccally or rectally to humans (with an average body weight of e.g. about 70 kg) for the treatment of migraine is 0.1 of active ingredient per unit dose. ~100 mg, and this amount is administered, for example, no more than 8 times/day, more commonly 1 to 4 times/day. Routine variations in dosage will be required depending on the age and weight of the patient and the severity of the condition being treated.

For oral administration, the unit dose is 0.5-50 mg.

For example, it is preferable to contain 2 to 40 og of active ingredient. Preferably, a unit dose for parenteral administration contains 0.2 to 5 mg of active ingredient.

The aerosol formulation is such that each measured dose or "-puff volume" emitted from the pressurized aerosol is 0. Each dose containing 2 to 2 Hg of a compound of the invention and administered from a capsule or cartridge in an inhaler or insufflator is 0.2 to 2 Hg.
Preferably, it is formulated to contain 1 g of OII.

The total daily dose by inhalation is in the range 1-100 mg.

The frequency of administration is several times a day, for example 2 to 8 times, with each administration giving for example 1.2 or 3 doses.

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

Preparation of Compounds According to another aspect of the invention, compounds of formula (I), as well as physiologically acceptable salts or solvates (eg, hydrates) thereof, are prepared by the following general method. In the following method, R1, R2, R3, R4, m and n have the same meanings as in general formula (I) unless otherwise specified.

According to one general method (A), a compound of general formula (1) is prepared by combining an amine of formula (n) with an acid of general formula (m): or a corresponding acylating agent, or a salt thereof, e.g. It can be produced by condensation with an organic or inorganic acid addition salt such as hydrochloride, hydrobromide, sulfate or maleate, or a creatinine sulfate adduct) or a protected derivative thereof.

The reaction resulting in the condensation of an amine of formula (n) with an acid of general formula (III) is preferably carried out in the presence of a coupling agent, for example a carbodiimide such as carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide. be done. The condensation reaction is conveniently carried out in a suitable reaction medium, preferably an anhydrous medium, at a temperature of -50 to +50°C, preferably -50°C.
It is carried out at a temperature of ~+30°C. Suitable solvents include:
Examples include halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N,N-dimethylformamide, ethers such as tetrahydrofuran, and mixtures of two or more such solvents.

The reaction, in the absence of a coupling agent, can be carried out in a suitable reaction medium such as a hydrocarbon (eg toluene or xylene), conveniently at a temperature of 50-120<0>C.

Acylating agents corresponding to the general (III) acids used in the preparation of compounds of formula (I) include acid halides such as acid chlorides. Such acylating agents are prepared by reaction of the acid of general formula (III) or a salt or protected derivative thereof with a halogenating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride. Other suitable acylating agents used in the preparation of compounds of formula (I) include:
Alkyl esters such as methyl esters, activated esters (e.g. 2-(1-methylpyridinyl) ester) and mixed anhydrides (e.g. sulfonyl halides such as pivaloyl chloride, methanesulfonyl chloride or lower alkali haloformates) (manufactured from haloformates, etc.). Acids of formula (m) are prepared as such in a manner analogous to method (B) below, for example by cyclization of a suitable hydrazine compound.

If an acylating agent corresponding to the acid of general formula (III) is used, the condensation process is carried out in an aqueous or non-aqueous reaction medium, conveniently at a temperature of -70 DEG to +150 DEG C. For this reason, condensation reactions using acid halides, anhydrides or activated esters can be carried out using amides such as N,N-dimethylformamide, ethers such as tetrahydrofuran or diethyl ether, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, or The reaction is preferably carried out at a temperature of from -5 to +25°C, optionally in the presence of a base such as a tertiary amine such as triethylamine or pyridine. Condensation reactions using alkyl esters include alcohols such as methanol,
It is conveniently carried out in a suitable reaction medium such as an amide such as dimethylamide, an ether such as tetrahydrofuran or diethyl ether, or a mixture thereof, at a temperature of 0 to 100<0>C. In some cases, the amine of formula (n) may itself act as a reaction solvent.

According to another general method (B), the compound of formula (1) is
Compound of general formula (IV): [In the above formula, Q is a group NR3R4 (or a protected derivative thereof)
or leaving atoms such as halogen atoms or groups (e.g. chlorine or bromine) or acyloxy groups (e.g. acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy,
acyloxy groups of carboxylic or sulfonic acids such as p-toluenesulfonyloxy or methanesulfonyloxy groups).

The reaction is conveniently carried out in an aqueous or non-aqueous reaction medium over 20 to
It is carried out at a temperature of 200°C, preferably 50-125°C.

Particularly preferred embodiments of general method (B) are described below.

When Q is a group NR3R4 (or a protected derivative thereof),
The method preferably includes, in the presence of a polyphosphoric acid ester,
It is carried out in a reaction medium consisting of one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichloromethane, dichlorodifluoromethane or mixtures thereof.

A mixture of polyphosphoric acid esters, referred to as "Reagent for Organic Synthesis" (Feeser and Feeser, John Wiley & Sons, 1967) ("Reagent").
s for Organlc, 5ynthesis'',
(Fleserand Flcscr, John
It is prepared from phosphorus pentoxide, diethyl ether and chloroform by the method described in [Wllcy and 5ons 1967].

Alternatively, the cyclization can be carried out in an aqueous or non-aqueous reaction medium in the presence of an acid catalyst. If an aqueous medium is used, this may be an aqueous alcohol (e.g. methanol, ethanol or isopropanol), an aqueous ether (e.g.
dioxane or tetrahydrofuran) and mixtures of these solvents, and the acid catalyst is an inorganic acid such as concentrated hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid (in some cases, the acid catalyst is It can also be used as a solvent.) In aqueous reaction media which may contain one or more ethers (e.g. those mentioned above) or esters (e.g. ethyl acetate), the acid catalyst is usually a Lewis acid catalyst such as boron trifluoride, zinc chloride or magnesium chloride. It is an acid.

When Q is a leaving group such as a chlorine or bromine atom, the reaction is carried out with an acid in an aqueous organic solvent such as an aqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueous aether (e.g. dioxane or tetrahydrofuran). It can conveniently be carried out in the absence of a catalyst at temperatures of 20 to 200<0>C, preferably 50 to 125<0>C.

In this method, the formula (
A compound of I) is produced.

According to one particular embodiment of general method (B), the compound of formula (1) is a compound of general formula (V).

or a salt thereof, and a compound of formula (Vf): OHC(CH2) 3Q (VI) (wherein Q has the same meaning as above) or a salt or protected derivative thereof (e.g. from a suitable alkyl orthoformate or diol) acetal or ketal, such as formed, or protected as a bisulfite addition complex) - prepared directly using suitable conditions as described above for the cyclization of a compound of formula (IV). can do.

It is noted that in this embodiment of the cyclization process (B), the compound of general formula (IV) can be prepared as an intermediate and reacted in situ to prepare the desired compound of general formula (1).

The compound of general formula (TV) can, if desired, be isolated as an intermediate in the process of preparing the compound of formula (1), but this process does not include the compound of formula (V) or its salt or When the protected derivative is stored in a suitable solvent such as an aqueous alcohol (e.g. methanol) at a temperature of e.g. Refers to the process of reacting with derivatives. If an acetal or ketal of a compound of formula (Vl) is used, it is necessary to carry out the reaction in the presence of an acid (eg acetic acid or hydrochloric acid).

Compounds of general formula (V) can be prepared by conventional methods, for example from the corresponding nitro compounds.

In another general method (C) for producing the compound of general formula (I), the compound of general formula (■): R1 (in the above formula, Y is an easily substitutable group) or its protection The derivative is reacted with an amine of formula R3R4NH.

The substitution reaction is conveniently carried out on a compound of formula (■), in which the substituent Y is a halogen atom (e.g. chlorine, bromine or iodine) or a group oR8 (OR8 is derived from, for example, a carboxylic acid or a sulfonic acid). acyloxy groups such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy groups).

The substitution reaction is performed using alcohols such as ethanol, cyclic ethers such as dioxane or tetrahydrofuran, acyclic ethers such as diethyl ether, esters such as ethyl acetate, amides such as N,N-dimethylformamide, and in an inert organic solvent such as acetone or ketones such as methyl ethyl ketone (optionally in the presence of water), -
It is convenient to carry out at temperatures of 10 to +150°C, preferably 20 to 50°C.

The compound of general formula (■) in which Y is a halogen atom is an acid (
For example, by reacting a hydrazine of general formula (V) with an aldehyde or ketone of formula (Vl) (or a protected derivative thereof) in which Q is a halogen atom in an aqueous alkanol (e.g. methanol) containing acetic acid or hydrochloric acid. can be manufactured.

Compounds of formula (■) in which Y is a group oR8 can be prepared from the corresponding compound in which Y is a hydroxyl group using a suitable activated N (e.g. anhydride or sulfonyl chloride) using conventional methods.
It can be produced by acylation or sulfonylation with. Under standard conditions, the alcohol intermediate has the formula (IV) where Q is a hydroxyl group (or a protected derivative thereof).
is produced by cyclization of the compound.

The compound of formula (I) is a compound of general formula (■): (in the above formula, W provides the necessary -(CH2)2NR3R4 group or -(CH2)2
or a salt or protected derivative thereof, which can be reduced to give a protected derivative of NR3R4.

-(CH2)2- and -NR3R4 required in the 3rd position
The groups can be formed by reduction steps carried out separately or simultaneously in any suitable manner.

Examples of the group represented by the substituent W include -(CM)
No -CH■CHNO2,222ゝ-(CH”) N -CH2CN.

223ゝ-CHCHO, -COCH2Z-1 -CH2CH-NOH and -CH(oH)CH2NR3R4 are al (Zlt7 dido group, group -NR3R4 or a protected derivative thereof).

Groups that are reduced to -(CH2)2 moieties in the 3-position include the corresponding unsaturation -1 and the corresponding groups with hydroxyl or carbonyl functionality.

Groups that are reduced to the group -NRR (R and R4 are both hydrogen) include nitro, azide, L-droxyimino and nitrile groups. In the latter case, reduction leads to the group -CH2
NH2 is produced, thereby giving -(CH2)2 part of the methylene group.

The required -NRR group in which R and/or R4 are other than hydrogen can be nitrile -CH in the presence of the amine R3R4NH.
Formed by reduction of 2CN or the aldehyde -CH2CHO.

A particularly suitable method for preparing compounds of formula (1) in which R and/or R4 are other than hydrogen is the suitable reaction of the corresponding compounds in which R3 and/or R represent hydrogen in the presence of a suitable reducing agent. reductive alkylation with aldehydes or ketones such as formaldehyde or acetone. In some cases (e.g. the introduction of groups R3 and/or R4 representing methyl), an aldehyde (e.g. formaldehyde) is condensed with an amine and the intermediate thus obtained is then reduced using a suitable reducing agent. .

It is noted that the choice of reducing agent and reaction conditions depends on the nature of the groups W and other groups present in the molecule.

W is, for example, a group -(CH2)2N02, -CH-CHN
o -(CH2) 2N3.2ゝ-CHCN, -CH2CN-NOH and -CH(OH)
Suitable reducing agents used in the above process for the reduction of the compound of formula (■) representing CH2NR3R4 include, for example, platinum, platinum oxide, palladium, palladium oxide or rhodium which can be supported on activated carbon, diatomaceous earth or alumina. Hydrogen in the presence of a noble metal catalyst such as Raney nickel or a metal catalyst such as Raney nickel. In the case of Raney nickel, hydrazine can be used as the hydrogen source. The process is carried out in a solvent such as an alcohol such as ethanol, an ether such as dioxane or tetrahydrofuran, an amide such as dimethylformamide or an ester such as ethyl acetate at a temperature of -10 to +50°C, preferably -5 to +30°C. This is convenient.

In the reduction method, W is a group such as -(CH2)2NO2, -CH-CHNo2, -(CH
2) 2N3. -CH(OH)CH2NR3R4 or -COCH2Z (Z is the same meaning as above) formula (
In the compound of (ii), borohydride or cyanoborohydride can also be carried out using an alkali metal or alkaline earth metal such as sodium or calcium cyanoborohydride; It is convenient to carry out the reaction in an alcohol such as ethanol or nitrile, such as acetonitrile, at a temperature of 10 to 100° C., preferably 50 to 100° C. In some cases, reduction with borohydride can be carried out in the presence of cobaltous chloride.

Reductive alkylation of the compound of formula (■) is carried out using an alkali metal or alkaline earth metal borohydride or cyanoborohydride. The reaction is carried out in an aqueous or non-aqueous reaction medium, conveniently an alcohol (eg methanol or ethanol) or an ether (eg dioxane or tetrahydrofuran), optionally in the presence of water.

It is convenient to carry out the reaction at a temperature of 0 to 100<0>C, preferably 5 to 50<0>C. In one specific embodiment of general formula (D), W is converted into a group by catalytic reduction with hydrogen in the presence of a catalyst such as palladium on charcoal or rhodium-supported alumina, and optionally in the presence of an amine NMR3R4. The formula (■
) is involved in the reduction of the compound. Reduction can be carried out in a suitable solvent such as an alcohol such as methanol or ethanol.

The compound of general formula (I') in which R4 is a hydrogen atom has 10
? It can also be produced by hydrogenolysis of a corresponding compound in which R4 is a benzyl group with hydrogen in the presence of a catalyst such as 6-palladium on carbon.

W is -(CH2)2N02, -CH-CHNo2, -CH2CN or -COCH2Z
The starting material or intermediate compound of formula (■) representing
Edited by Houlihan, 1972, Wiley Interscience, New York ["A Chemistry o
f' l1eterocycllcCoLIlpoun
ds-Indoles Part It', Chap
ter Vl.

edited by W, J, I! oulihan
(1972) Wiley Inter-scientific
E, New York].

Compounds of formula (■) in which W is a group -CH2CHO are prepared by oxidation (e.g. with Jones' reagent) of compounds of formula (■) in which Y is a hydroxyl group. Compounds of formula (■) in which W is the group -CH2CH-NOH are prepared by treatment of the corresponding aldehyde with hydroxylamine hydrochloride under standard conditions.

Intermediate compounds of formula (■) in which W is a group -(CH2)2N3 can be prepared by standard methods to intermediate compounds of formula (■) in which Y is a halogen atom.
■) Manufactured from the compound.

Standard reducing agents such as sodium borohydride can be used to prepare compounds of formula (■) where W is a group -CH(OH)CH2NR3R4 from corresponding compounds of formula (■) where W is a group -COCH2NR3R4. can be used.

According to another general method (E), a compound of formula (1) or a salt or protected derivative thereof according to the invention is converted into another compound of formula (I) by conventional methods.

For example, a compound of general formula (1) in which one or more of R2, R3, and R4 is an alkyl group can be obtained from a compound of formula (1) in which one or more of R2, R3, and R4 is a hydrogen atom,
Compound L (R is the desired x
R2, R3 or R4 group of . Alkylating agents are, for example, alkyl halides (eg methyl or ethyl iodide), alkyl tosylates (eg methyl tosylate) or dialkyl sulfates (eg 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. It is. 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, sodium or potassium methoxide, ethoxide or t-butoxide. and tetrabutylammonium fluoride. When an alkyl halide is used as the alkylating agent, the reaction can be carried out in the presence of an acid scavenger such as propylene or ethylene oxide.

The reaction is conveniently carried out at a temperature of -20 DEG to 100 DEG C.

Formula (where one or both of R3 and R4 represent propenyl)
Compounds of I) are similarly prepared using appropriate compounds of formula RL or (Rx)2S04.

According to another embodiment of general method (E), R1 is a group R5C
0NH(CH2), - or the general formula representing the group R7S 02 N (CH2) p- (
The compound of 1) is a corresponding compound of the general formula (1) in which R1 represents H2N (CH2) p-, and a group R5C〇- or R
It can be produced by reacting with a 75O2- introduction agent. Suitable reagents include acids of formula R5C0OH, acylated derivatives thereof and sulfonylating agents corresponding to acids of formula R7503H.

Acid R5C0OH used in this embodiment of general process (E)
and derivatives of R75O3H, general method (A)
These include acid halides such as carboxylic acid chlorides and sulfonyl chlorides, mixed anhydrides, alkyl esters, and activated esters such as 2-(1-methylpyridinyl) ester, as described above. The acylation reaction with an acid of formula R5C0OH, its acylated derivative or a sulfonylating agent corresponding to the acid R7S 03 H can be carried out according to the general method (
It is carried out using reaction conditions similar to those described above for A).

According to another embodiment of general method (E), R1 is a group R5R
A compound of general formula (1) representing 6NC0(CH2)p- can be produced by reacting a corresponding compound of general formula (1) where R1 represents R502(CH2), - with an amine R5R6NH. The displacement reaction with an amine of formula R5R6N H is carried out using reaction conditions similar to those described above for general method (C).

Compounds of general formula (I) in which R□ represents H2N- can also be prepared by another general process (F) consisting of reduction of a compound of general formula (X): i.

Reduction is carried out, for example, with hydrogen in the presence of a metal catalyst. The catalysts used are noble metal catalysts such as platinum, platinum oxide, palladium, palladium oxide or rhodium or Raney nickel, which can be supported on activated carbon, diatomaceous earth or alumina. In the case of Raney nickel, hydrazine can be used as the hydrogen source. Reduction in general method (F) involves alcohol such as ethanol,
It is convenient to carry out in a solvent such as an ether such as dioxane or tetrahydrofuran, an amide such as dimethylformamide, an ester such as ethyl acetate. The reduction is carried out at a temperature of -10 to +50°C, preferably -5 to +30°C.

Compounds of general formula (X) can be prepared by cyclization of the corresponding hydrazine as described in method (B). Alternatively, the compound of formula (X) where n is 0 is an indole of general formula (XI): ), the formula (Xll)
The compound: can be produced by reacting with -carbon oxide and a palladium catalyst.

The reaction can also be carried out in the presence of a base.

Palladium catalysts include, for example, palladium salts obtained from organic acids such as acetates or from inorganic acids such as chlorides or bromides, triads such as triphenylphosphine or tri(2-methylphenyl)phosphine palladium complexes, There are palladium complexes, such as lylphosphine complexes, or finely divided palladium metal, such as palladium on charcoal. Triarylphosphine palladium complexes can be prepared by reacting a palladium salt such as palladium acetate or palladium chloride with an appropriate triarylphosphine.
Can be generated on the spot. The reaction is carried out in the presence or absence of a solvent.

Suitable solvents include nitriles such as acetonitrile;
Examples include alcohols such as methanol or ethanol, amides such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide, and water. The reaction is 11
It is convenient to carry out at temperatures between 0 and 150<0>C.

According to another general method (G), the general formula (I) of the invention
The compound or its salt can be produced by subjecting the protected derivative of general formula (1) or its salt to a protecting group elimination reaction. .

Therefore, in order to avoid undesirable side reactions, it is necessary to protect one or more unstable groups in the molecule at an early stage in the reaction process for producing the compound of general formula (1) or its salt. desired. For example, protonation (pro
It is necessary to protect the group NRR (R and/or R represents hydrogen) with a group that can be easily removed by tonation ) or at the end of the reaction process. Such groups include, for example, aralkyl groups such as benzyl, diphenylmethyl or triphenylmethyl, acyl groups such as N-benzyloxycarbonyl, t-butoxycarbonyl or phthaloyl.

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

The subsequent removal of the protecting group is carried out in a conventional manner.

Thus, aralkyl groups such as benzyl are removed by catalysis (e.g. palladium on charcoal) or hydrogenolysis in the presence of sodium and ammonia, and N
The acyl group, such as -benzyloxycarbonyl D, is removed, for example, by 10-water decomposition with hydrogen bromide in acetic acid, or by undergoing reduction, for example catalytic reduction. Phthaloyl groups are removed by hydrazinolysis (eg, treatment with hydrazine hydrate) or by treatment with -class amines (eg, methylamine).

In some cases of the above general methods (A) to (F),
As mentioned above, it may be necessary or desirable to protect unstable groups in the molecule. Therefore, the reaction steps necessary for the deprotection of the protected derivative of general formula (1) or a salt thereof are carried out after the above-mentioned methods (A) to (F).

According to another aspect of the invention, the following reactions may be carried out in a suitable order, if necessary and/or desired, by methods (A) to (
F) is carried out after: (i) removal of the protecting group, and (11) formation of the compound of general formula (1) or a physiologically acceptable salt or solvate thereof (e.g. hydrate) Conversion to.

If it is desired to isolate a compound of the invention as a salt, e.g. an acid addition salt, the free base of general formula (1) may be combined with a suitable acid in a suitable solvent (e.g. aqueous ethanol). Preferably, it is carried out by treating with equal or more atinine sulfate.

Starting materials or intermediate compounds for the preparation of the compounds of the invention are:
It can be manufactured in a manner similar to that described in GB 2035310.

In the same way as used as the last main step in the manufacturing steps, the general method described above for the preparation of the compounds of the invention can be used to introduce the desired group at an intermediate step in the preparation of the required compounds. You can also use it. For example, the necessary group at the 5-position is introduced either before or after the cyclization to form the indole nucleus. It is therefore noted that in such multi-step reactions, the reaction order should be chosen such that the reaction conditions do not influence the groups present in the molecule desired in the final product.

The following examples are intended to explain the invention in more detail. All temperatures are in °C.

Chromatography was performed conventionally using silica gel (Merck, Kieselgegel 80, Item No. 7734) or silica (Merck 9385) unless otherwise indicated.
) and flash chromatography on silica [Macherly-Nagel
), by thin layer chromatography (TLC) on Polygram).

Intermediate 1 3-(2-(dimethylamino)ethyl] -N-(2-
(4-nitrophenyl)ethyl)-1H-indole-
5-Carboxamide 5-iodo-N in dry acetonitrile (5 ml).

N-dimethyl-IH-indole-3-ethylamine (
100mg), I)-nitrophenethylamine (801
I1g), tributylamine (0.3ml) and dichlorobis(triphenylphosphine)palladium(II)
) (24 mg) under carbon monoxide atmosphere.
Stir at reflux for an hour and then at room temperature overnight (16 hours). The solvent was removed under reduced pressure in the presence of silica gel (Merck 9385). Impregnated silica was applied to a silica column (Merck 9385) as a packing material, and dichloromethane-ethanol-
Elution with ammonia (75:8:1) gave the title compound (47a+g) as an oil.

TLC silica, dichloromethane-ethanol-aqueous ammonia (75:8:1) Rf O,19 (main component),
Detection uv, I PA% KMnO4 Intermediate 2 3-(2-(dimethylamino)ethyl)-1H-indole-5-acetic acid 3-(2-(dimethylamino)ethyl)-IH in 2N sodium hydroxide (80 ml) A suspension of -indole-5-carbonitrile oxalate (5,6 g) was heated at 80'' for 4 hours. The reaction mixture was adjusted to pH by dropwise addition of concentrated hydrochloric acid.
7 and the reaction mixture was evaporated under reduced pressure. The residue was extracted with a methanol-chloroform (1:10) mixture, filtered and concentrated under reduced pressure to give a foam (4.0 g).

Actual value: C, 66, 1, H, 8, 0; N, 10. 3 ;C
HNO・0.2H20°14 1ta 2 2 0.3C2H60 calculated value: C, 66, 5; H, 7, 7, N, 10. 6%.

H,O analysis content 1.5% H-Ow / w -0,
2 mol H2O.

Example I N-[2-(4-aminophenyl)ethyl]-3-(2
-(dimethylamino)ethyl] -IH-indole-
5-carboxamide 10% P d o / in absolute ethanol (10 ml)
A suspension of C (1 g of 50% water paste 34II) was stirred in a hydrogen atmosphere at room temperature under pressure for 0.5 hour. ethanol(
A solution of Intermediate 1 (98+ng) in 7ml) was added and the mixture was stirred for 4 hours. After the catalyst was removed, the furnace liquid was concentrated under reduced pressure to obtain an oil (approximately 100 mg), which was mixed with silica gel (
Purified by Merck product number 9385) column chromatography. Elution with isopropyl alcohol-diethyl ether-water-aqueous ammonia (20:20:8:1) gave the title compound (50mg) as a foam.

TLC silica, isopropyl alcohol-ether-water-ammonia (20:20:8:1) Rfo, 30,
Detection uv, IPA NMRδ (DMSO-d6) δ2.30 (6-H
, s, NMe2); 2.60 (2H, brt.

CHNMe 2); 2.70 (2H, b r t
.

□2 phdan H2); 2.90 (2H, brt.

-CHCHNMe2); 4.86 (brs.

□22 NH2); 8.38 (IH,br t, NdanCo) and 11.04 (IHbrs Indole N
H) Example 2 N-(2-C4-(acetylamino)phenyl]ethyl]-3-[2-(dimethylamino)ethyl]-IH
-indole-5-carboxamide acetyl chloride (0,
32 ml) of the product of Example 1 (
It was added dropwise to a stirred solution of 1.6 g) over 10 minutes at Oo under a nitrogen atmosphere.

The solution was warmed to room temperature and stirring continued for 17 hours.

The reaction was stopped by adding water and the resulting solution was stirred for 0.5 h. The solvent was removed under reduced pressure (the last traces of water were azeotropically distilled with toluene) and the residue was dissolved in methanol (20 ml). A powder was obtained by concentrating the solution under reduced pressure in the presence of silica gel (Merck Product No. 7734), which was applied as a filler to a silica column (Merck Product No. 9385).

Dichloromethane-ethanol-aqueous ammonia (50:
8=1) and the title compound (634m
g), which was further purified by HPLC to give the title compound (174+ng) as a foam.

TLC silica, dichloromethane-ethanol-aqueous ammonia (25:8:1) Rf O,38, detection uv,
IPA actual value: C, 66, 9iH, 7, 2; N, 13. 2CHN
OO, 3C2H60°23 28 4 2' 0.8H20 calculated value: C, 67, 4; H, 7, 5, N, 13. 3% cases
3 3-C2-C dimethylamino)ethyl] -N-[2-
(4-((Methylsulfonyl)amine]phenyl]ethyl)-IH-indole-5-carboxamidopyridine (694 ■) in a cold (approximately 10') stirred solution of the product from Example 1 in 15 ml of nitrogen atmosphere. Methanesulfonyl chloride (0.28 ml) was processed.

Stirring was continued for 26 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethanol (approx. 20ml). Water (about 10m
1) was added to the solution followed by solid potassium carbonate until two layers were observed. The aqueous phase was separated from ethanol (2X10ml
) and then the combined organic phases were concentrated under reduced pressure to give an oil (approximately 1.5 g). Isopropyl alcohol-diethyl ether-water-aqueous ammonia (
65:120:16:2) to give the impure title compound (364 mg) as an oil and the pure title compound as an oil, which was closed with dry ether, Solid object (1
000g) mp106-109° (decomposition) was obtained.

TLC alumina, isopropyl alcohol-diethyl ether-water-ammonia (65:120:16:2)R
f O, 7, Detected uvS IPA actual value: C, 58, 6, H, 6, 7, N, 12. OCH
NOS, 0.5C2H60°0.95H20 Calculated value: C, 59,0, H, 7,0, N, 12.0% Example 4 4-[2-([(3-(2-aminoethyl)- 1H
-indru-5-yl]carbonyl]amino]ethyl]
Methyl benzoate/1/2 succinic acid/hydrate (4:2
: 3) (1) 4- (2-[((3-(2-[((phenylmethoxy)carbonyl]amino]ethyl]-IH-indol-5-yl]carbonyl]amino]ethyl)methyl benzoate 3- (2-(((phenylmethoxy)carbonyl)
Amino]ethyl-IH-indole-5-carboxylic acid solution was diluted with 1.1'-carbonyldiimidazole (0,32
4g) and stirred for 2 hours at room temperature (solution A). A suspension of methyl 4-(2-aminoethyl)benzoate hydrochloride (0,435 g) in anhydrous tetrahydrofuran (20 ml) was treated with triethylamine (0,28 ml) and stirred for 1 hour at room temperature (suspension B). ).

Suspension (B) was added to solution (A) and stirred at room temperature for 48 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to obtain a gum (approximately 1.3 g), which was coated with silica gel (Merck 77
34) Chromatographed and eluted with isopropyl acetate. Separating the product as crystals from the appropriate components;
Collected, dried, the title compound (0.34 g) mp151
-153° was obtained.

(ii) 4-[2-[[[3-(2-aminoethyl)-IH-indol-5-yl]carbonyl]amino]
ethyl] methyl benzoate, 1/2 succinic acid, hydrate (4
: 2 : 3) A suspension of ethanol 910% palladium oxide on carbon (50% water paste 0.35 g) was reduced in advance by stirring for 0.5 hour under a hydrogen atmosphere.

Product of step (i) (0,3
A solution of 33 g) was added to the catalyst suspension and the mixture was stirred under an atmosphere of hydrogen for 0.75 h until hydrogen uptake (18 ml) ceased. The catalyst and solvent were removed by filtration and rotary evaporation, respectively, and the free base (0,22
g) was obtained. Free base (0.22 g) in hot isopropanol (2 ml) was dissolved in hot isopropanol (2 ml).
The mixture was treated with a hot solution of succinic acid (0.037 g). (
After removal of the solvent (by evaporation under reduced pressure), the residue was triturated with anhydrous ether to give the title compound mp17 as a powder (0,225 g).
0-5° was obtained.

TLC silica, dichloromethane-ethanol-ammonium hydroxide (35:8:1) Rf O,4, detection uv
, IPA Actual measurements: C, 63, O, H, 6,05, N, 8.99 C, HN
O0,5C4H604°21 23 3 3' 0°75H,O calculated value: C,63,07;H,6,33;N, 9. 59 Example 5 3-(2-aminoethyl)-N-(2-C4-(dimethylamino)phenyl]ethyl)-LH-indole-
5-carboxamide-dihydrochloride (1) [2-(5-[[
2-(4-dimethylaminophenyl)ethyl]amino]
phenylmethyl[carbonyl]-IH-indol-3-yl)ethyl]carbamate φl/dihydrate 3-[2-[[
(phenylmethoxy)carbonyl]amino]ethyl]
A solution of -IH-indole-5-carboxylic acid (1,69 g) was added to a solution of N,N'-carbonyldiimidazole (0,
89 g) and heated to reflux with stirring for 1 hour.

A solution of 2-(4-dimethylaminophenyl)ethylamine (0.82 g) in anhydrous tetrahydrofuran (10 ml) was added to the solution and the mixture was stirred at room temperature for 20 hours.

The solution was evaporated to dryness under reduced pressure and the residue was mixed with water (150ml) and extracted with ethyl acetate (4X40ml).

The combined extracts were mixed with an 8% aqueous sodium bicarbonate solution (3
Wash with 30 ml of MgSO4) and dry.
Evaporation gave a gum (2,5+r). This material was chromatographed on silica gel (200 g, Merck 77B4) and isopropyl acetate/petroleum ether (b
p60-80°) (1:1) then eluted with isopropyl acetate. By evaporation of the appropriate components, a solid (2.3 g) is obtained.
This was triturated with anhydrous ether to give the title compound (1.86 g) mp139-142'' as a powder.

TLCfuran, dichloromethane-ethanol-0,88
Ammonium hydroxide (100:8:1) RfO,45,
Detection uv, IPA (11) 3-(2-aminoethyl)-N-C2-(4-
(dimethylamino)phenyl]ethyl]-1H-indole-5-carboxamide dihydrochloride ethanol (50
A suspension of 10% palladium oxide on carbon (50% water paste 1.0+r) in ml) was pre-reduced under hydrogen atmosphere with stirring for 0.5 h.

Product (1) of step (1) in ethanol (100 ml)
0 g> was added to the pre-reduced catalyst and the mixture was stirred under hydrogen for 1.5 hours until hydrogen uptake (60 ml) ceased.

The catalyst and solvent were removed by filtration and rotary evaporation, respectively, to give a gum (0.9 g), which was subjected to column chromatography on silica gel (100 g of Merck 7734) and dichloromethane/ethanol 10.88 ammonium hydroxide (50/ 8/1). Evaporation of the appropriate components gives the title compound free base (0
, 65g) was obtained. This material (0,65 g) was mixed with hot ethanol (20 ml) treated with excess ethereal hydrogen chloride.
) and diluted with ethyl acetate (2Qml). The solution was concentrated until it started to become cloudy, cooled and a solid crystallized out. After removing the solid material, add it to ethyl acetate (10 ml).
The title compound (0,415
g) mp210-212° was obtained.

TLC silica, dichloromethane-ethanol-0,88
Ammonium hydroxide (25:8:1) RfO, 45, detection UV, IPA actual value: C, 55,83; H, 6, 34°N, 12. 01, CI, 18. 64C2
, H28N40.2HC1,0,6H20°0.4HC
1 Calculated value: C, 56,20; H, 6,65; N, 12.48. CI, 18.95% Example 6 3-(2-Aminoethyl)-N-[(4-(1-pyrrolidinyl)phenylcomethyl]-IH-indole-5
-Carboxamide I/2 succinate (i) (2-
(5-[[[[4-(1-pyrrolidinyl)phenyl]methyl]amino]carbonyl] -1H-indru3-
phenylmethyl[yl]ethyl]carbamate 3-[2-[[
(phenylmethoxy)carbonyl]amino]ethyl]
A solution of -IH-indole-5-carboxylic acid (1,69 g) was added to a solution of 1,1-carbonyldiimidazole (0,89 g).
) and heated under reflux for 1 hour. A solution of 4-(1-pyrrolidinyl)phenylmethylamine (0.88 g) in anhydrous tetrahydrofuran (10 ml) was added and the resulting solution was stirred at room temperature for 48 hours. The mixture was evaporated to dryness under reduced pressure to give a foam (>2.4 g) which was chromatographed in petroleum ether (bp 60-80') and petroleum ether (bp 60-80')/isopropyl acetate (1: Purified by elution with 1). Evaporation of the appropriate fractions gave the title compound (0,8'zr) as a powder.
mp154-157' was obtained.

(ii) 3-(2-aminoethyl)-N-[(4-(1
-pyrrolidinyl)phenylcomethyl] -1H-indole-5-carboxamide 1/2 succinate 10% palladium oxide on carbon (
A suspension of 0.8 g of 50% water paste was heated under a hydrogen atmosphere.
Stirred for 65 hours. Step in ethanol (100ml) (
A solution of the product of i) (0.75 g) was added to the suspension of the prereduced catalyst and the i) mixture was stirred for 4 hours under an atmosphere of hydrogen. The suspension was filtered and the filtrate was evaporated under reduced pressure to obtain a gum (0.35 g), which was subjected to silica column chromatography and dichloromethane/ethanol 10.8 g.
8 Ammonium hydroxide mixture (200/8/1 to 25/
8/1). Evaporation of the appropriate fractions gave the free base of the title compound as a gum, which was converted into a solid (0,
079g). Free base (0,079sr
) in propatool (2 ml) and methanol (3 ml).
ml) in a hot mixture of isopropanol (2 ml
) in a hot solution of succinic acid (0,0134 g).

Upon concentration of the solution and subsequent cooling, the title salt crystallized out as a solid (0,056 g) mp234-8@.

Actual value: C, 67,99; H, 7,08; N, 13.03; CHN 00C2H302 calculated value: C, 68,39; H, 6,93; N, 13.29% Example 7 N-(2 -[4-(2-amino-2-oxoethyl)phenyl]ethyl] -3-[2-(dimethylamino)
Ethyl]-IH-indole-5-4-[(aminocarbonyl) in dry 1,4-dioxane (50 ml)
A suspension of [methyl]benzeneacetic acid (1.58 g) was added to
It was then cooled and treated with dry pyridine (1.3 ml) followed by trifluoroacetic anhydride (2.31 ml). The resulting solution was stirred for 1.5 hours under a nitrogen atmosphere at less than 15°C. Water (10ml) was added to the solution and the solvent was removed under reduced pressure.

The residue was dissolved in water (100 ml) and ethyl acetate (100 ml).
Separate the aqueous layer and add ethyl acetate (100ml)
Extracted with. Dry the combined extracts M g S
O4) was concentrated under reduced pressure to give a solid (approximately 3 g), which was purified by flash chromatography. Elution with 1% acetic acid in dichloromethane gave the ms compound mpH6-117@(200■) and mpH5- as a crystalline solid.
Two samples of 117@ (500 mg) were obtained.

(11) 4-(Cyanomethyl)benzeneacetamideProduct of step (1) in dry tetrahydrofuran (11
To a stirred fine suspension of 5a+g) was added triethylamine (0.175 ml) and then diphenylphosphoryl azide (0.28 ml) at room temperature under a nitrogen atmosphere. A saturated solution of ammonia in dry tetrahydrofuran (10ml) was added to the reaction mixture and stirring continued for 5 hours. Remove the solvent under reduced pressure,
The residue was purified by flash chromatography eluting with dichloromethane 2910% acetic acid to give the title compound (approximately 30 mg) as a solid, mp 158-160'' (
Decomposition) was obtained.

(lll) 4-(2-Aminoethyl)benzeneacetamide hydrochloride The product of step (Ii) (136a+g) in ethanolic hydrogen chloride (10 ml) was dissolved in absolute ethanol (10 ml) under 1 atmosphere of hydrogen at room temperature for 30 hours. 10 pre-redeemed
% palladium oxide on carbon (50% water base) 150mg)
Hydrogenated with. The catalyst is removed from the furnace, the furnace liquid is evaporated under reduced pressure,
The impure title compound (approximately 40 mg) was obtained as a solid.

The catalyst was washed with hot ethanol (100 mg) and the ethanolic solution was concentrated in vacuo to give more pure title compound (133 mg) as a crystalline solid.

TLC silica, dichloromethane-ethanol-acetic acid (1
50:8:1) Rf O,08, detection uv.

PA (iv) N -(2-(4-(2-amino-2oxoethyl)phenyl)ethyl] -3-(2-(dimethylamino)ethyl) -IH-indole-5-carboxamide oxalate diphenylphosphoryl azide (0,27 ml) of 3-[(2-di,methylamino)ethyl]-IH-indole-5-carboxylic acid (144 mg) in triethylamine (0,2 ml) and dimethylformamide (10 ml) under nitrogen atmosphere. and the product (1) of step (ii[)
33 mg) into a stirred suspension. The reaction mixture was gradually warmed to room temperature and stirred for 25.5 hours. The resulting solution was vacuum sealed (to about 1.5 ml) and applied directly to a silica gel column (Merck product number 9385; 2.5 cm diameter). Elution with dichloromethane-ethanol-aqueous ammonia (25:8:1) gave the free base of the title compound (179 mg) as a foam.

TLC silica, dichloromethane-ethanol-aqueous ammonia (25:8:1) Rf O,31, detection uv,
The IPA foam (169 mg) was dissolved in absolute ethanol (1 ml) and oxalic acid (39 m
g) solution was added. Ether (30'ml) was added to the resulting precipitate. Pour off the solvent and remove the solid with ether (
30 ml) and dried under reduced pressure at room temperature for 30 hours to give the title compound (2021I1 g, 97%) as a fine powder.
p70-72' (foamed) was obtained.

Actual measurements: C, 60,3, H, 6,4, N, 10.9C23H28
N402°C2H204.

0.68H20 calculated value: C, 60,7; H, 6,4, N, 11. 3%H2
0 analysis value: 2.46% H20 w/w 0.68 mol.

Example 8 3-[2-(dimethylamino)ethyl] -N-C2-
(4-((Methylsulfonyl)amino]phenyl]ethyl) -IH-indole-5-acetamidooxalate diphenylphosphoryl azide (1,73ml) was dissolved in dimethylformamide (140ml) and triethylamine (
Intermediate 2 (1,0 g) and N-(
A cold (water bath) solution of 4-(2-aminoethyl)phenylcomethanesulfonamide (0,87 g) was added and the mixture was stirred for 62 hours. The resulting solution was evaporated to dryness under reduced pressure,
The residue was preadsorbed onto silica (7734.5 g). Purification by flash chromatography eluting with dichloromethane-ethanol-aqueous ammonia (100:8:1) gave the free base of the title compound (>1.0 g) as an oil, which was dissolved in hot ethanol (7 ml). Dissolve oxalic acid (0.25 ml) in ethanol (2 ml).
g, 2.78×10 3 mol) was added. The solvent was evaporated under reduced pressure to obtain a foam, which was added to Nitil (50 ml).
The title compound (0.92K) was obtained as a foam.

TLC silica, dichloromethane-ethanol-aqueous ammonia (50:8:1) Rf 0.5, detection uv+I
PA Actual value: C, 54,8, H, 6,1; N, 9. 9°C23
H3ON403S゛02H2°4゛0.7H20 calculated value, C, 55, 1, H, 6, 2; N, 10. 3%.

H20 analysis actual value: 1.83% H20 w/w Ran 0.55 molar equivalent Example 9 3-C2-(dimethylaminoethyl)-N-(4-[[
(methylamino)sulfonyl]methyl]phenyl] −
1H-indole-5-acetamidooxalate trimethylacetyl chloride (0.27ml) was dissolved in dichloromethane (100ml) and triethylamine (0.7ml).
4-Amino-
N~Methylbenzene methanesulfonamide hydrochloride (0,
48g) was added and the mixture was stirred overnight. methanol(
50 ml) was added to the resulting solution and the mixture was stirred for 10 minutes. The solvent was evaporated under reduced pressure and the residue was purified using silica (7734
, 5 g) and purified by flash chromatography eluting with dichloromethane-ethanol-aqueous ammonia (75:821) to give the free base of the title compound (0.6 g) as a colorless oil. This was dissolved in hot ethanol (20 ml), and ethanol (
A solution of oxalic acid (0.13 g) in 3 ml) was added. After cooling, the title compound was removed from the solution as a solid (0.59 g), mp
210-213@ (foamed).

Actual measurement value: C, 55.2, H, 6.0; N, 10. 5;CH
NOS, C2H204 calculated: C,55,6; H,5,8; N, 10.8% Example 1O N-(2-(4-(acetylamino)phenyl]ethyl)-3-(2-( dimethylamino)ethyl]-IH-indole-5-acetamide hydrochloride (1) 3- (2
-(dimethylamino)ethyl)-N-[2-(4-nitrophenyl)ethyl]-IH-indole-5-acetamide hydrochloride diphenylphosphoryl azide (2, 1 ml
) in dimethylformamide (200 ml) and triethylamine (1,4 ml) of intermediate 2 (1,2 g>
and 4-nitrophenethylamine hydrochloride (1,0sr)
and the mixture was stirred for 1 hour. The solution was allowed to warm to room temperature and stirring was continued for a further 12 hours. The resulting solution was evaporated to dryness under reduced pressure and the residue was dissolved on silica (
9385,3g) was adsorbed in advance. Column chromatography (7747.125 g of silica) dichloromethane-ethanol-aqueous ammonia (50:8:1)
Purification by elution with gave the impure free base of the title compound. Second column (silica 7747°50g
) with dichloromethane-ethanol-aqueous ammonia (100:8:1) to give the free base of the title compound (0.8 g) pure as an oil, a portion of which (0.8 g) was obtained.
20 g> was dissolved in a mixture of ethanol (1 ml) and isopropanol (8 ml). The pH was adjusted to 1 by adding ethereal hydrogen chloride. Addition of diethyl ether gave the title compound (0.20 g) as a foam.

TLC silica, dichloromethane-ethanol-aqueous ammonia C50:8:1) Rf O,5, detection uv+I
PA (11)N -[2-(4-(acetylamino)phenyl]ethyl)-3-(2-(dimethylamino)ethyl]
-IH-indole-5-acetamide salt A solution of the free base of the product of step (1) (0,5 g) in ethanol (35 ml) and ethanolic hydrogen chloride (6 ml) was heated to 10% palladium at room temperature and under atmospheric pressure for 30 minutes. Hydrogenated over charcoal (50% water paste, 0.5g). erase the catalyst,
Washed with methanol (20ml). The combined solution was evaporated to dryness under reduced pressure, and the residue was preadsorbed on silica (7734, 2 g). By chromatography and eluting with dichloromethane-ethanol-aqueous ammonia (50:8:1), N-[2-(4-aminophenyl)ethyl)-3-[2-(dimethylamino)ethyl] - IH-indole-5-acetamide (0,39
g) was obtained. Acetyl chloride (0.08.7ml) was added to a solution of the amine (0.37g) and triethylamine (0.17ml) in dichloromethane (40ml) and the mixture was stirred for 30 minutes. Acetyl chloride (0.02ml)
was added and stirring continued for 30 minutes. Methanol (20m
1) was added to the mixture and then stirred for 10 minutes. The solution was evaporated to dryness under reduced pressure, and the residue was purified with silica (7734, 1 g
) was adsorbed in advance. Chromatography with dichloromethane-ethanol-aqueous ammonia (50:8:1)
) to give the pure free base of the title compound (0.35 g) as an oil, which was dissolved in a mixture of ethanol (3 ml) and Impropatol (10++1). Add ethereal hydrogen chloride to pH 1
and addition of diethyl ether precipitated the title compound (0.27 g) as a foam.

TLC silica, dichloromethane-ethanol-aqueous ammonia (50:8:1) Rf 0.2, detection uv+
IPA actual measurement value: C, 62, 4, H, 7, 2, N, 12. 1°CH
N OHCl, 0.9H20 calculated value: 24 30 4
2゛c, 62.8. H, 7, 2, N, 12. 2%.

HO analysis actual value: 3.70% H20W/W 0.9 molar equivalent Example 11 N-(3-(4-(aminocarbonyl)phenyl]propyl)-3-[2-(dimethylamino)ethyl] -1H
-5-carpoxamidone oxalate (i) 3- [2-
(dimethylamino)ethyl]-N-(2-propynyl)
-1H-indole-5-carboxamide oxalate 3-(2-(dimethylamino)ethyl) IH-indole-5-carboxylic acid (2,0)f was dissolved in dry pyridine (130 ml) and dry dimethylformamide ( 20 ml) of the mixture (heating is necessary for complete dissolution).

The solution was cooled in a water bath and thionyl chloride (2.35ml)
was dripped. The mixture was stirred at room temperature for 4 hours or analyzed by silica TLC (diethyl ether-isopropyl alcohol-
Water-aqueous ammonia (20,20:8:1) showed an incomplete reaction.

The reaction mixture was recooled in a water bath and further treated with thionyl chloride (0,
3ml) then propargylamine hydrochloride (2.36g
) was added. The resulting solution was stirred at room temperature for 16 hours.

The TLC was repeated using the same solvent system as previously shown to show the presence of some starting material and additional thionyl chloride (0.3 m
l ) and propargylamine hydrochloride (0.4 g) were added. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure to give a viscous oil, which was mixed with dichloromethane-ethanol-aqueous ammonia (50:8:1) and applied to a silica column. ``Flash'' elution using the same solvent system yielded the free base of the title compound 880 as a foam.
mg was obtained. A less pure sample of the free base of the title compound (0,214 g) was also obtained. A portion (50+ng) of the title compound free base was dissolved in methanol (0.5ml) and oxalic acid (16.5mg) was added as a solid.

Diethyl ether (10ml) was added to give a gummy precipitate.

The large rubbery particles were removed with a spatula and the remaining material was stirred at room temperature for 6 hours to form a precipitate. The precipitate was poured into the bottom of the furnace, but it immediately turned into a rubbery substance. The gum was dried under vacuum at 60'' for 10 hours to obtain 20 mg of the title compound as a foam.

Actual measurement value: C, 59, 4, H, 6, 2, N, 11. 2゜CH
N2H204,0,2H20 calculation: C,59,6, H,5,9; N, 11.6%.

(il)4-(3-(((3-(2-(dimethylamino)ethyl)-1H-indol-5-yl]carbonyl]amino]-2-propynyl]benzoic acid methyl oxalate 4-iodobenzoic acid Methyl (731 mg), step (+)
The free base of the product (826a+g) and bis(triphenylphosphine)palladium dichloride (63mg)
was dissolved in a mixture of diethylamine (50ml) and tetrahydrofuran (50ml).

Copper iodide (1) (38 mg) was added and the reaction mixture was brought to room temperature.
Stirred with FjA for 18 hours. The solvent was evaporated under reduced pressure to give an oil, which was dissolved in dichloromethane-ethanol-aqueous ammonia (75:8:1) and applied to a silica column (Merck product no. 9385).

“Flash” elution using the same solvent system gave the title compound (998 mg) as a foam, of which a portion (10
Oxalic acid (23III) in methanol (0.5 ml) was dissolved in methanol (3.5 ml).
A solution of was added. Diethyl ether (100 ml) was added and the title compound was dissolved as a solid (97 mg) mp16B-7°
It was isolated as (decomposition).

(iii) 4-[3-(((3-2-(dimethylamino)ethyl)-IH-indol-5-yl]carbonyl]amino]propyl]benzoic acid methyl oxalate of step (11) as free base; Product (17B+ng
) was dissolved in methanol (40 ml) and activated carbon (150 ml) was dissolved in methanol (40 ml).
a+g) was added. The mixture was heated to reflux for 2 hours and the activated carbon was removed from the hot solution by filtering through cotton. The cold (room temperature) solution was added to a pre-reduced suspension of 10% palladium oxide on charcoal (50% aqueous paste, 80 mg) in ethanol (40 ml). The mixture was hydrogenated under 1 atmosphere of hydrogen for 4 hours. The catalyst was removed in a "hyflo" furnace and the solvent was evaporated under reduced pressure to give a gum, which was mixed with dichloromethane-ethanol-aqueous ammonia (50:
8:1) and applied to a silica column (Merck product number 9385). The free base of the title compound (ll
1 mg) was obtained. A portion of the title compound free base (99 mg
) in methanol (3 ml), methanol (0,
A solution of oxalic acid (22 mg) in 5 ml) was added and diethyl ether (50 ml) was added to give a suspension which was stirred at room temperature for 6 hours. The title compound was isolated as a gummy solid by filtration and dried under reduced pressure on Milo 0'' for 20 hours to give a foam (94 mg).

Actual all values: C, 63, 0, H, 6, 6, N, 8.
7°C24H29N3o3. C2H2o4 calculated value: C,
62.8, H, 6.3, N, 8.5%.

(iv) of step (fil) as N-[3-4-(aminocarbonyl)phenyl]propyl)-3-(2-(dimethylamino)ethyl]-IH-indole-5-carboxamide oxalate free base. The product was dissolved in methanol (30 ml) and the solution saturated with ammonia gas. The mixture was heated in an autoclave at 110° for 72 hours. The solvent was evaporated under reduced pressure to give an oil, which was dichloromethane-ethanol-aqueous. Ammonia (50:8:
1) Dissolve in a silica column [Merck product number 9385
．． 4c+n x 6 inches (about 15 cm) in diameter. Starting material 2 was obtained by “flash” elution using the same solvent system.
61 mg and 218 ωg of the free base of the title compound were obtained,
A portion of the free base (207 mg) was dissolved in methanol (2 ml).
of oxalic acid (4 mL) in methanol (0.5 ml).
7,5a+g, 0. 53 mmol) of the solution was added.

Diethyl ether (50 ml) was added and the resulting gummy precipitate was stirred at room temperature for 6 hours, giving the title compound (215+ng) as a solid, mp 133-143° (foam mp 7).
0”) was obtained.

Actual measurement value: C, 62,0; H, 6,6, N, 11.2°C23H2
8N402. C2H2o4 calculated value: C, 62, 2, H,
6,3; N, 11.6%.

TLC silica, dichloromethane-ethanol-aqueous ammonia (50:8:1) Rf o, 07° Example 12 3-(2-(dimethylamino)ethyl) -N-(2-
(3-[(methylsulfonyl)amino]phenyl]ethyl]-IH-indole-5-carboxamide oxalate (i) 3-(2-(dimethylamino)ethyl)-N
-(2-(3-nitrophenyl)ethyl]-IH-indole-5-carboxamide-12' (cooling bath temperature) in anhydrous pyridine (7 ml)
A suspension of 3-((2-dimethylamino)ethyl]-IH-indole-5-carboxylic acid (0,15 g) in water was treated with thionyl chloride (0,052 ml) to give a
．． Stirred for 5 hours. The resulting mixture was warmed to about O'' over 1.5 hours. The suspension was recooled to about -12° and
Treated with a solution of m-nitrophenethylamine (0,107g) in anhydrous pyridine (1ml). 0.5 at -12°
After stirring for an hour, the resulting solution was warmed to room temperature over 1.5 hours and then stirred at room temperature for 18 hours. Divide thionyl chloride into two portions (0.02 ml and 0.052 ml) approximately -1
Added at 2* over 4 hours. Stirring was then continued for 3 days at room temperature. The solvent was removed by rotary evaporation and the residue was subjected to flash chromatography in dichloromethane.
Ethanol-0,88 aqueous ammonia (100:8:1
). Rotary evaporation of the appropriate portions yielded the title compound (0.4 g) as a gum.
I got it.

TLC silica, dichloromethane-ethanol-0,88
Aqueous ammonia (100:8:1) RfO02, uv/
IPA (11)N-(2-(3-aminophenyl)ethyl)
-3-(2-dimethylaminoethyl)-1H-indole-5-carboxamide hydrochloride ethanol (15ml)
) A solution of the product of step (i) (0.26 g) was heated with hydrogen in the presence of 10% palladium oxide on carbon (0.4 g of 5096 water paste, previously reduced in 15 (ml) of ethanol) until hydrogen absorption ceased. Added. Removal of the catalyst and solvent gave a gum (0.3 g), which was subjected to flash chromatography to dichloromethane-ethanol-0.88
Purified by elution with aqueous ammonia (50:8:1). Rotary evaporation of the appropriate portions gave the free base (0.13 g) as a foam. TLC silica, dichloromethane-ethanol-0,88 aqueous ammonia C
25:8:1) Rfo, 6, detection uv/ip
A solution of the free base (0,12 g) in ethanol (10 ml) was treated with excess ethereal hydrogen chloride and the resulting solution was evaporated to dryness to give the title compound (0,1
15,) was obtained.

TLC silica, dichloromethane-ethanol-〇, 88
Aqueous ammonia (25:8:1) RfO56, detection uv
/IPA (iii) 3-[2-(dimethylamino)ethyl]-N-(2-(3-((methylsulfonyl)amino]phenyl]ethyl']-LH-indole-5-carboxamide oxalate ( 1: 1) anhydrous pyridine (9
ml) Free base of the product of middle step (N) (0.23 g)
A stirred cold (-15') solution of was treated with methanesulfonyl chloride (0.05ml) and the resulting solution was allowed to warm to room temperature over about 2 hours. After stirring at room temperature for about 24 hours, the solution was cooled to about 11° and further added with methanesulfonyl chloride (0
,05ml) and stirring was continued for 20 hours at room temperature.

The solvent was removed by rotary evaporation and the resulting gum was subjected to flash chromatography using dichloromethane-ethanol-0,88 aqueous ammonia (50:8:1
). Rotary evaporation of the appropriate fractions gives the free base of the title compound as a gum (
0.155 g) was obtained.

TLC silica, dichloromethane-ethanol-0,88
Aqueous ammonia (25:8:1) RfO96, u v
/IPA Free base (0,155 g) in absolute alcohol (2 ml)
) was treated with a hot solution of oxalic acid (0,0325 g) in hot absolute alcohol (2 ml). Methanol (
5 ml) was added to redissolve the precipitated gummy salt. Rotary evaporation of the solvent produced the title compound (0,
12g) mp140 150° (shrinking at 80″) was obtained.

TLC silica, dichlorocomethane-ethanol-〇, 88
Aqueous ammonia (25:8:1) RfO16, uv/I
PA actual measurement value: C, 55, 1, H, 5, 9, N, 10. 5;CH
NO3, CHO 222843224°0, lH2O calculated value.

C, 55.4; H, 5.8; N, 10.8%.

The following examples are examples of compounds of the present invention containing 3-(2-aminoethyl)-N-[2-[4-(dimethylamino)phenyl]ethyl]-IH-indole-5-carpoxamide dihydrochloride as the active ingredient. This is an explanation of pharmaceutical prescriptions. Other compounds of the invention can be formulated in a similar manner.

Tablet for oral administration a+g/tablet Active ingredients 10 Magnesium stearate BP' 0.5 Anhydrous lactose
99 active ingredient is sieved and mixed with anhydrous lactose and magnesium stearate. The mixture was then transferred to an 8.0 m 11 recessed punch-equipped mass stay (Man
asty) Compress into tablets with F3 tablet machine.

Injection for intravenous administration mg/ml Active ingredient: 0.6 mg Sodium chloride BP Applicable: 2 Water for injection BP
Adjust the strength of the solution by adding 1.0 ml sodium chloride and adjust the pH by adding acid or alkali to the optimal stable pH of the active ingredient and/or adjust to promote dissolution of the active ingredient. . Alternatively, appropriate buffer salts are used.

The solution is prepared, clarified, filled into appropriately sized ampoules and sealed by glass fusing. The injections are sterilized by heating in an autoclave in one of the acceptable cycles.

Alternatively, the solution is filter sterilized and filled into sterile ampoules under aseptic conditions. The solution can also be charged under an inert atmosphere of nitrogen or other suitable gas.

Claims (1)

[Claims] 1. Compounds of general formula (I) and physiologically acceptable salts and solvates thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the above formula, R_1 is the group R_5R_6N-, the group R_5O
_2C(CH_2)_p-, group R_5R_6NCO(CH_2)_p-, group R_5CO
NH(CH_2)_p-, group R_5R_6NSO_2(CH_2)_p- or group R_
7SO_2NH(CH_2)_p- (R_5 and R_6 may be the same or different and each represents a hydrogen atom or a C_1_-_3 alkyl group, or R_5 and R_6 together with the nitrogen atom to which they are bonded represent a saturated Forms a monocyclic 5- to 7-membered ring.R_7 is C_1_-_3
Represents an alkyl group. p is 0 or 1). R_2 represents a hydrogen atom or a C_1_-_3 alkyl group. R_3 and R_4 may be the same or different and each represents a hydrogen atom, a C_1_-_3 alkyl group, or a 2-propenyl group. m is 0 or an integer of 1-4. n is 0 or 1 (however, m and n are never both 0)]. 2, R_1 is a group R_5R_6N-, R_5O_2C(CH_2)_p-, R_5R_6NCO(CH_2)_p-, R_5CONH(CH_2)_p-, R_5R_6NSO_2(CH_2)_p- or a group R_
7SO_2NH(CH_2)_p- (R_5 and R_6 may be the same or different, and each hydrogen atom represents a C_1_-_3 alkyl group), the compound according to claim 1. 3. R_1 is R_5R_6N -, R_5O_2C(CH_2)_p-, R_5R_6NCO(CH_2)_p-, R_5CONH(CH_2)_p- or R_5R_6NSO_2(CH_2)_p- (R_5 and R_6 may be the same or different, and each represents a hydrogen atom or a methyl 4. R_1 is H_2NCOCH_2-, CH_3SO_2NH-, H_2NCO-, (CH_3
)_2N-, CH_3O_2C-, pyrrolidino and CH
A compound according to claim 1 representing a group selected from _3NHSO_2CH_2-. 5. The compound according to any one of claims 1 to 4, wherein R_2 represents a hydrogen atom or a methyl group. 6. The compound according to any one of claims 1 to 5, wherein m is 2. 7, R_3 and R_4 may be the same or different,
Each represents a hydrogen atom or a C_1_-_3 alkyl group,
A compound according to any one of claims 1 to 6. 8, R_2 represents a hydrogen atom, R_3 and R_4 may be the same or different and each represents a hydrogen atom or a methyl group, m represents 2, and R_1 is a group H_2NCOC
H_2-, CH_3SO_2NH-, CH_3CONH
-, H_2NCO-, (CH_3)_2N-, CH_3O_2C-, CH_3
The compound according to claim 1, which represents an NHSO_2CH_2- or pyrrolidino ring, and the substituent R_1 on the phenyl ring is present at the meta or para position. 9, R_1 is a group (CH_3)_2N-, CH_3O_2C-, H_2NCOCH_2- or CH
2. A compound according to claim 1, which represents _3CONH- and the group R_1 is in the para position. 10,3-(2-aminoethyl)-N-[2-[4-(
Dimethylamino)phenyl]ethyl]-1H-indole-5-carboxamide, 4-[2-[[[3-(2-
The compound according to claim 1 selected from the group consisting of methyl (aminoethyl)-1H-indol-5-yl]carbonyl]amino]ethyl]benzoate, and physiologically acceptable salts and solvates thereof. . 11. At least one compound of formula (I) defined in any one of claims 1 to 10, or one or more physiologically acceptable salts or solvates thereof; A pharmaceutical composition containing a carrier or diluent. 12. A method for producing a compound of general formula (I) or a physiologically acceptable salt or solvate thereof defined in any one of claims 1 to 10, comprising: (A) general formula ( Amine of II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II), Acid of general formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) Or the corresponding acylating agent or its (B) Compounds of general formula (IV): ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the above formula, Q is the group NR_3R_4 (or its protected derivative) or (C) Compounds of general formula (VII): ▲Numerical formulas, chemical formulas, tables, etc.▼(VII) (In the above formula, Y is an easily substitutable or a protected derivative thereof with an amine of formula R_3R_4NH, or (D) Compound of general formula (VIII): ▲Mathematical formula, chemical formula, table, etc.▼(VIII) [In the above formula, W is required -(CH_2)_2NR_3R_4 group or -(C
H_2)_2NR_3R_4] or a salt or protected derivative thereof; or (E) for the production of a compound of general formula (I), a
) or a salt or protected derivative thereof is subjected to an interconversion reaction, or (F) for the production of a compound of general formula (I) in which R_1 represents H_2N-, a compound of general formula (X): ▲ Formula, There are chemical formulas, tables, etc. ▼(X) is reduced or (G) the protected derivative of the compound of general formula (I) or its salt is subjected to a reaction to remove one or more protecting groups, and then the necessary or desired If so, the compound obtained from any of steps (A) to (F) can be prepared by (H) (i) removing any of the protecting groups and (ii) converting the compound of general formula (I) or a salt thereof. 1. A method for producing indole derivatives, which comprises subjecting them to one or two further reactions consisting of conversion into physiologically acceptable salts or solvates.