JPS61158960A - Indole derivative, manufacture and pharmaceutical composition - Google Patents

Abstract

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

Description

[Detailed description of the invention]

The present invention relates to indole derivatives, to processes for their preparation, to pharmaceutical compositions containing them, to their pharmaceutical uses IIc, and in particular to compounds and compositions for use in the treatment of migraine. Migraine pain is associated with excessive dilation of the overhead vasculature, and known treatments for migraine include the administration of compounds with vasoconstrictive properties, such as ervitamin. However, Elvitamin is a non-selective vasoconstrictor that constricts blood vessels throughout the body and has undesirable and potentially dangerous side effects. Migraines can also be treated by administering analgesics, usually in combination with antiemetics, but such treatments are of limited value. Therefore, there is a need for safe and effective drugs for the treatment of migraine that can be used to prevent or alleviate chronic headaches and for compounds with selective vasoconstrictor activity. play such a role. The inventor has now discovered some indole derivatives that have potent and selective vasoconstrictor activity. The present invention is based on the general formula (I) I AlkNR3R4 R1R2N802A In the expression, R2 is a hydrogen atom, 01-, an alkyl group, a C3-6 alkenyl or a C5-7 cycloalkyl group, or a Fe#t
or phenyl(0,-4)alkyl group [However, the phenyl ring does not need to be substituted or is often
child% (! Alkyl% C1-5 alkoxy1-
! I or hydroxy group or L group -NRaRb, or -0ONRaR6 (However, Ra and Rb may be the same or different, and each represents a hydrogen atom, C
1-3 alkyl or C3-6 alkenyl groups, which together with the nitrogen atom to which they are attached represent a saturated monocyclic 5- to 7-membered ring [provided that this may contain additional heterofunctionality, e.g. R3 and R4 may be the same or different. Honestly,
Each hydrogen atom -% Cl-5 represents an alkyl or zolohenyl group or R3 and R4 together form an aralkylidene group, Alk is unsubstituted or has not more than 2 C
Indole and its , salts and solvates. All optical isomers of compounds of general formula H and mixtures thereof, including racemic mixtures thereof, are encompassed by the present invention. The present invention also includes: Encompassed within its scope are atomic isomers of Compound H and mixtures of such isomers. With respect to general formula (T), the alkyl group and the alkyl part of the alkoxy group are straight-chain or branched containing 1 to 3 carbon atoms, or in the case of R1 1 to 6, preferably 1 to 3 carbon atoms. It may be a branched alkyl group. An example of an alkyl group is methyl. Includes ethyl, propyl and inpropyl groups. Preferably the alkenyl group contains 3 Wa or 4 carbon atoms, examples of which include propenyl and butenyl groups. Cycloalkyl groups preferably contain 5 or 6 hydrogen atoms and examples include cyclopentyl and cyclohexyl groups. The alkyl part of the phenylalkyl group preferably contains la or 2 carbon atoms, as for example in benzyl and phenylethyl groups. The aralkylidene group is preferably an arylmethylidene group such as benzylidene. When R2 represents a substituted phenyl or phenyl(0l-4)alkyl group, the substituents may be in the ortho, meta or nosora positions. The halogen substituent on the phenyl ring in general formula m may be, for example, a fluorine, chlorine or bromine atom. The alkenyl chain m is, for example, the formula %. is an integer). R2 is substituted phenyl or phenyl (C4-4)
When representing an alkyl fund, preferably m and n are each zero, such that the sum of m and n together does not exceed 2;
Represents engineering or 2. Formula (1) O compound is an alkenyl chain -(OH2)rrl
O11=0H(CH2). - E with respect to the double bond in
It will be appreciated that it can exist in the - or 2-configuration. The present invention includes within its scope both isomeric forms as well as mixtures thereof. In general, the compounds of the invention in the E configuration can be represented structurally as the preferred nE configuration. In the compounds of general formula (T), alkenyl [A' is preferably of the formula %, where mIfi is as previously defined, preferably is or is and n is zero or l. most preferably zero). A preferred class of compounds according to the invention therefore has the general formula (r') R, R2N802R2N302(OH2),
Al kNRsR4 (wherein, R1, R2, R3, R4
, Alk and m are as defined above] and their physiologically acceptable salts and solvates (eg hydrates). In the 16 compounds of general formulas (r) and (r'), Alk
preferably represents an unsubstituted alkyl chain, in particular an unsubstituted alkyl chain containing 2 carbon atoms. R, Vi is preferably a hydrogen atom or a C1-6 alkyl group, and R2 is preferably a hydrogen atom, a C1-3 alkyl group, a C5-7 cycloalkyl group, or substituted or unsubstituted phenyl 1fcld It is a phenyl (C1-4) alkyl group. It is particularly preferred that one of R1 or R2 represents a hydrogen atom. When R2 represents a substituted phenyl or phenyl (CI-4) alkyl group, it is preferred that R1 represents a hydrogen atom or C1-3 alkyl. Phenyl or phenyl (01,
, -4) Preferred substituents on the argyl group are the C4-3 alkoxy group and the formula -0ONRaRb (where Ra and Rb
may be the same or different, and each is a hydrogen atom or a C1-3 alkyl group). R3 and R4 may be the same or different and preferably each represents a hydrogen atom or a C1-3 alkyl group. A particularly preferred class of compounds according to the invention is of the general formula (T
) (wherein Rla is a hydrogen atom or a cl-3 alkyl group (
For example, methyl), )R
2a is a hydrogen atom% C1-3 alkyl group (e.g. methyl or ethyl) or phenyl or phenyl<01
．． -2) represents an alkyl group [provided that the phenyl ring is unsubstituted or substituted with a C alkoxy group (for example, methoxy) or a group -cONH2-], and R3a and R4a are each a hydrogen atom or 01-3 and physiologically acceptable salts and solvates (eg hydrates) thereof. In compounds of formula (Ta), the total number of carbon atoms in R5a and R4a preferably does not exceed 2 and most preferably each of R3a and R4a represents a methyl group. In compound (Ta), ma preferably represents zero. Preferred compounds according to the invention are (E) -2-[: 3- (2-(dimethylamino)
(K) -2-(3-C2-(dimethylamino)ethyl)-LH-indol-5-yl)-N-(2 -phenylethyl)edensulfonamide, (bound-2-(3-(
2-(dimethylamino)ethyl]-IH-indol-5-yl)-N-((4-me)xyphenyl)methyl]edensulfonamide and the physiologically acceptable salts and solvates of these compounds ( For example, hydrates). Acid addition salts of compounds of general formula (I) formed with suitable physiologically acceptable inorganic or organic acids, such as hydrochloride, bromine W# salt, sulfate, nitrate, phosphoric acid; salt, tartaric acid, citric acid, fumarate, maleic acid group,
This includes acid groups and sulfonate salts, such as mesylic acid groups. Other examples of indoles of general formula (■) include oxalate and creatinine sulfate adducts. The invention extends to other physiologically acceptable equivalents of the compounds according to the invention, ie physiologically acceptable compounds that are converted in vivo to koji compounds. Examples of such equivalents include physiologically acceptable, metabolically labile N-acyl derivatives. The compounds of the invention potently and selectively constrict the carotid artery of anesthetized dogs, while having a negligible effect on blood pressure. The selective vasoconstrictor effect of the compounds of the invention was demonstrated in vitro. Compounds of general formula H are useful in the treatment and prevention of pain resulting from dilatation of the overhead vasculature, particularly migraine headaches such as overhead headaches and related conditions. Compounds of general formula (■') are preferred due to their vasoconstrictive action. The invention Vi also includes a compound according to the invention or the like. Pharmaceutical compositions suitable for use in human medicine containing at least one physiologically acceptable salt or solvate (e.g. hydrate) and formulated for administration by any convenient route. provide. Such compositions may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients. Accordingly, the compounds according to the invention may be formulated in a form suitable for administration orally, bucally, parenterally or rectally or by inhalation or insufflation. For oral administration, the pharmaceutical compositions may contain, for example, 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),
Alternatively, it may take the form of tablets or capsules made by conventional means with pharmaceutically acceptable excipients such as wetting agents (eg, sodium lauryl sulfate). 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 presented as a dry formulation for constitution with water or other suitable reagents before use. may be done. Such liquid preparations may contain suspending agents (e.g. sorbitol syrup, methylcellulose or hydrogenated edible fats), emulsifiers (e.g. lecithin or acacia), non-aqueous agents (e.g. almond oil, oily esters or ethyl alcohol) and They may be prepared by conventional means with pharmaceutically acceptable additives such as preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid).Liquid preparations may be prepared by conventional buffering, where appropriate. For oral administration, the compositions may take the form of tablets or tongue lozenges formulated in conventional manner.The compounds of the invention may be administered by injection. or may be formulated for parenteral administration by continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules or in multi-dose containers, with an added preservative. Compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous media and may contain formulating agents such as suspending agents, stabilizing and/or dispersing agents and (
or) may contain reagents to adjust the tonicity of the solution. Alternatively, the active ingredient may be in powder form for constitution with a suitable reagent, eg, sterile pyrogen-free water, before use. The compounds of the invention may also be formulated into rectal compositions containing conventional herbal bases such as cocoa powder or other glycerides. For administration by inhalation, the compounds according to the invention can be prepared from a pressurized nozzle using a suitable propellant such as dichlorochloromethane, trichlorochloromethane, dichlorotetrachloroethane, carbon dioxide or other suitable gas. Alternatively, it is conveniently provided in the form of an aerosol spray from a nebulizer. In the case of pressurized aerosols, the dosage unit can be measured by providing a tube for dispensing a metered amount. Capsules and cartridges, eg of 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. (average weight, e.g. about 709) for the treatment of migraines
Suggested dosages of the compounds of the invention for oral, parenteral, buccal or rectal administration to humans are e.g.
0.1-I Q of active ingredient per unit dose which can be administered up to 1 times, more usually from 1 to 4 times per day.
It is O■. It will be appreciated that it may be necessary to make routine variations in dosage depending on the age and severity of the patient and the severity of the condition being treated. Due to oral administration, the unit dose is 0.5 to 5 of the active ingredient.
It would be preferable to contain from 0 to 40, for example from 2 to 40. The unit dose for parenteral administration is 0.2 to 0.2 of the active ingredient.
It would be preferable to contain 5g #9. The aerosol formulation is such that each metered dose or "puff 1" dispensed from a pressurized aerosol contains from 0.2 to 2 to 2 of a compound of the invention and into an inhaler or insufflator. Capsules or cartridges are 0.2-2
It is preferable to adjust it so that it contains 0 and 2 pieces of waste. Overall daily dose fT by inhalation is 1 mg to 100n9
It would be within the range. Administration is done several times daily, e.g.
It may be 2 to 8 times giving 2 or 3 doses. If desired, the compounds of the invention may be administered in combination with one or more therapeutic agents such as analgesics, anti-inflammatory agents, and antiemetics. In addition to their vasoconstrictor action, compounds of general formula H are also useful as intermediates for the preparation of other indole derivatives. Thus, the compound of formula (1) is reduced to form A1 kNR3R4 R1R2NS O2Al, 8/■ where R1, R2, R3, R4 and Alk are as defined above and A is 2-5 (representing an alkyl containing 5 carbon atoms) can be provided. Compounds of formula (1) in which R2 represents a substituted 7"°" or mineral-substituted 71enyl (C4-4) alkyl group are disclosed in Published European Application No. 147 of the present inventor.
It is described in No. 107. R2 is a hydrogen atom s C1
-5 alkyl, C5-6 alkenyl or C5-7 cycloalkyl group or unsubstituted phenyl or phenyl ((!, -4) Formula (1
Compounds of 1) are disclosed in published UK Application No. 2150932A to the inventor. Reduction of a compound of formula (T) to give a compound of formula (n) can be carried out by methods well known in the art. Thus, for example, compounds of formula (I) can be reduced by catalytic hydrogenation using heterogeneous or homogeneous methods. Heterogeneous catalysts that can be used 1d −y =
- nickel; nickel reduced using sodium borohydride; and negative metals such as platinum, platinum oxide, radium, rhodium or ruthenium oxide, which may be supported, for example, on charcoal, diatomaceous earth or alumina. Includes metals. Hydrazine may also be used as hydrogen source in the case of 2 Ni. Examples of homogeneous catalysts include chlorotris(triphenylphosphine)rhodium and pentacyanoconolate.N-catalytic hydrogenations include alcohols such as ethanol, ethers such as dioxane or tetrahydrofuran, amyl, flI, and dimethylformamide. , esters, for example ethyl acetate, can be conveniently carried out in a solvent such as ethyl acetate and at a temperature of -10 to +50°C, preferably -5 to +300°C.The reaction can be conveniently carried out at atmospheric pressure, but Higher pressures can be used, for example up to 5 atmospheres. The compounds of the invention can also be used at temperatures of 0-120°C. Sodium in ethanol or sodium in hexamethylphosphoramide and t- The following compounds of general formula (1) which can be made from the corresponding compounds of formula (1) by the above method are novel compounds. and constitutes another feature of the invention: 3-(2-(dimethylamino)ethyl]-N-methyl-
IH-indole-5-pronogunsulfonamide P1 3-[2-(dimethylaminocoethyl)-N,N-dimethyl-ta-yne P-ru-5-ethanesulfonamide, 3-[2-(dimethylamino)ethyl ]-N-(2-phenylethyl)-1H-indole-5-ethanesulfonamide, 3-(2-(dimethylamino)ethyl]-y-(l-methylethyl)-1H-indole-5-ethanesulfone Amide. 3-(2-(dimethylamino)ethyl]-N-ethyl-IH-indole-5-ethanesulfonamide, 3-((2-(dimethylamino)ethyl)-N-phenyl-IH-indole-5- Ethanesulfonamide and N-cyclobenti-3-[2-(dimethylamino)ethyl)-1H-indole-5-ethanesulfonamide. According to another aspect of the invention, compounds of general formula H and their Salts and solvates can be made by the general methods outlined below, in which R1, R2, R3, R4, A, Alk, m and n
is as defined for general formula (T) unless specified otherwise. According to the general method (A), the compound of the general formula H has an indole of the general formula , NEIO2A = CH2(Is') (wherein -
h=cH2 represents a C2-5 fluorenyl chain]. The reaction will generally be carried out in the presence of a palladium catalyst and a base. The catalyst may be, for example, a radium or palladium salt on charcoal. The radium salts that can be used as catalysts include salts of organic acids, such as acetate, and salts of inorganic acids, such as chloride or bromide. The base may be, for example, a tertiary nitrogen base such as triethylamine or tri-n-butylamine or an alkali metal carbonate, such as sodium carbonate. The reaction can optionally be carried out in the presence of a phosphine, for example a triarylphosphine such as to1J phenylphosphine or tri-tolylphosphine/. If the process is carried out using a compound of formula (1) in which X represents a bromine atom, phosphine should be present. This reaction is a small excess of alkene (with respect to indole) (
V). It is generally preferred that an excess of base (eg, about 3 equivalents) and an excess of phosphine (eg, about 2 equivalents) is also used. General method (A) can be carried out in the presence or absence of a solvent. Anhydrous or aqueous reaction media containing one or more solvents can be used. Suitable solvents include nitriles, such as acetonitrile; alcohols, such as methanol or ethanol; amines such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoramide; and water. The reaction may conveniently be carried out at a temperature of 25-200°C, preferably 75-150°C. In the compound of formula (fV), the moiety -A2=CH2 preferably represents the group -(CH)0H=OH2, where m is zero or an integer from ml to 3.General method (A It will be appreciated that the compound of formula (t) made by //, /\/A I kNR3Ra I II 11 \, /"\, / (■ (In the formula, A represents a - bond or a C4-3 alkyl chain) aldehyde, with the group R1R2N day 02A- as the base. Suitable reagents useful for forming the group R, R2NEIO2A -i can be made by reacting with a reagent useful for forming, for example, the general formula (vn RIR2NSO2A CH=P(R5)3(Vll , A4 represents a bond or a cl-3 alkyl chain such that the total number of carbon atoms in A3 and A4 does not exceed 3 and R5 is an alkyl, such as methyl or aryl such as phenyl or tolyl, ylide or the general formula (in which A5 represents an alkyl chain containing from 1 to 4 carbon atoms such that the total number of carbon atoms in A3 and A5 exceeds 4 and R6 is an alkyl chain such as Methyl; represents an aryl such as phenyl or an aralkyl such as benzyl. The reaction with a ylide of formula (■) is conveniently carried out in an anhydrous reaction medium which may contain one or more organic solvents. Solvents that can be used include AmiP,
Examples include dimethylformamide; ethers, such as acyclic ethers such as ethyl ether and cyclic ethers such as tetrahydrofuran; and hydrocarbons such as xylene and toluene. The reaction is -70 to +1
It can be conveniently carried out at a temperature of 50°C. Phosphate esters of the formula (vlD) can be prepared in the presence of a base, e.g. a metal hydride such as sodium hydride or potassium hydride; an alkali metal alkoxide such as potassium t-butoxide; or an organolithium base such as butyl lithium. will preferably be reacted with an aldehyde of the general formula A suitable solvent can be expressed by the formula (
as described above for the reaction of Vl) with IliF,
Ami)%. Includes ethers and hydrocarbons. The phosphorus ylide of the formula (VD is the formula (capital) 5+ RlR2N802A P (R5) 3E-(7) (wherein A5 and R5 are as defined previously and
- represents a halogen ion, e.g. chloride, bromide or iodide; or a sulfonate anion, e.g. methanesulfonate or p-toluenesulfonate), is reacted with a base. It can be created by Bases that can be used are organolithium compounds, such as n-butyllithium and phenyllithium; metal hydrides, such as sodium hydride; metal amides, such as sodium amide; alkali metal alkoxides, such as sodium and potassium methoxide, ethoxide or tit-butoxide; and carbonates of alkali metals, e.g.
Includes IJum. The formation of the phosphorus ylide can be carried out, for example, in an organic solvent or a mixture of solvents as described for general process (B). In certain embodiments of general method (B), aldehyde P of general formula - is a ylide of general formula (■) and aldehyde 1 of general formula (■
It may be reacted directly with the phosphonium salt of formula (■) in the presence of a base using the reaction conditions as described above for the reaction with. Compounds of formula (to) are prepared by converting the corresponding nitrile of formula (Iy) (where A is as defined above for general formula (V)) with hydrogen in a solvent such as tetrahydropurofuran. It can be made by reaction with a reducing agent such as di-isobutylaluminum oxide, followed by hydrolysis, which may be carried out, for example, by addition of water. The reaction can be carried out at a temperature of -70 to 30°C. Compounds of formula (r!'J) can be prepared by cyclization of the corresponding hyPlazone in a manner analogous to method (D) described below. Compounds of general formula m can be prepared by another general can be made according to method (n), which method comprises formula (X) (wherein
A6 represents a leaving atom or group xl, for example a C alkyl chain substituted by a halogen atom, a hydroxy group or an acyloxy group] from HX (i
-consisting of detachment. The group A6 can be represented, for example, by the formula %. If X in radical A represents a halogen atom, this may be, for example, bromine or chlorine. Acyloxy can be derived from carzenic acid or sulfone radicals, such as acetoxy, chloroacetoxy, p-nitrozoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy groups. When xl represents a halogen atom or an acyloxy group, the removal is carried out thermally, for example at a temperature of 30 to 200° C., or an alkali metal alkoxide, for example sodium or potassium, is
-butoxide; hydroxides of alkali metals, for example potassium hydroxide; or tertiary amine bases, such as triethylamine. The reaction with the tomb is -lO~+
It can be carried out in an organic reaction medium at temperatures in the range of 150°C. Solvents that can be used are alcohols, such as ethanol or tert-butanol: amides P1, such as dimethylformamide P; sulfoxides, such as dimethyl sulfoxide; halogenated hydrocarbons, such as methylene chloride; ketones, such as acetone; and esters such as ethyl acetate and the like. Includes mixtures of solvents. When Xl represents a hydroxy group, a compound of formula 00 can be heated with an acid such as sulfuric or phosphoric acid to provide a compound of formula (ma). Compounds of formula 00 in which xl. represents an acyloxy group can be prepared, for example, by reacting the corresponding compound in which xl is a pyroxyl group with a suitable acylating agent, such as an acid halide, for example methanesulfonyl chloride. . Compounds of the formula (η) in which xl represents a hydroxy group can also be prepared by, for example, by reaction with a suitable phosphorus trihalide.
It can be used to make the corresponding compounds where xl is a halogen atom. A compound of the formula in which xl represents a hydroxyl group (the compound itself is a compound of the formula Another common method for making compounds of general formula H (D
) is represented by the general formula (XI) (wherein Q is a group NR3R4 (or a protected derivative thereof) or a halogen atom (e.g. bromine or bromine)
or acyloxy groups, such as acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy,
p-nitrobenzoyloxy, p-toluenesulfonyloximo t, <H is a leaving atom free group such as calxyl or nurphonic acyloxy such as methanesulfonyloxy group). Become. The reaction is carried out in an aqueous or non-aqueous reaction medium and from 20 to
It can be conveniently carried out at giA of 200°C, preferably 50-125°C. A detailed embodiment of the method is described below. When Q is a group NR3F4 (or a protected derivative thereof), it is desirable to use an organic solvent of -100 g or more, preferably chloroform, dichloromethane, chloroform, dichlorodichloromethane or mixtures thereof. It is carried out in the presence of a polyphosphate ester in a reaction medium which may contain halogenated hydrocarbons.
John Wiley and Sons, Inc.
Fie*er 1 and Fie-Qe, published in 1967.
It is a mixture of esters that can be made from phosphorus pentoxide, diethyl ether and chloroform according to the method described in J. R. 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 impronozonol) or an aqueous ether (e.g. dioxane or detrahydrofuran) and a mixture of such solvents and the acid catalyst is e.g. It may be a concentrated acid or a valent acid such as sulfuric acid or acetic acid (in which case the acid catalyst also serves as the reaction solvent). In an anhydrous reaction medium, this is -1! ether(
The acid catalyst will generally be a Lewis acid such as boron trifluoride, zinc chloride or magnesium chloride. When Q is a leaving atom spanning group such as a chlorine or bromine atom, the reaction is conveniently carried out with an aqueous alcohol ( It can be carried out in an aqueous solvent such as methanol, ethanol or impronol) or an aqueous ether (eg dioxane or tetrahydrofuran). This process results in the formation of compounds of formula m in which R and R4 are both hydrogen atoms. According to a particular embodiment of this process, the compound of t(1) is a compound of formula (Xll) or a compound thereof under suitable conditions as described above for the cyclization of a compound of general formula (XI). Using the formula (X mark) 0HOc+H2AlkQ,
(XI) (where q is as defined above)
or a compound thereof or a protected derivative thereof (such as an acetal or kecoul, formed with a suitable alkyl orthoformate or diol and protected as a FIM sulfite addition complex). It can be made directly by reaction. In this embodiment of the cyclization process (DJ) the compound of general formula (XI) is formed as an intermediate and can be reacted in situ to form the desired compound of general formula m. The compound (XI) is, for example, 20 to
aqueous alcohol (e.g. methanol) at 30°C
Preparation of a compound of formula (I) by reacting a compound of formula (XI) or a loaded or protected derivative thereof with a compound of formula (XI) or a protected derivative thereof in a suitable solvent such as It may be isolated as an intermediate during the engineering process. If the acetal or ketal of the compound of formula (XI) is used! It may be necessary to carry out the reaction in the presence of (for example acetic acid or hydrochloric acid). Compounds of general formula (XIT) can be prepared, for example, from the corresponding nitro compounds using conventional methods. General' Another general method for making the compound gold of t(Tl) with the general formula (XTV) R1R2NSo2A, Alk!\〆\
/ l It II (XIV)゛,
VIII. (wherein Y is an easily replaceable atom or group), or a protected derivative thereof, with an amine of the formula R3R4NH. In the substitution reaction, substituent Y is a leaving atom or group such as a halogen atom (e.g. hawk, bromine or iodine) or a group 0R7 (however, OF+7 is, for example, acetoxy,
an acyloxy group which can be derived from canzenic acid or sulfonic acid, such as chloroacetoxy, dichloroacetoxy, )+770 loacetoxy, p-nitrobenzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy groups) (XTV)
can be conveniently carried out for compounds of The reverberation reaction is from -lO to +150°C, preferably from 20 to
50° C. (optionally in the presence of water) inert solvents (such as alcohols, such as utanol; cyclic ethers, such as dioxane or tetrahydrofuran; acyclic ethers, such as diethyl ether; and ketones such as acetone or methyl ethyl ketone. Compounds of general formula (XIV) in which Y is a halogen atom are , an aldehyde or ketone of formula (XI) in which Q is a halogen atom (1fc
A compound of formula (XIV) in which Y is a group OR7 can be prepared by a conventional method of total reaction with a hydrazine of general formula (XII) using a conventional technique. By acylation with a suitable activated S (e.g. acid anhydride or hissulfonyl), intermediate alcohols can be prepared from the corresponding compounds in which Y is a hydroxyl group. The compound of general formula H can be prepared by cyclization of a compound of formula (XT) (or a protected derivative thereof) which is a group of where 2 is a leaving atom or group), the indole of the general formula (X
Vr) MIE( / (XVI) can also be prepared by other general methods (F)K including reacting with compounds of general formula (XVI)
Examples of suitable leaving atoms or groups in the compounds are halogen atoms (such as fluorine, fluorine or bromine atoms) or
R8 (where R8 represents an aryl group, e.g. a hydrocarbyl group such as phenyl); the aryl group is unsubstituted or a halogen atom; or nitro; cyano; amino; amino; alkyl may be substituted by one or more substituents, such as methyl; alkoxy, such as methoxy; acyl, such as acetyl, and alkoxycarzenyl, such as ethoxycarzenyl. The functional group is preferably a phenoxy group. The reaction is conveniently carried out in the presence of a solvent and can be carried out in an aqueous or non-aqueous reaction medium. The reaction medium is therefore optionally in the presence of water. Below, ethers, such as dioxane or tetrahyfuranamides, such as N,N-dimethylformamide or N-
Methylpyrrolidone; alcohol-A, such as methanol or ethanol; esters, such as utilyl acetate; nitriles, such as acetonitrile; It may contain more organic solvents. In the case where the formula (XvI
) can itself serve as a solvent. If desired, the amitrilysis can be performed using a tertiary amine (e.g. triethylamine or pyridine); an alkoxide

It can be carried out in the presence of a base such as a hydride (eg potassium oxide); a hydride (eg hydrogen carbonate); or an alkali metal carbonate (eg potassium carbonate). The reaction can be conveniently carried out at temperatures between -20°C and +150°C. The starting material for general formula (XV) is, for example, general formula (X■)2'
f of \, 2, (in the formula, 2 and Q are as defined in the explanation)
It can be made by cyclization of arsenic compounds. The cyclization can be carried out in the general method described above (analogous to DJ). In another general method (according to Gl, the compound of formula H according to the invention or its The derivatives can be converted into other compounds of formula (I) using conventional methods. For example, compounds of general formula (■) in which one or more of R1, R2, R3 and R4 are alkyl groups. The compound has the formula RxL
(wherein Rx represents the desired R1, R2, R3 or R4 group and L represents a leaving atom such as a rogen atom or a tosylate group or g) or a sulfate (Rx) such as 2S04 By reaction using a suitable alkylating agent, a compound of the formula (I
I can be made from the corresponding compound of I. Thus, the alkylating agent may be, for example, an alkyl halide (eg methyl iodide or iodine), an alkyl tosylate (eg methyl tosylate) or a dialkyl sulfate (eg dimethyl sulfate). The alkylation may be conveniently carried out in an inert organic solvent such as an amide (eg dimethylformamide), an ether (eg tetrahydrofuran) or an aromatic hydrocarbon (eg toluene), preferably in the presence of a base. Reverse bases are, for example, alkali metal hydrides such as arsenium or potassium hydride; alkaline amides such as sodium amide; alkali metal carbonates such as sodium toronate; methoxides, nidoxides or methoxides of sodium or potassium. alkali metal alkoxy P such as 1-butoquinide; The reaction can be conveniently carried out at temperatures between -20° and 100° C. R1 represents an alkenyl group, R2 represents an alkenyl, phenylalkyl or cycloalkyl group and (
or) A compound of formula (■) in which one or both of R3 and R4 represents propenyl is a compound of formula RxL or (Rx)2S
04 can be similarly made using the appropriate compound. Other general methods (according to Isao, the general formula (T
) or its derivatives can be obtained by subjecting a protected derivative of general formula (T) or a salt thereof to a reaction that removes one or more protecting groups.Thus, compounds of general formula Early in the reaction sequence for the preparation of the compound (1) or its salt, it may be necessary to protect one or more sensitive groups in the molecule in order to avoid undesired side reactions. It may be desirable, for example, it may be necessary to protect the group NR3R4 in which Rs and (as well as) R4 represent a hydrogen atom, by protonation or with a group that can be easily removed at the end of the reaction sequence. Such groups include, for example, aralkyl groups such as diphgonylmethyl or triphenylmethyl; Cleavage after the protecting group or groups can be accomplished by conventional methods. Thus, an aralkyl group such as triphenylmethyl can be cleaved by treatment with a dilute acid, e.g. dilute acid. and acyl groups such as N-penzoylogicalzenyl can be removed by hydrolysis, e.g. with hydrogen bromide in acetic acid. Phthaloyl groups can be removed by hydrazitolysis (e.g. hydrazine hydration). As will be appreciated, the general method (A) described above
In some of ~(G),
It may be necessary or desirable to protect all sensitive groups in a molecule as described above. Therefore, the reaction step involving deprotection of the protected derivative of general formula (11) or its salt can be performed as described in any of the previously described methods (A) to
It may be performed after (G). Thus, according to another aspect of the invention, if necessary and/or desired, any of the processes (A) to (Gl) may be followed by the following reactions in any suitable order: (1) Removal of any protecting groups; (ii) Physiologically acceptable salts or solvates (
For example, conversion of a compound of general formula m or a salt thereof into a hydrate]. If it is desired to isolate a compound of the invention as a salt, e.g. as an acid addition, this is preferred;
using a suitable acid or vice versa □A suitable solvent (
This can be achieved by treating the free base of general formula H with creatinine sulfate in eg aqueous ethanol). The starting materials or intermediate compounds for the preparation of compounds 16 according to the invention are e.g.
It can be made by a method similar to that described in A2035310 and A2124210. ! ! ! As well as being used as the last major step in the building sequence, the general methods presented above for the preparation of the compounds of the present invention can also be used at intermediate stages in the preparation of the required compounds. It may also be used to introduce groups. Thus, for example, the required group in the 5-position may be introduced before or after the cyclization to form the indole nucleus. It should therefore be appreciated 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 desired molecule in the final product. . The invention is further illustrated by the following examples. Every m degree is an eddy current in °C. Chromatography was performed by conventional methods using silica gel (Merck Kieselgel #6 Q, Art 7734) or silica (Merck 9385) unless otherwise stated.
) on flash chromatography (W(!-8till, M'Kahn and A-
Mitra) and silica (Macherly-Nagel, Polydurum)
It was carried out either by thin layer chromatography (t, 1.c,) on Polytraml (t, 1.c, ). The following abbreviations are chromatography, t, 1. Define the eluent used for c: fA) [methylene chloride-ethanol-0,88 ammonia 50:8:l. (B) Salt f? , methylene-ethanol-0,88
Ammonia 100:8:l. (0) Methylene chloride-ether i:t. (Method Methylene chloride-ethanol-0,88 ammonia 200:8:1゜(II) Cyclohexane-ether 2:1゜(n'
, clohexane-ether 1:1 intermediate using UV light for detection and a spray reagent such as potassium permanganate (KMnO4) in 1.1. Constantly inspected by c. Indole intermediates were further detected by spraying using aqueous ceric sulfate (Oe''), and tryptamine was detected by spraying using solutions of iodoplatinic acid (PA) or ceric sulfate. (Varian) 90MH7 using KM390 equipment or Bruker (Brt+ker)
) A M'! Take WM25 (250 using one device)
M) I, proton (1H) nuclear magnetic co-rl
! A k (n, m, r) spectrum was obtained. S = singlet wire, d
= doublet, word = triplet, m = multiplet and q = quartet. The small reactor is manufactured by Beers & Wariner Limited (Pi
erce & Warriner Ltd, ) (UK)
Solid walled glass container with screw cup and Teflon facing desk, supplied by Preparation Example 1 N-Mef-2-Propenesulfonamide - Dry methylamine gas was bubbled into a solution of 2-propenesulfonyl chloride in dry ether (50 WI!) while maintaining an internal temperature of 78°. The flow of methylamine was then stopped and the reaction mixture was stirred for a further 45 min at -78°. After being allowed to warm up to ambient temperature r, water (100 m/m) was added and the reaction mixture was acidified (
511HO1:, Hl). The ether layer was separated and the aqueous phase was extracted with dichloromethane (5XlO ('1 m/ml). The combined organic extracts were dried (over Na2S04) and concentrated in vacuo to give the title compound (1,4
1) was obtained. T, 1. c. ((Rf O, 65 N, m, r, δ(CjDO15) 2-80 (3H*
d, 802NHMe), 3.72 (2H. d, 01112802NH), 5.3 - 6.2
(3H, m, 0H2=(Jl) Production example 2
) dosalt ftS2-10 loethanesulfonyl (8,15,)i
Dissolved in benzene (30 ml), the solution was cooled to 5°, stirred well and treated with 2-phenylethylamine (20,) in benzene (12,5 ml). The mixture was stirred for a further hour and then washed with dilute acid (25d) and sodium bicarbonate (8%, 50d). When dried, 1 m of oily material (10,3,...) was obtained. Distillation of this oil gave raw product W as an oil (2,2), which was further purified by flash chromatography (y) to give the exact compound as an oil. t, 1. c(?) Rf 0.3 (kMn04). Production Example 3 Cyclopentylamine (
+'1.5, ) and triethylamine (27,8r
nl) mixed with anhydrous ether (2
2-chloroetha/sulfonyl (16
, 2,) dropwise over 665 hours. The mixture was allowed to stand for one hour to reach 15°;
The suspension was filtered and the P solution was concentrated in vacuo to give an oil (1
0,5,)'II, which was purified by chromatography (X) chloromethane). The obtained oil (1,5,
) was distilled at 135°/6 mmHy to give the title compound (1,2,) as an oil. t, 1. c, (dichloromethane) Rf o, 5 (
KMnO4). Preparation Example 4 Sulfonamide P 4 in dry dichloromethane (20+ml) at -78°
A cooled solution of methoxybenzylamine (22) and triethylamine (2,8++tJ!1 was transferred under nitrogen to a solution of cyclized 2-chloroethanesulfonyl (4,9,) in dry dichloromethane (20m) at -78° The mixture was stirred for 4 hours while warming to room temperature and then cooled overnight. Water (approximately 10 ml/liter) was added and the organic layer was separated.
/) and Kansui C501! Wash with II water, (Machi SOa±
) and evaporated under reduced pressure. Purification of the residue by chromatography (dichloromethane) yields a powder (
The title compound was obtained as 2,). Melting point 68-69° Production Example 5
-aminomethylbenzamiptn, ss,) and triethylamine (t,lI/) under nitrogen for 30 min.
was added to a solution of 2-chloroethanesulfonyl chloride (+1.63, ) in DMF (4FnA) at 0°. The mixture was left to warm at room temperature and stirred for 18 days. The mixture was evaporated to a semisolid (2, 789),
This was purified by column chromatography (DJ) to obtain the title compound as a solid (0,54,). Melting point 1
42-144°. Analysis actual value: a, 5n, n; a, 5.3; N, tl,
5. . C1°H42N 203S: Theoretical value: C! , 511.
0; H, 5, 0; N, LL, 7%. Preparation Example 6 P-phenyl)hydrazone 4-
Solution of iodophenylhydrazine (2,) 5r:3rin-
4-dimethylaminobutanol and diethyl acetal (2,6) were stirred at room temperature. The resulting solution was diluted with sodium bicarbonate (50d) and ethyl acetate (2x, which was used directly in the next step. t-1,c, (R) [n
3Product of a(+) in chloroform<80ml) (
2,3,) and a solution of polyphosphoric acid ester (40,)
Refluxed for minutes. The solution was added to ice (300,), stirred for 20 minutes, poured into 2N aqueous sodium carbonate (100n1g) and extracted with chloroform (2x100). Dry the combined organic extracts (over Na2SO4).
"Dried and evaporated in vacuo. The resulting oil was purified by flash chromatography (B) to give the pure free base as a solid. Ethanol C20 ml
The solution of the tomb (fl, 92 f) in j was mixed with methanol (
Oxalic acid (n, 28.NC) in oxalic acid (n, 28.NC) was added and the title compound was precipitated. Melting point 176-177°i, 1.c, (
B) Rf O,3. Analysis actual measurement M c, 4t, s; H, 4, z; N, 6.9
゜C12"151N2-C2H2o4"Theoretical value: C
,41,3;H,4,1;N. 6.55%. Example 1 (K) -3-(3-(2-(dimethylamino)ethyl)2-prope/sulfonamide The product of Preparation Example 1 in oxalate acetonitrile (3rnl)
247■), 5-bromo-N,N-dimethyl-IH-indole-3-ethanamide 78m salt (650■), nozoradium acetate (8,3F1), lyorthotolylphosphine (26,3mQ), and Triethylamine (1
, 1)Fll) was heated for 24 hours at 105-110° in a reactor type @/J1. On cooling to ambient temperature, the reaction mixture was poured into water (20 m/) and the emulsion was extracted with ethyl acetate (3 x 50 m/). The combined organic extracts were dried (over Na2S04) and concentrated in vacuo. Seven-layer chromatography (B) of the residue gave the free base as a foam (2831119). Anhydrous ether/-k (n, 5tul) in free I11 group (2
The filtered solution of 72,5 mq) was added to absolute ethanol (0,5 mq).
A solid was precipitated from Mayuki ethanol during sflutting. After filtering the filter, washing with ether (20 m/liter), drying, and recrystallizing from ethanol (20 m/liter), the title compound was obtained as a powder (98~). Melting point: 93-95° Analytical actual value. : 0,52.4;H,6,5;N,10.
2゜C16H23N502S, C2H204: Theoretical value:
C, 52,5; H, 6,1; N. 10.2%. N, m, r, δ((!D3800D3)(2,66(
3H,s, SO2NHMe)]. 6,88 (IFi, d, CH2CH=Cl
), 7.2-7.7 (4H, m, marriage family) Example 2 Using a method similar to that in Example I, the appropriate alkenesulfonamide and the reaction Φ conditions shown in Table 1. The following compounds were made. (at (El -2-[3-C2-(-dimethylamino)ethyl]-LH-indol-5-yl]ethenesulfonamide oxalate fusion 192° (decomposition) Analysis actual value: Cj, 49-4 ;H,5,5;N,1(
1,5°c, 4H4,N302S, C2H204,n,
44H20: W theoretical value: c, 49. +;■(,N to 5
, io, 7chi. N, m, r, δ(('!D3ROCD3)2.8
5 (6H, -j1Me21, 3.1-3.35 (4H,
m, CH2('!H2N), 7.15+In, d, 5o
2CH=CH), 7A3 (I H, d, B
O2CH=CH), 7, 38.0 (4H, rn
, aromatic)(b)fg)-2-[3-42-(dimethylamino)ethyl)-IH-indol-5-yl]-N
-Methyledenesulfonamide oxalic acid group melting point 189-1900 Analysis zenith 11 value: c, 50.95:H, 6,2:N,
Lo, 45° C15H21J02S, C2H204,0
, 21H20: Theoretical value: C, 50, 9: H, 5-9:
N + 10.5 min. N, m, r, δCCD3SOCD3) 2.83 (6H,
s, NMe2)3.05-3.35(4H,m,OT(
,,OH,2N),7.01(LH,d,5o
20:CH), 7.45 (IH. d, 5o20H=CH), 7.3-8.0 (5H, m,
Aromatic 1NH302) (C) (E) -2-C3-(2
-(dimethylamino)ethyl)-tH-indole-5
-il]-N. N-dimethylethenesulfo/amiriya melting point 136~
138° Analysis actual value: c, 5t, 6; H, 6,0; N, 9.5
. c, 6H23N302S, C2H204, (1,53H
20,0,33C2H60:Cj, 51.4;H
, 6, 4; N, 9.6% = (theoretical value) N, m, r, δ (
CD3 days 0CD3) 2.75 (6H,s, E102NM
e2), 2.84 (6J aromatic),. (d) (barrel-2-[3-[2-(dimethylaminocoethyl)-1H-imbil-5-yl]-N-(2-phenylethylfuytenylphonad 47 malic acid)
1 melting point 1815~l
89' Analysis actual value: C, 62,6; H, 6,4: N, 9.0
. CH2CH2N3028.0.5C4H404,O,0
L3H20:Cj, 62.9:H,6,4;N,
9.2 Regret: (Theoretical value N, m, r, δ (CD3SOCD3) 2.27 (6H,
t, NMe2), 2.56 (2H, m. CH2NMe7), 2.75-2.9 (4H, m
, CH2CH214 and PhCH,,0H2). 3.16(2H, m, 0H2NH8Q2n, 6.9(l
Jd, 6102CH=CH), 7.15-7.9(IO
H, m, aromatic +NHBO2CH=OH). Melting point: 125-129° Analysis actual value: C, 53,1; I (, 6° 5; N, 9.
8. OHN O, Cj HO, O, 12H2o: Theoretical value:
C, 53.4; H, fi, 4; N, 9.8%. N, m, r, δ (CjIt2SOCD3) 1.12 (6
H, d, OHM, 2), 2.79 (6F (.s, NMe2), 3-05-3-2 (4H,
rn, CH2CH2N ) + 3-37 (IJ(
, rn vcHM ), 7.02 (LH, d, 802
Hit=CH), 7.3-8. fl(5H, aromatic + EI
O20H=C)(). Melting point 200-20k0 Analysis actual value: (3,56,3; H, 6,7; N, 10
．． 7゜C16H23N302S. n, 5c4H404,
0,151 (20: Theoretical value: C. 56.6; H, 6,6; N, 11.0%. N, m, r, δC0D380CD3)1. LO(3H,
t, 502NHCH20H5), 2.40(6H+'
+ NMe2, 2.7-3.0C6H, m, cg2
cw2y and S O2NHCFi 2aH,), 7. O
tC■a, d, 5o2aH=cFr), 7.25-7.
95 (5FI, m, aromatic +502C) 5-yl]ethenesulfonamide ripm melting point 202
~203° Analysis actual value: 0,55. i; H, fi, 5; N, 9.
1 n(!, gH27N302B, 02H204,Q,
27H20: F M! tii ti 2 0, 55
．． 3; H, 6, 4; N, 9.2%. N, m, r, δ (cD310D3), L, 4-1.9
(8H, m, cyclopentylmethylene proton)
, 2.83 (6H, q, NM, e 2 ], 3.
115-3, 35 (4H, m, CH2CH2N)
, 3 , :55 (IH, m, 802NH sub) ,
7.02 (IH, d, 5O70H=OH), 7-3
-8.11 (5H, m, aromatic + EI020) (=CH
) (hl (El -2-C3-C2-(tumethylamino)ethyl2H-yneP-5-yl)-N-Melting point 203-205° (decomposition) Analysis actual value: C, 59,4; H, 5 ,7;N,9.4
. C20H25N 302 S, n-sc 2a2o
4. fl, 5H20-Q, 25K 10H: Theoretical value: 0,59.1; H, 6,1; N, 9. fi
Many. N, m4. δ(CD3day O(!D3>2.5311-T
, Q, NMe23,2.8-:1.0+4H. m, desired 2ffH2N), 7.11-8.11 (1,2H
, m, aromatic + IFc + 20H=CH--1-2NH) (Ten) 4-
Methoxyphenyl]methyl]ethenesulfonamide oxalate melting point 1fi6-169° Analysis actual value: C, 57, 1:H, 6, 0:N, 8.2
．． . C2□H27N303S, C2H404: Theoretical value: C
, 57,2; H, 5,8; N, 8.3% Example 3 5-iodo N,N-dimethyl-IH-indole-3-ethanamine oxalic acid salt (0,
65, ), 4-CC(ethynylsulfonyl)amino]methyl]benzamide (0,4(1,), noradium acetate (161119) and triethylamine (0,7 ml
) was heated at 100° for 22 hours in a 5 ml "mini reactor". Evaporate the mixture to form an oil (1
,659)t? ! , this was subjected to column chromatography (B
) to give a solid (245~). This was dissolved in methanol (2M) and a solution of oxalic acid (521FI&) in methanol (2ml) was added. When the mixture is evaporated, a foam (288WII?) is obtained;
When this is recrystallized from ethanol/toluene and combined with similarly prepared material, a solid <312r
The title compound was obtained as nq). Melting point 145-150° Analysis actual value: 0,56.4; H, 5,4; N, 9.7
゜024H28N40. S, 0.1 (I F!t, o)
T, 11.32 mol Toluene:c, 57.65:H,
5,8; N, to, 2%: (theoretical value) Example 4 A solution of the product of Example 1 (237,5 ■) in absolute ethanol (C2CNrTl) was heated to 24% at ambient flow rate and pressure.
10% noradium oxide (4501
Hydrogenated over N9.50% aqueous paste). The reaction mixture was filtered through a Celibot sand pad and washed thoroughly with ethanol (10 tl/) and the combined filtrates were concentrated in vacuo. Flash chromatography (A) of the residue reveals an oil (
184,5~) to give the product as
Dissolved in ~tanol (1 ml) and filtered through a cotton wool plug. To this solution, add absolute ethanol t 0.5 am7! > 6-acid anhydride (51,4
1n9) (add solution D and during sflutting,
A crystalline material was precipitated. The salt was filtered, dried and recrystallized from absolute ethanol C5ml) to give the title compound as an amorphous powder (80ml). Melting point 141-143° (softening point 131') Analysis actual value:
C, 52,1; H, 6,6; N, 9.95° C16H
25N302S, C2H204: Theoretical value: c, 52.
3; H, 6,6; N, 10.2%. N, m, r, δ(CD3SOCD5n 1.98(2H,
m, 0H2CH2(!H2So2NH)2.53(d,
μtsu H80□), 2.83+6J*, NMe2), 2
．． 7-3.35 (8H. m, ('!H2CH2NMe2 and 0H2CH2
CH28021JH), 6.85-7.45 (5H,
m, aromatic raw NH302). Example 5 The following compounds were prepared according to the method of Example 4 using starting materials and reaction conditions omitted from Table a below. Borate melting point 176-178° Analytical Observation: a, 49 .45;H,5,9;N,to
, 6゜014H2, N502S, 02Fi204-0
．． 32H20: Theoretical value: (!, 49.1; 1'l, 6
．． 1; N, 10.7%. N, m, r, δ (CDs day 0 (D3) 2.86 (6H,
s, NMe2), 3.0-3.4 (8H. m, CI! CFi 80 NH and aH2ca2NM
e2), 6.85-7.55 (6H, m, aromatic raw 80
2NH2). (b) 3-(2-(dimethylamino)ethyl]-N-methyl-IH-indole-5-ethanesulfonamide 3,44+41,rn, C2H204280
2NHMe), 7, 0-7-5 (4H, m, aromatic]. (c) 3-(2-(dimethylamino)ethyl)-N, N
-Dimethyl-1) I-indole-5-ethanesulfonamide oxalic acid group melting point 130-135° Analysis actual value: 0,51.4; H, 6,8; N, 9.8
゜(! 16H25NS028, 02H20a, 0
-26H20: Theoretical value: C! ,51.7;H,6,6
;N, 10.05%. N, m, r, δ (CD3r0cD5) 2.81 (12H
, II, Me2NE[]2 and OH2CH2NMe2
), 7, 1)-7, 55 (4H, m, aromatic)
(ψ 3-[2-(-umethylamine]ethyl]-N-
(2-Phenylethyl)-1EI-indole-5-ethanesulfonamide oxalic acid group melting point 155-156° Analytical trace 1 value: c, 58.5; H, 6,4; N, 8.
3゜(!22H29N302R,a 2H204,n
-08H20: Theoretical value 0,58.7;H,6,4;N
, 8.6%. N, m, r, δ(r'D3SOCD332.82
(6H, ;, NMe2), 2.75-3.35f5.9
5-7.5 (LOH, m, aromatic raw NH302). Melting point 168-170° Analysis actual value: C, 53,3; H, 6,8; N, 9.6
゜(117H27N302S, C2H204,0,lH
2O: Theoretical value: (!, 53.2; H, 6, 8: N, 9
．． 8 '1°N, m, r, δ (CD3r30cD5) 1.16 (6
Jd, OHMe2), 2.82 (61(.s, NMe2), 3.0-3.35 (8H, m, OH
OH20H2N, and NHFJO21:H, (IH21
, l'i, 98-7.5 (5H, aromatic + infant 02
) Honamide oxalate group melting point 158-159° Analysis actual value: C, 52,1; J6.5; N, 10.5
゜0.6H25N302S, 02H204,0,03H
20: Theoretical value: (!, 52.2; H, 6, 6; N, 1
Section 0.1. N, m, r, δ (CD, E100D3) 1.12 (3
N(,t,MeCH2N1'1802), 2.95-
3.35 (IOH, m, MeOH2NHEIO20H
20H,2 and OH2CH2NMe2) 17.0-
7.55 (5H, m, aromatic raw NH802). Tansulfonamide oxalate melting point 181-182° Analysis actual value: a, 55. ．． 4; H, 7, 0; N, 8.
9゜C19H29N30□S, a2H204: Theoretical value:
a, ss, 5; u, 6. g; N, 9.2%. N, m, r+δCCD5SOC'D3) 1.4-1.9
h (8H, m, cyclointhyl 0H2X 4) 2.83
(64s, NMe2), 3.0-3.36 (8H, m,
8026.98-7.52<47 (, m, aromatic). Melting point 142-144° Analysis actual value: C, 55,9; H, 6,2; N, 8.0
゜C2zH29N 305S, C2H404, 0, 5
H20: Theoretical value: 0,56.0; H, ti, 3; N,
8.2%. N, m, r, δ(('!D580CD,)2.83 (
6H,s, NMe2), 2.9-3.35 (8H.m, GH2CH2SO2NH and OH20OH20H2
N, 3.75 (3H,s, OMe). 4.15 (2H, d, 0H2aadayo□), fi, 8
-7.45 (FIR, m, aromatic). Example 6 The product of Example 2h in absolute alcohol (30 mA)
A solution of 10% palladium oxide (74011) previously reduced on charcoal for 18 h at room temperature and pressure
1! ii+: 5 pre-reduced in ethanol 20g
0% aqueous paste]. The mixture was filtered through a sandoserite nozzle and washed thoroughly with ethanol (1501/). The filtrate was concentrated in vacuo, the residue taken up in ethanol (30 at) and treated with Raney nickel (~50 instant) for 30 minutes. The nickel was removed by filtration and the filtrate was rehydrogenated for an additional 18 hours. The catalyst was removed by filtration through a sand-cellulose solution and the filtrate was concentrated in vacuo. 7 cyclochromatography of the residue (N
gave the product as a low melting solid (103Iny). The filtered solution of the solid in warm anhydrous ethanol (Ca1l) was dissolved in an ethanolic solution of oxalic anhydride ([1/25~)
added to. Amorphous solids are precipitated during sflutting,
This was filtered, air dried (1 hour) and recrystallized from ethanol (3ON) to give the title compound as an amorphous powder. Melting point 144-1.46° Analysis Measured value 20.58.9; H, 6.6; N, 9. n. CzoH2sN so 2B, Q, 502FI2
0 a -0-4C2H60,0,7H20: Theoretical value:
C, 5g, 5; H, 6,7; N, 9.4%. N, m, r, δ (cD3SOCD3) 2.63 (6H,
s, NMe2) 2.98 (4H, m. day 020H2CH2), 6.8-7.5 (9H, m, aromatic). The following example shows (Ee -2-(3-(2- (
Figure 2 illustrates a pharmaceutical formulation according to the invention containing dimethylaminocoethyl)-1H-indol-5-yl)-N-[(4-methoxyphenyl)methyl]ethenesulfonamide oxalate. Other compounds of the invention can be formulated in a very similar manner. Tablet direct compression for oral administration my/tablet active ingredient
24 Calcium hydrogen phosphate B, P,' 95.1
0 Cross Force Lumerose Sodium USF
2.00 Magnesium stearate B, P,
0.50 compression weight
100 ■Rice Suitable grade for direct compression Sift the active ingredient before use. Calcium hydrogen phosphate, croscarmellose (f:!rO8Carme-
11ose) Weigh the sodium and active ingredient into a clear polyethylene bag. The powder was mixed by vigorous shaking and then magnesium stearate was weighed and added to the mixture which was further mixed. Next, it was equipped with a punch with a 5°5NII flat slanted blade, and a mane stay (
Manesty) Using a F3 tablet machine, io
The mixture was compressed into tablets with a target compression weight of o my. Tablets can also be made by other conventional methods such as wet granulation. Tablets of other strengths can be made by varying the ratio of active ingredient to lactose or compression weight and using a suitable punch. The tablets may be film coated with a suitable film forming agent such as hydroxypropyl methylcellulose using standard techniques. Alternatively, tablets may be sugar coated. Capsule ■/Capsule active ingredient 2.4 Rice starch 1500 196.6
Magnesium stearate BP
1. nO filling weight
The active ingredient in the form of zoo, on rice direct compression starch was sieved and mixed with excipients. The mixture was filled into hard gelatin capsules of size 2 using a suitable machine. Other dosages can be made by varying the fill weight and, if necessary, changing the capsule size to suit. Syrup In915WLl Dosing Activity Minutes 2.4 Buffers Flavors Colors Preservatives Thickeners Sweeteners Purified Water 50 amlKfl II Active Ingredients, Buffers, Flavors, Colors, Preservatives. The thickener and sweetener were dissolved in some water, the volume of the solution was adjusted and mixed. The produced syrup was filtered to make a pure syrup. Herbal medicine active ingredients for transrectal administration 2.41n9 Witepsol H2S 1
．． 0. Amount of rice Adeps Solidus B-H,
Iuro, (Adeps Solidus Ph, Ku
A suspension of the active ingredient in molten Uitepsol of a suitable grade (r, ) is made using a suitable machine. It shone in a pear-shaped shape. Injection for intravenous administration ■ / ml Active ingredient 0.6N9 Sodium chloride Required amount Water for injection BP Amount to make 1, Qlnl Sodium chloride may be added to adjust the tonicity of the solution, and the optimum stability of H and (Also) H may be adjusted using an acid or alkali to facilitate dissolution of the active ingredient. The injection solution is sterilized by heating in an autoclave using an appropriate cycle of the autoclave. Alternatively, the solution is sterilized by filtration and filled into sterilized ampoules under aseptic conditions. An inert atmosphere of nitrogen or other suitable gas may be provided. Biological Tests Regarding the E Os o value (molar concentration of the compound required to produce 50% of its maximum effect) and 5-hydroxytryptamine. The concentration ratio of Br, J, Pha-rma
col, 1, 1985, 86, 697-704
rey), Em, J., Belen (M, , T, P
erren) and Nie, Day. Constriction of isolated saphenous veins of dogs was determined for compounds of the invention according to the method described by Watta (A, D, Watta). The following results were obtained. Equal force atL ratio zb i, s x to-6122d
3.9 x 1O-73f32f 2.3
X 10-636211, t x 1O-7*(143
'4 1, I X 10' 13
5d 1.3X10-→ 79 dormitory Se
t, txio' 14 US - Average of 2 results US - Average of 4 results CD5g (i.e. 50 of maximum increase in carotid resistance)
%] is 0.1μ
/Kf administration starting with da and then 1000μ, 7y
,yS? The compound of Example 2I was determined by administering the compound intravenously to anesthetized companion beagle dogs at 15 minute intervals, giving progressively higher doses up to a cumulative dose of . Carotid blood flow was measured using a current test needle and the peak increase in carotid vascular resistance was recorded at each dose. Vascular resistance f (8axena) (European Journal of 7 Armacolo Ku (F
ur, ,T, Ph5. The CD5° was calculated as K and found to be >43 μf/N (average of two results). The dog's blood pressure was also recorded during the above test. Compound of Example zi showed no significant effect on blood pressure at doses up to 1000μ,/KII.Representative: Patent attorney Masamitsu Akizawa and one other person

Claims (11)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) {In the formula, R_1 represents a hydrogen atom, C_1_-_6 alkyl or C_3_-_6 alkenyl group,
2 is a hydrogen atom, C_1_-_3 alkyl, C_3_-_
6 alkenyl or C_5_-_7 cycloalkyl group, or phenyl or phenyl (C_1_-_4)
Alkyl group [However, phenyl ring may be unsubstituted or halogen atom, C_1_-_3 alkyl, C_
1_-_3 alkoxy or hydroxy group or group -NRaRb or -CONRaRb (However, Ra and Rb may be the same or different, and each is a hydrogen atom, C_1_-_3 alkyl or C_3_-_6
may represent an alkenyl group or be substituted by a saturated monocyclic 5- to 7-membered ring (which may further contain a heterofunctionality) together with the attached nitrogen atom] R_3 and R_4 may be the same or different and each represents a hydrogen atom, C_1_-_3 alkyl or propenyl group, or R_3 and R_4 together form an aralkylidene group, Alk represents an alkyl chain containing 2 or 3 carbon atoms, which may be unsubstituted or optionally substituted by not more than two C_1_-_3 alkyl groups, and A^1 is 2 to representing an alkenyl chain containing 5 carbon atoms} and its salts and solvates. (2) A^1 is a group -(CH_2)_mCH=CH(CH_2)_n- (in the group, m is zero or an integer from 1 to 3, n is zero or an integer from 1 to 3, and m and n does not exceed 3). (3) General formula (I') ▲Mathematical formulas, chemical formulas, tables, etc.▼(I') (In the formula, R_1, R_2, R_3, R_4 and Alk are as defined for the general formula (I). and m is zero or an integer from 1 to 3) and its physiologically acceptable salts and solvates. (4) An indole according to any one of claims 1 to 3, wherein Alk represents an unsubstituted alkyl chain containing 2 carbon atoms. (5) An indole according to any one of claims 1 to 4 having an E-configuration with respect to the double bond of the 5-substituent. (6) General formula (Ia) ▲Mathematical formulas, chemical formulas, tables, etc.▼(Ia) [In the formula, R_1_a represents a hydrogen atom or a C_1_-_3 alkyl group, and R_2_a represents a hydrogen atom or a C_1_-_3 alkyl group. or phenyl or phenyl (C_1_-_2) alkyl group (however, the phenyl ring is unsubstituted or C
_1_-_3 alkoxy group or group -CONH_2), R_3_a and R_4_a each represent a hydrogen atom or a C_1_-_3 alkyl group, and ma is zero or 1. Indole and its physiologically acceptable salts and solvates as described in Section 1. (7) (E)-2-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-N-methylethenesulfonamide, (E)-2-[3-[2- (dimethylamino)ethyl]
-1H-indol-5-yl]-N-(2-phenylethyl)ethenesulfonamide, (E)-2-[3-[
2-(dimethylamino)ethyl]-1H-indole-
5-yl]-N-[(4-methoxyphenyl)methyl]
Claim 1 selected from ethensulfonamide
Indole and its physiologically acceptable salts and solvates as described in Section 1. (8) an indole of general formula (I) or a physiologically acceptable salt thereof as defined in claim 1, together with one or more pharmaceutically acceptable carriers or excipients; A pharmaceutical composition comprising an effective amount of at least one solvate as an active ingredient. (9) General formula (II) characterized by reducing the indole of general formula (I) as defined in claim 1 ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (Formula A method for preparing a compound in which R_1, R_2, R_3, R_4 and Alk are as defined in claim 1 and A represents an alkyl chain containing 2 to 5 carbon atoms. (10) 3-[2-(dimethylamino)ethyl]-N-
Methyl-1H-indole-5-propanesulfonamide, 3-[2-(dimethylamino)ethyl]-N,N-dimethyl-1H-indole-5-ethanesulfonamide, 3-[2-(dimethylamino)ethyl ]-N-(2-phenylethyl)-1H-indole-5-
Ethanesulfonamide, 3-[2-(dimethylamino)ethyl]-N-(1-methylethyl)-1H-indole-5-ethanesulfonamide, 3-[2-(dimethylamino)ethyl]-N-ethyl -1H-indole-5-ethanesulfonamide, 3-[(2-(dimethylamino)ethyl] -N-phenyl 1H-indole-5-ethanesulfonamide, and N-cyclopentyl-3-[2-(dimethylamino) )ethyl]-1H-indole-5-ethanesulfonamide. (11) (A) General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, X represents a leaving atom or group, and Al
k, R_3 and R_4 are as defined in claim 1) in the formula (IV) R_1R_
2NSO_2A^2=CH_2 (IV) (in the formula, -A^
2=CH_2 represents a C_2_-_5 alkenyl chain and R_1 and R_2 are as defined in claim 1) or (B) formula (V) ▲ Numerical formula, chemical formula, table etc. ▼(V) an aldehyde of (wherein A^3 represents a direct bond or a C_1_-_3 alkyl chain and Alk, R_3 and R_4 are as defined in claim 1), Group R_1R_2NSO_2A^1- (However,
R_1, R_2 and A^1 are as defined in claim 1. ▼(X) (wherein R_1, R_2, R_3, R_4 and Alk are as defined in claim 1 and A^6 is C_2_ substituted by a leaving atom or group X^1 −_5 represents an alkyl chain), H
(D) General formula (X I ) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X I ) [In the formula, R_1, R_2, Alk and A^1 are patent claims and Q is the group NR_3R_4 (wherein R_3 and R_4 are as defined in claim 1) or a protected derivative thereof or a leaving atom or group. or by cyclizing the compound of the general formula (X
IV) ▲Mathematical formulas, chemical formulas, tables, etc.▼(XIV) (In the formula, R_1, R_2, A^1 and Alk are as defined in claim 1, and Y
is an easily replaceable atom or group or a protected derivative thereof). is reacted with an amine of formula R_3R_4NH (wherein R_3 and R_4 are as defined in claim 1) or (F) general formula (XV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XV) (wherein A^1, Alk, R_3 and R_4 are as defined in claim 1 and Z is a leaving atom or group) by the general formula (XVI) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XVI) (wherein R_1 and R_2 are as defined in claim 1) or (H) converting a compound of general formula (I) or a salt or protected derivative thereof into another compound of general formula (I) as defined in claim 1; a protected derivative of general formula (I) or a salt thereof as defined in 1
subjected to a reaction to remove one or more protecting groups,
and if necessary and/or desired,
After any of the methods A to G, (i) any protecting group or groups are removed and (ii) the compound of general formula (I) or a salt thereof is of the general formula (
I) A method for producing indole or a salt or solvate thereof.