HU193304B - Process for preparing indole derivatives and pharmaceutical compositions comprising the same as active substance - Google Patents

Abstract

Indole derivs. of formula (I) and their physiologically acceptable acid addn. salts are new: Ind= indol-3-yl substd. by CH2OH or COW and opt. also by 1 or 2 alkyl, alkoxy, OH, F, Cl or Br; W= H, OH, alkoxy or amino (opt. substd. by 1 or 2 alkyl); A= (CH2)n or CH2S(O)xCH2CH2; n= 2-5; x= 0, 1 or 2; both Y are H, or together they form a double bond; one Z= Ar and the other is H; Ar= phenyl (opt. substd. by 1 or 2 of alkoxy and/or OH, or by methylenedioxy) or is 2- or 3-thienyl; all alkyl have 1-4C.

Description

A is - (CH ₂ ) n -, or -CH ₂ -S-CH ₂ -CH ₂ -CH ₂ -, n is 2, 3, 4 or 5, and each of the two Y groups is hydrogen or taken together as a CC bond. , one of Z is Ar, the other of Z is hydrogen, and

Ar is phenyl optionally substituted by alkoxy or hydroxy, or 2- or 3-thienyl.

The compounds of the present invention have, inter alia, anti-parkinson and anti-neuroleptic activity, and are useful in the treatment of depression and psychiatric disorders.

-1193304 ι

The present invention relates to novel indole derivatives and to pharmaceutical compositions containing them.

The process of the present invention provides compounds of formula (I) wherein

Ind is indol-3-yl substituted with hydroxymethyl or COW, which may be monosubstituted by alkoxy, hydroxy, fluorine, chlorine or bromine,

W is hydrogen, hydroxy, alkoxy, amino or N (dialkyl),

A is - (CH ₂ ) n - or -CH ₂ -S-CH ₂ -CH ₂ -, n is 2, 3, 4 or 5 each Y is hydrogen or taken together as a CC bond, one Z is Ar and the other Z is hydrogen; and

Ar is unsubstituted or phenyl substituted with one or more alkoxy or hydroxy groups, or 2- or 3-thienyl, and in each case the alkyl groups have from 1 to 4 carbon atoms and n can only be 2 or 3 if hydroxylmethyl or COW are simultaneously substituted. residues 4, 5, 6 or 7 of the indol-3-yl group.

The invention also relates to processes for the preparation of physiologically acceptable salts of the compounds of formula (I) above.

Compounds similar to those of formula I are described in U.S. Patent 3,639,414 and Austrian Patent No. 36833/83.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds useful as pharmaceutical compositions.

It has now been found that the compounds of formula I and their physiologically acceptable salts possess valuable pharmacological activity. They have particularly prominent effects on the central nervous system, in particular their dopamine-stimulated presynaptic (neuroleptic) or postsynaptic (anti-parkinson) effects. More specifically, the compounds of the invention of the formula I induce contralateral rotational properties in rats with hemiparkinsonian disease (described in Ungerstedt et al., Brain Sl. 24, 1970 / 485-493) and inhibit tritiated dopamine agonists and antagonist binding to striatal receptors (described in Schwarz et al., J. Neurochemistry 34, 772-779 (1980)) and Creese et al., European J. Ph'armacol. 46, 377-381 (1977)] and inhibit the tongue and jaw reflexes of narcotic rats [Barnett et al., European J. Pharmacol. 21 (1973) 178-182 and lhan et al., European J. Pharmacol., 33, 61-64 (1975)] and because of their antihypertensive and analgesic activity, catheterized mild spontaneous rats (SHR (NIH-MO) CHB-EMD strains, assay method, Weeks and Jones, Proc. Soc. Exptl. Biok Med., 104, 644-648 (1960)] to reduce directly measured blood pressure when administered via the stomach.

The compounds of formula (I) and their acid addition salts prepared according to the invention are useful as active ingredients in pharmaceutical formulations and as starting materials for the preparation of other active ingredients.

The compounds of formula (I) obtained by the process of the present invention may contain one or more asymmetric carbon atoms, such as racemates, or mixtures of racemates with multiple asymmetric carbon atoms.

In the process of this invention, the preparation of novel compounds of formula (I) may be carried out according to methods known in the art (e.g., Houben-Weyl, Methoden Der Organischen Chemie, Georg-Thieme, Stuttgart, or John Wiley and Sons, Inc., New York). in one of the methods described in the literature), under the reaction conditions required for the methods described, or other methods known in the art and not described above.

In the process of the invention, the starting materials may also be used, if desired, in which case they are directly converted to the compounds of formula (I) without isolation.

The process of the invention may be prepared from compounds of general formula (I), when a compound of formula, wherein X ¹ is X or NH2 and X is chlorine, bromine or iodine, hydroxyl or formed reactive group hidroxilcsoport- (II) with a compound of formula III wherein X ² and X ³ may be the same or different and when X '= NH 2 they are always X, otherwise -NH- and Y and Z are as defined above.

In the indole derivatives of formula (II), preferably X is X and accordingly in formula (III) X ² and X ³ together are preferably NH. Preferably X is chlorine or bromine, but it may be an iodine, hydroxy or reactive hydroxyl group, preferably a C 1-6 alkylsulfonyloxy or a C 6-10 arylsulfonyloxy group such as methanesulfonyloxy or benzenesulfonyl. oxy, p-toluenesulfonyloxy, or 1 or 2-naphthylsulfonyloxy.

Accordingly, the preparation of the indole derivatives of the formula I by reaction of the compounds of the formula Ind-A-Cl or Ind-A-Br with the piperidine or tetrahydropyridine derivatives of the formula III in which X ³ and X ^{2 are} combined. -NH (hereinafter referred to as compounds of formula IIa) are prepared.

The compounds of the formula (II) and in particular the compounds of the formula (III) are partly known, and the new compounds are prepared in a similar manner. Compounds of formula II (A = = -CH ₂ -S-CH ₂ -CH ₂ -) compounds of formula V and thiols are -HS-CH ₂ -CH ₂ -X '- such as HS-CH ₂ CH ₂ OH. The primary alcohols of formula Ind-A-OH are obtained from the corresponding carboxylic acids or their esters which are treated with thionyl chloride, hydrobromic acid, phosphorus tribromide or the like to form the corresponding halide of formula Ind-A-Hal. Sulfonyloxy compounds can be prepared by reacting alcohols of the formula Ind-A-OH with sulfonyl chloride.

The iodine compounds of Formula Ind-AJ are prepared by reacting the appropriate p-toluenesulfonic acid ester with potassium iodide, while the Ind-A-NH ₂ amines are prepared by reacting the halides with phthalimide potassium or reducing the corresponding nitrile.

The pyridine derivatives of formula (IIIa) are largely known (e.g., German Patent Publication No. 2260816) and the 3,4-dehydropiperidine derivatives can be prepared by reacting 3- or 4-piperidone with the organic and then hydrolyzed to the corresponding 3-Ar-3-hydroxy or 4-Ar-4-hydroxypiperidine compound followed by 3- or 4-Ar-3 Dehydrated to 4-dehydropiperidine. Compounds of formula III, wherein X ² and X ³ are each X, may be prepared by di-esters of alkyl-OOC-CH ₂ -CYZ-CYZ-COO-alkyl HO-CH ₂ -CH ₂ CYZ-CYZ-CH It is reduced to _2- OH diols and then reacted, if desired, with thionyl chloride or phosphorus tribromide.

Conversion of compounds of formula (II) and (III) from the literature is carried out according to known procedures for alkylation of amines. The reaction may be carried out in a sealed tube or autoclave by direct melting of the components or may be carried out in the presence of an inert solvent. Suitable solvents are, for example, hydrocarbons such as benzene, toluene or xylene; ketones such as acetone or butanone; alcohols such as methanol, ethanol, butanol or isopropanol; ethers such as tetrahydrofuran or dioxane; amides such as N-methylpyrrolidone, nitriles such as acetonitrile; or optionally a mixture thereof with one another or with water. The reaction is preferably carried out using an acid scavenger such as an alkali or alkaline-earth hydroxide, carbonate or bicarbonate, or a weak acid salt of an alkali or alkaline-earth metal, such as sodium, potassium or calcium, but may also be used. and also a base such as trimethylamine, dimethylaniline, pyridine or quinoline, or an excess of the amine compound Ind-A-NH ₂ or the piperidine derivative (III). The reaction temperature is from 0 to 150 ° C, usually from 20 to 130 ° C, and the reaction time is from a few minutes to 14 days, depending on the conditions used.

The compounds of formula (I) may also be prepared by reducing a compound of formula (I) having a carboxyl group in place of a methylene group to a methylene group, or a pyridyl group containing a tetra or hexahydropyridyl group in formula (I). ) in a compound of the formula: hydrogenation to a hexahydropyridyl group. Preferred starting materials for the reduction are compounds of formula (IV), and nascent hydrogen or complex metal hydrides or the Wolff-Kishner process are preferably used for the reduction.

The starting material used for the reduction in formula (IV) is Indol-hydroxy-methyl or COW-substituted indol-3-yl which may be further substituted by alkoxy, hydroxy, fluorine, chlorine or bromine. .

L is a chain corresponding to A or A in which one or more -CH ₂ groups may be replaced by -CO

Q is a group of formula (c) or (b) wherein one of Z 'is Ar, the other Z' is a strong acid anion, and Ar is phenyl, unsubstituted or monosubstituted with alkoxy or hydroxy, and at the same time L cannot be A and Q (c).

Compounds of formula (IV) may be prepared by reacting, for example, 4-Ar-1,2,3,6-tetrahydropyridine or 4-Ar-pyridine with compound of formula (VIII) wherein Ind, L and X ¹ are as defined above. .

When the reduction is carried out using nascent hydrogen, it is obtained, for example, by treating various metals with weak acid or base, for example, by treating zinc with alkaline or acetic acid, but also sodium or other alkali metals such as ethanol, isopropanol, butanol, etc. - or in an isoamyl alcoholic or phenolic medium. Alternatively, an aluminum-nickel alloy may be used in an alkaline-aqueous medium, optionally in the presence of ethanol. It also produces nascent hydrogen in aqueous or alcoholic solutions of sodium or aluminum amalgam. The conversion can also be carried out in a heterogeneous phase, preferably in an aqueous phase and in a benzene or toluene phase.

Metal hydrides such as lithium aluminum 3 may also be used as reducing agents

-3193304um hydride, borohydride, diisobutylaluminum hydride or NaAl- (OHCH ₂ CH ₂ OCH ₃ ) 2 -H ₂ 'or diborane, optionally in the presence of a catalyst such as boron trifluoride, aluminum chloride or in the presence of lithium bromide. Suitable solvents are, for example, the following solvents:

ethers such as diethyl ether, di-n-butyl ether, tetrahydrofuran, dioxane, diglyme or 1,2-dimethoxyethane, and hydrocarbons such as benzene. For the reduction with sodium borohydride, it is preferable to use alcohols such as methanol or ethanol as well as aqueous alcohols as solvents. The reduction is generally carried out at a temperature of -80 to -150 ° C, in particular 0 to 100 ° C.

Compounds of formula (IV) wherein Q (b) and An preferably chlorine, bromine or CH₃SALT₃is preferably carried out with sodium borohydride in the presence of water and methanol or ethanol or a mixture thereof and optionally in the presence of a base such as NaOH at a temperature of 0 to 80 ° C.

The reduction of one or more carbonyl groups can also be accomplished by the Wolff-Kishner process, whereby the starting material is treated with anhydrous hydrazine under pressure in absolute ethanol at 150-250 ° C. Sodium alcoholate may be used as the catalyst. The reduction may be modified according to the Huang-Minlon procedure, whereby the reaction is carried out in the presence of a hydrazine hydrate, a high boiling water miscible solvent such as diethylene glycol or triethylene glycol, and mites such as sodium hydroxide. After boiling for -4 hours, the water is distilled off and the resulting hydrazone is max. Decompose at 200 ° C. The Wolff-Kishner reduction may also be carried out at room temperature in dimethylsulfide with hydrazine.

The compound of formula (I) which has a cyano group at the COW group is hydrolyzed to a carboxyl or carbamoyl group, or a compound of formula (I) having an indole-protected nitrogen protecting group which is solvolitically cleaved.

Suitable starting materials for solvolysis include, for example, the 4-, 5-, 6-, or 7-cyanoindole derivatives which are converted to the corresponding carbamoyl derivatives or the 4-, 5-, 6-, or 7-carboxylic acid compounds of formula (I). -indole derivatives, or 1-acylindole derivatives (which correspond to formula I, but in the 1-position of the indole ring an acyl group, preferably an alkanoyl, alkylsulfonyl or arylsulfonyl group, preferably methane, benzene or p-toluenesulfonyl group) which is hydrolyzed to the corresponding indole derivative in the 1-position, for example in acidic, or even more neutral or alkaline, at temperatures between 0 and 200 ° C.

Preferably, the basic catalyst is sodium, potassium or calcium hydroxide, sodium or potassium carbonate, or ammonia. The solvent is most preferably water, but lower alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or dioxane, sulfones such as tetramethylene sulfone or mixtures thereof, especially aqueous mixtures, may also be used. Hydrolysis can also be carried out by aqueous treatment alone, especially at the boiling point.

Compounds of formula I (A = -CH ₂ -S-CH ₂ CH ₂ -) may also be prepared by reacting Mannich bases of formula V with thiols of formula VI or salts thereof.

The starting compounds of formulas (V) and (VI) are partially known or can be readily prepared by analogy to known compounds. For example, the Mannich bases of formula (V) may be obtained from the indoles of formula Ind-H with formaldehyde and the amine of formula HN (R) ₂ , and the thiols of formula (VI) by the bases of formula (IIa) and HS-CHa-CH3-. prepared ^X1 thiol derivatives (wherein the protected SH groups) was obtained.

The reaction of the compounds of formula (V) and (VI) is carried out in an inert solvent at a temperature of -20 to 250 ° C, preferably 60 to 150 ° C. Suitable solvents are, for example, hydrocarbons such as benzene, toluene, xylene or mesitylene; tertiary bases such as triethylamine, pyridine or picoline; alcohols such as methanol, ethanol or butanol; glycols and glycol ethers such as ethylene glycol, diethylene glycol, 2-methoxyethanol; ketones such as acetone; ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide; sulfoxides such as dimethyl sulfoxide or a mixture thereof. The thiols of formula (VI) are first converted to the corresponding mercaptide, preferably by reaction with sodium or potassium hydroxide, with sodium or potassium ethylate, to give the corresponding sodium or potassium mercaptide.

The compounds of formula (I) may also be prepared by cleaving water of formula (VII), wherein one of E is -OH and the other of E is hydrogen, to form a double bond. Compounds of formula (VII) may be prepared, for example, by reacting compounds of formula (II) (X '= X) and compounds of formula (IX) wherein E and Z are as defined above. The water disintegrant is preferably acetic acid, hydrochloric acid or a mixture thereof, and the reaction is preferably carried out in a solvent such as water or ethanol.

If desired, a compound of formula (I) may be converted to another compound of formula (I) by known methods.

-4193304

The ether compounds of the formula I in which the Ind group and / or the Ar group is monosubstituted with an alkoxy group may be cleaved to the corresponding hydroxyl derivative. The cleavage may be effected by treatment with dimethylsulfide boron tribromide, in the presence of a solvent such as toluene, an ether such as tetrahydrofuran or dimethylsulfoxide, or by fusing with pyridine or aniline hydrohalide at 150-250 ° C, or by reaction with diisobutylaluminum hydride, 110 ° C.

Further, COW groups can be converted to another COW group by known methods. For example, the aldehyde group may be oxidized to a carboxyl group such as MnO ₂ using dichloromethane as a solvent, or the carboxyl group may be reduced, for example diisobutylaluminum hydride in toluene. The carboxyl groups may also be esterified, for example by treatment with alcohols in the presence of an acidic catalyst or by reaction with diazoalkanes. The carboxylic acids can be converted to the corresponding chloride by treatment with acid chloride (e.g. SOCl ₂ ) and then treated with ammonia to the corresponding acid amide. Acid amides can also be prepared by directly treating the carboxylic acids with ammonia or amine. Solvolysis carried out under the same conditions as described above yields the corresponding carboxylic acid from esters or amides. Particularly preferably, the carboxylic acids can be prepared from the carbamoyl derivatives by treatment with NaOH or KOH in an aqueous medium of glycol or glycol ether, for example diethylene glycol monomethyl or ethyl ether, conveniently at a temperature of 50 to 200 ° C. .

Reduction of C0W, such as formyl, alkoxycarbonyl or carboxyl groups, yields a hydroxymethyl group. The reaction is conveniently carried out using a complex hydride such as LIAlH ₄ , but the ester or aldehyde groups may also be reduced by the methods detailed above, preferably under the reaction conditions mentioned therein. Conversely, hydroxylmethyl groups can be oxidized, for example, with MnO ₂ or CrO ₃ , or a derivative thereof, to formyl or carboxyl groups.

The bases of the formula I can be converted into the corresponding acid addition salt with a physiologically acceptable acid. For example, the following acids may be used: inorganic acids such as sulfuric acid; a hydrohalic acid such as hydrochloric acid or hydrobromic acid; phosphoric acids such as orthophosphoric acid; nitric acid; sulfamic; and organic acids such as aliphatic, alicyclic, araliphatic, one or more basic aromatic or heterocyclic carboxylic, sulfonic, or sulfuric acids such as formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, boric acid, pimelic acid, fumaric acid , lactic acid, succinic acid, malic acid, benzoic acid, salicylic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethane disulfonic acid, 2-hydroxyethane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfuric acid.

The salts of the compounds of formula (I) may be liberated with the free base with a strong base such as sodium or potassium hydroxide or sodium or potassium carbonate.

The invention also relates to a process for the preparation of a pharmaceutical composition comprising the compounds of the formula I or their salts as active ingredients. These formulations contain the active ingredient, optionally in combination with another active ingredient, in admixture with one or more carriers, and optionally other excipients. These formulations can be used in both human and veterinary medicine. Suitable carriers include organic or inorganic materials which are suitable for parenteral (e.g., oral), parenteral or topical application and do not react with the active ingredient. For example, water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petrolatum. For enteral administration, the treatment of secondary amenorrhea, premenstrual syndromes, unwanted maternal lactation, and generally as a prolactin inhibitor, as well as for the treatment of cerebral disorders such as migraine, and especially for ergot alkaloids in geriatrics, is also indicated.

Similar to the administration of known formulations (e.g., bromocriptine, dihydroergocornine), the formulations of the invention generally contain from 0.2 to 500 mg, preferably from 0.2 to 50 mg, of the active ingredient per unit. The daily dose is usually 0.001 to 13 mg / kg body weight. Lower doses (0.2-1 mg / dose, 0.001-0,005 mg / kg) are used in the treatment of migraine, while higher indications are considered for the other indications. Dosages should be adjusted according to the patient to be treated (age, weight, general health, diet, interval between doses, route of administration, combination of drugs, degree of disease). Oral administration is preferred.

In the following examples, "usual work-up" means as necessary adding water to the product, extracting it with dichloromethane, separating the organic phase, drying over sodium sulfate, filtering, evaporating, chromatographing on silica gel and / or crystallizing. Temperature values are given in ° C.

Example 1

28.4 g of 3- (4-chloro-2-thia-butyl) -indole-5-carboxylic acid methyl ester or 32.8 g of 3- (4-bromo-2-thia-butyl) -indole-5 carboxylic acid methyl ester (prepared by reacting gramine 5-carboxylic acid methyl ester with 2-mercaptoethanol

-5193304 reacting 3- (4-hydroxy-2-thia-butyl) - forming inclined-5-carboxylic acid methyl ester in-face and treated with _SOCl2 or _PBr3 azide azide], and 16 g of 4- A solution of phenyl-1,2,3,6-tetrahydropyridine in 100 ml of acetonitrile was stirred for 12 hours at 20 ° C to give 3- [4- (4-phenyl-1,2,3), after usual work-up. 6-Tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxylic acid methyl ester ("P") hydrochloride. M.p. 202-203 ° C. Yield: 81% _;

In a similar manner, the following compounds were prepared starting from the corresponding compounds of formulas II and 111:

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxymethylindole, m.p. 178 ° C

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-hydroxymethylindole, m.p. 118-120 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -6-hydroxymethylindole, m.p. 142-143 ° C

Ethyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-methoxy-indole-2-carboxylic acid, m.p. 138-140 ° C.

2-hydroxymethyl-3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-methoxyindole; mp: 164165 ° C,

2-hydroxymethyl-3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole, m.p. 159-161 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -4-methoxy-indole-6-carboxylic acid, m.p. 160-162 ° C

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -4-ethoxycarbonylindole 3- [4- (4-phenyl-1,2,3) , 6-tetrahydropyridyl) -2-thia-butyl] -5-ethoxycarbonylindole 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -6- ethoxycarbonylindole, m.p. 127-129 ° C. 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -7-ethoxycarbonylindole.

Example 2

2.64 g of methyl 3- (4-amino-2-thia-butyl) -indole-5-carboxylic acid (obtained from methyl 3- (4-bromo-2-thia-butyl) -indole-5-carboxylic acid) ester and phthalimide potassium, followed by hydrolysis of the product) and 2.15 g of 1,5-dichloro-3-phenyl-2-pentene (which is 3-phenyl-2-pentene-1,5-diacid diethyl). ester or LiAlH ₄ were prepared by reacting and treating the obtained product with _SOCl2 azide) was heated in 40 ml of water and 40 ml of acetone at room temperature for 24 hours and the product was worked up in the usual manner. M.p. 202-203 ° C. Yield: 24%.

Example 3

23.4 g of LiAlH _{4 are} suspended in 1100 ml of anhydrous tetrahydrofuran and 41.6 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -1,4-dioxobutyl] are added dropwise with stirring. Indole-5-carboxylic acid methyl ester (m.p. 218 ° C.). 4- (5-Methoxycarbonyl-3-indoyl) -4-oxo-butyric acid and 4-phenyl-1,2,3,6-tetrahydropyridine The reaction mixture was heated to reflux for 1 hour, cooled, quenched with water and caustic soda and worked up in the usual manner to give 3- [4- (4-phenyl-1,2, 3,6-Tetrahydropyridyl) -butyl] -5-hydroxymethylindole, m.p. 178 DEG C., Yield: 59%.

Proceeding as above, the following dioxo esters are obtained:

Methyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -1,4-dioxobutyl] -indole-4-carboxylic acid, m.p. 228 ° C.

Methyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -1,4-dioxobutyl] -indole-6-carboxylic acid, m.p. 237 ° C.

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) -1,4-dioxobutyl] -indo-1-7-carboxylic acid methyl ester, m.p. 208 ° C. the following compounds were prepared:

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -4-hydroxymethylindole, m.p. 183-184 DEG C. 3- [4- (4-phenyl-1). , 2,3,6-tetrahydropyridyl) butyl] -6-hydroxymethylindole, m.p. 179 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -7-hydroxymethylindole, m.p. 178 ° C.

Similarly, 3- [4- (4-Oxo-4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-2-carboxylic acid in LiAlH _{4 in} THF was still 3- [4- (4 -phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-2-carboxylic acid (m.p. 206-208 ° C).

Example 4

4.51 g of 1- [4- (5-carboxy-3-indolyl) butyl] -4-phenylpyridinium bromide (obtained from 3- (4-bromobutyl) indole-5-carboxylic acid and 4- Phenylpyridine) was dissolved in NaOH (50 mL) and NaBH ₄ dissolved in water (20 mL) was added with stirring and the reaction mixture was stirred for 3 hours at 60 ° C. After usual work-up, 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -butyl] -indole-5-carboxylic acid is obtained, m.p. 284-285 ° C. Yield: 54%.

Example 5

35.5 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyrid 1) butyl] -5-cyanoindole (m.p. 67 DEG C. from the corresponding 5-formyl compound). oxime), a mixture of 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether was stirred for 3 hours at 140 [deg.] C., and after cooling the product was worked up in the usual manner. - [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) methyl] indole-5-carboxamide, m.p. 200-205 ° C. Yield: 65%.

Similarly, by hydrolysis of the corresponding nitrile, the following compounds were prepared:

3-12- (4-phenyl-1,2,3,6-tetrahydropyridyl) ethyl] indole-5-carboxamide,

3- [3- (4-phenyl-1,2,3,6-tetrahydropyridyl) -propyl] -indole-5-carboxamide

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-4-carboxamide

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-6-carboxamide, m.p. 226 DEG C. 3- [4- (4-phenyl-1,2,3) , 6-Tetrahydropyridyl) -butyl] -inco-7-carboxamide, m.p. 203 ° C.

-6193304

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-methoxyindole-6-carboxamide,

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxyindole-6-carboxamide

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -7-chloroindole-4-carboxamide

3- [4- (4-m-Hydroxy-phenyl-1,2,3,6-tetrahydro-pyridyl) -butyl] -indole-5-carboxamide

3- [4- (4-p-Hydroxy-phenyl-1,2,3,6-tetrahydro-pyridyl) -butyl] -indole-5-carboxamide

3- [5- (4-phenyl-1,2,3,6-tetrahydropyridyl) pentyl] indole-5-carboxamide

3- [4- (3-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxamide

3- (4- (3- (m-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxamide 3- [4- (3- (m-hydroxyphenyl)) -1,2,3,6-tetrahydropyridyl) butyl] indole-6-carboxamide 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] - Indole-5-carboxamide 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-6-carboxamide 3- [4- (4-phenyl) 1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-4-carboxamide 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxamide 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-6-carboxamide 3- [4- (4-phenyl-1- 1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-7-carboxamide 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-Methoxyindole-6-carboxamide 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-hydroxyindole-6-carboxamide 3- [ 4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -7-chloro-indole-4-carboxamide 3- [4- (4- (m-hydroxyphenyl) -) 1,2,3,6-Tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxamide 3- [4- (4- (p-Hydroxy-phenyl) -1,2,3,6-tetrahydro-pyridyl) -2-thia-butyl] -indole-5-carboxamide 3- [4- (3- (m-hydroxy) phenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxamide 3- [4- (3- (m-hydroxyphenyl) -1,2,3,6- tetrahydropyridyl) -2-thia-butyl] -indole-6-carboxamide 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole -5-carboxamide 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-6-carboxamide 3- [4- (4 -phenyl-piperidino) -butyl] -indole-5-carboxamide

3- [4- (4-Phenyl-piperidino) -butyl] -indole-6-carboxamide

3- [4- (4- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxamide

3- [4- (4- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxamide

3- [4- (4- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxamide

3- [4- (4- (p-hydroxyphenyl) piperidino) butyl] indole-6-carboxamide

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxamide

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxamide

3- [4- (3- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxamide

3- [4- (3- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxamide

3- [4- (4-Phenyl-piperidino) -2-thia-butyl] -indole-5-carboxamide

3- [4- (4-phenyl-piperidino) ^-2-1 to ti butyl 1] indole-6-carboxamide

3- [4- (4- (m-Hydroxy-phenyl) -piperidino-2-thia-butyl] -indole-5-carboxamide

3- [4- (4- (m-Hydroxy-phenyl) -piperidino) -2-fia-butyl] -indole-6-carboxamide

3- [4- (4- (p-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-5-carboxamide

3- [4- (4- (p-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-6-carboxamide

3- [4- (3- (m-Hydroxy-phenyl) -piperidino-2-thia-butyl] -indole-5-carboxamide

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-6-carboxamide

3- [4- (3- (p-hydroxyphenyl) piperidino) -2-thia-butyl] indole-5-carboxamide

3- [4- (3- (p-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-6-carboxamide.

Example 6

The procedure of Example 5 was followed except boiling for 16 hours. 3- (4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid, m.p. 283-285 DEG C., 70% yield.

In a similar manner, the following compounds were prepared by hydrolysis of the corresponding nitrile:

3- [2- (4-phenyl-1,2,3,6-tetrahydropyridyl) ethyl] indole-5-carboxylic acid methyl sulfonate, m.p. 219-222 ° C (dec.).

3- [3- (4-phenyl-1,2,3,6-tetrahydropyridyl) -propyl] -indole-5-carboxylic acid hydrochloride, m.p. 251-253 ° C (dec.).

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-4-carboxylic acid, m.p. 277-280 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-6-carboxylic acid, m.p. 268 DEG C. 3- [4- (4-phenyl-1,2,3) , 6-Tetrahydropyridyl) butyl] indole-7-carboxylic acid, m.p. 262-265 ° C 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-methoxyindole -6-Carboxylic acid 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxyindole-6-carboxylic acid 3- (4- (4-phenyl-1,2) , 3,6-Tetrahydropyridyl) butyl] -7-chloroindole-4-carboxylic acid, m.p. 263-266 ° C 3- [4- (4- (o-methoxyphenyl) -1,2,3), 6-Tetrahydropyridyl) butyl] indole-5-carboxylic acid 3- [4- (4- (n-methoxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid 3 - (4- (4- (p-methoxyphenyl) -1,2,3,6-tetrahydropyrdif) butyl] indole-5-carboxylic acid 3-] 4- (4- (o-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid 3- [4- (4- (m-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] - Indole-5-carboxylic acid 3 [4- (4- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid 3 [4- (4- (3-methoxy) -4-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole 5-Carboxylic acid 3 [4- (4- (2-thienyl) -1,2,3,6-tetrahydropyridyl) 7

-7193304

butyl] -indole-5-carboxylic acid hydrochloride, m.p. 281284 ° C (dec.),

3- [4- (4- (3-Thienyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid 3-] 5- (4-phenyl-1,2,3,6 -tetrahydropyridyl) -pentyl] -indole-5-carboxylic acid

3- [4- (3-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid

3- [4- (3- (p-methoxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid 3- [4- (3- (m-hydroxyphenyl) 1) -1,2,3,6-Tetrahydropyridyl) butyl] indole-5-carboxylic acid 3- [4- (3- (m-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl ] -indole-6-carboxylic acid 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid 3- [4- (3- (o-Hydroxy-phenyl) -1,2,3,6-tetrahydro-pyridyl) -butyl] -indole-6-carboxylic acid 3- [4- (4-phenyl-piperidino) -butyl] -indole-5-carboxylic acid

3- [4- (4-Phenyl-piperidino) -butyl] -indole-6-carboxylic acid

3- [4- (4- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxylic acid

3- [4- (4- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxylic acid -3- [4- (4- (p-hydroxy-phenyl) -piperidino) -butyl] - indole-5-carboxylic acid

3- [4- (4- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxylic acid

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxylic acid

3- [4- (3- (m-Hydroxy-phenyl) -piperidinobutyl] -indole-6-carboxylic acid

3- [4- (3- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-5-carboxylic acid

3- [4- (3- (p-Hydroxy-phenyl) -piperidino) -butyl] -indole-6-carboxylic acid

3- [4- (4-Phenyl-piperidino) -butyl] -7-chloro-indole-4-carboxylic acid

3- [4- (3- (m-hydroxyphenyl) piperidino) butyl] -7-chloroindole-4-carboxylic acid.

Example 7

4.68 g of 1-benzenesulfonyl-3- [4- (4-phenyl-1,2,3),

6-Tetrahydropyridyl) butyl] indole-5-carboxylic acid methyl ester (which is methyl 1-benzenesulfonyl-3- (4-chlorobutyl) indole-5-carboxylic acid) and

Prepared by reaction of 4-phenyl-1,2,3,6-tetrahydropyridine with Kg (1 g) in water (7 ml) and ethanol (14 ml), the reaction mixture was concentrated in the usual manner after concentration. 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid, m.p. 284-285 ° C. Yield: 78%.

Example 8

Dissolve 2.76 g of Na in 180 ml of ethanol and add 21.9 g of 1- (2-mercaptoethyl) -4-phenyl-1,2,3,6-tetrahydropyridine (4-phenyl-1,2 Obtained by reaction of 3,6-tetrahydropyridine with thioglycolic acid by reduction of 1- (2-mercaptoacetyl) -4-phenyl-1,2,3,6-tetrahydropyridine with LiAlH ₄ ) and 23.2 g of gram-5. methyl carboxylic acid was added and the reaction mixture was refluxed for 16 hours, concentrated and worked up in the usual manner to give product P, m.p. 202203 ° C, yield 68%;

In a similar manner, the following compounds were prepared from the corresponding compounds of formulas V and VI:

Methyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-methoxy-indole-6-carboxylic acid

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-methoxy-indole-6-carboxylic acid ethyl ester, hydrochloride, m.p. 169-173 ° C. C

Methyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-hydroxyindole-6-carboxylic acid

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thiabutyl] -5-hydroxyindole-6-carboxylic acid ethyl ester 3- [4- (4-phenyl-1) , 2,3,6-Tetrahydropyridyl) -2-thia-butyl] -7-chloroindole-4-carboxylic acid methyl ester.

Example 9

3.91 g of 3- [4- (4-hydroxy-4-phenyl-1-piperidyl) butyl] -indole-5-carboxamide (obtained from 3- (4-bromobutyl) -indole-5-carboxamide and 4-piperidone) followed by reaction of the product with phenyl lithium and hydrolysis of the product) with 40 ml of hydrochloric acid for 2 hours at 50 ° C, and working up the reaction mixture to give 3-14- (4-phenyl-1,2, 3,6-Tetrahydropyridyl) butyl] indole-5-carboxamide, m.p. 200205 DEG C., 50% yield.

Example 10

A mixture of 3.92 g of 3- [4- (3- (m -methoxyphenyl) piperidino) butyl] -5-hydroxymethylindole and 3.5 g of pyridine hydrochloride is stirred for 3 hours at 160 ° C. . Usual work-up of the reaction mixture gave 3- [4- (3-m-hydroxyphenylpiperidino) butyl] -5-hydroxymethylindole, m.p. 9495 ° C, yield 23%.

Example 11 3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxymethylindole (g) was dissolved in THF (1.6 L) and ether (300 mL) was added followed by with stirring, 55 g of MnO ₂ . After stirring for 16 hours at 20 ° C, additional 100 g of MnO ₂ are added in small portions and stirring is continued for another 100 hours at 20 ° C. Filtration and work-up gave 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-formyl indole, m.p. 131 ° C. Yield: 40%.

Similarly, by oxidation of the corresponding hydroxymethylindole, the following compounds were prepared:

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -2-formylindole, m.p. 129-130 ° C. 2,3,6-tetrahydropyridyl) butyl] -4-formylindole

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -6-formylindole

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] · -7-formylindole

-8193304

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridine) -2-thia-butyl] -4-formylindole

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-formylindole

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-formylindole

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -7-formylindole.

Example 12

3.9 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -butyl] -6-hydroxymethyl-indole in 50 mL dichloromethane was reacted with 9 g _MnO2 azide, After stirring at 40 ° C for 60 hours, the insoluble material is filtered off. After customary working up 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -butyl] indole-6-carboxylic acid, melting point of ^268? C. Yield: 38%.

Example 13

3.88 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-formyl indole are dissolved in 80 ml of dichloromethane, treated with 9 g of MnO ₂ and the suspension is Stir at 40 ° C for 48 hours. The filtrate was worked up in the usual manner to give 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid, m.p. 284-285 ° C. Yield: 39%.

Example 14

4.04 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydro-pyridyl) butyl] -indole-5-carboxylic acid are suspended in 25 ml of toluene and under a nitrogen atmosphere, 3 times molar volumes of diisobutyl- aluminum hydride (as a 20% solution in toluene) was added dropwise, stirred under reflux for 2 hours, then cooled, quenched with water and worked up in the usual manner. 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-formylindole, m.p. 131 ° C. Yield: 60%.

Example 15

0.76 g of lithium aluminum hydride is suspended in 30 ml of THF and 4.04 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole are added under stirring under nitrogen. -5-carboxylic acid dissolved in 40 mL of THF. The reaction mixture was stirred for 2 hours at 20 ° C, quenched with dilute sodium hydroxide solution, then water, filtered and worked up in the usual manner. 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxymethylamine, m.p. 178 ° C. Yield: 72%.

Example 16

0.57 g of lithium aluminum hydride is suspended in 20 ml of THF and 4.18 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridine 1) - is stirred at 20 ° C under a nitrogen atmosphere. butyl] indole-5-carboxylic acid dissolved in 40 mL of THF was added. The reaction mixture was stirred for 1 hour at 20 ° C, quenched with dilute sodium hydroxide solution, then water, filtered and worked up in the usual manner. The product is 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxymethylindole

M.p. and 178 ° C. Yield: 89%.

In a similar manner, the corresponding ester is prepared from the corresponding ester hydroxymethyl compounds and 2-hydroxymethyl-3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl]. m.p. 162-163.5 ° C. Hydrochloride salt m.p. 174-175 ° C.

Example 17

Lithium aluminum hydride (0.57 g) was suspended in THF (20 mL) and 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-formyl (3.88 g) was added under nitrogen. -indole dissolved in 40 mL of THF. The reaction mixture was stirred for 1 hour at 20 ° C, quenched with dilute sodium hydroxide solution, then water, filtered and worked up in the usual manner. 3- (4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxymethylindole, m.p. 178 DEG C., 92% yield.

Example 18

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid (4.04 g) was dissolved in absolute ethanol (50 ml) and hydrochloric acid was added under reflux for 2 hours. the reaction mixture is refluxed for another hour and then worked up in the usual manner. The product was ethyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid. R _f = 0.65 (silica gel, CH ₂ CH ₂ / CH ₃ OH 8: 2) Yield: 72%.

Similarly, the following compounds are obtained by esterification:

Methyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-2-carboxylic acid, m.p. 114.5115 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl]

indole-4-kaTbonsav methyl ester

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid methyl ester hydrochloride, m.p. 232-235 ° C.

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-6-carboxylic acid methyl ester

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-7-carboxylic acid methyl ester

Ethyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-2-carboxylic acid, m.p.

115 ° C

3- [4- (4-Phenyl-1,2,3,6-tetrahydro-pyridyl) -butyl] -indole-4-carboxylic acid ethyl ester 3- [4- (4-phenyl-1,2,3) , 6-Tetrahydropyridyl) -butyl] -indole-6-carboxylic acid ethyl ester ·

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-7-carboxylic acid ethyl ester 3- [4- (4-phenyl-1,2,3,6) -tetrahydropyridyl) butyl] -5-methoxyindole-6-carboxylic acid methyl ester 3-] 4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-methoxyindole- 6-Carboxylic acid ethyl ester 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxyindole-6-carboxylic acid methyl ester 3- [4- ( 4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxyindole-6-carboxylic acid ethyl ester 3- [4- (4-phenyl-1,2,3), 6-Tetrahydropyridyl) butyl] -7-chloroindole-4-carboxylic acid methyl ester, hydrochloride, m.p. 219-221 ° C.

Ethyl 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -7-chloroindole-4-carboxylic acid

-9193304

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid butyl ester.

Example 19

3- [4- (4-Phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid (4.04 g) was dissolved in chloroform (30 mL), saturated with HCl gas, and 1.8 g of thionyl was added dropwise. chloride and reflux for 2 hours. The reaction mixture was evaporated, toluene (30 ml) was added and evaporated again. The residue was dissolved in chloroform (20 mL), 50 mL of chloroform saturated with ammonia was added dropwise to the solution, stirred at 20 ° C for 2 hours, filtered and the filtrate was concentrated. The residue was worked up in the usual manner and the product was 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxamide, m.p. 207-208 ° C.

In a similar manner, the following compounds are obtained from the corresponding acids using thionyl chloride and the corresponding amine:

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid N, N-dimethylamide, m.p. 124-160 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -indole-5-carboxylic acid N, N-dipropylamide hydrochloride, m.p. 151-153 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-2-carboxylic acid N, N-dimethylamide. R f = 0.72 (silica gel, CH ₂ Cl ₂ / CH ₃ OH 8: 2).

Example 20,,

Dissolve 4.18 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridine) butyl] indo-5-carboxylic acid methyl ester in 30 ml of dimethylformamide. 02 moles of concentrated ammonium hydroxide (D-0.9) at 20 ° C. The reaction mixture was stirred for 1 hour and worked up in the usual manner. 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid, m.p. 207-208 ° C. Yield: 68%.

Example 21

37.3 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-carbamoylindole, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl- The mixture of ether was refluxed for 6 hours, then cooled, acidified and worked up in the usual manner. The product was 3- (4- (4-phenyl-1,2,3,6-tetrahydropyridine) butyl) -indole-5-carboxylic acid, m.p. 284-285 ° C. Yield: 72%.

Example 22

4.5 g of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -5-methoxy-6-ethoxycarbonylindole in 20 ml of water for 30 minutes. and refluxed with 100 ml of 2N KOH in ethanol and worked up in the usual manner to give 3- [4- (4-phenyl-1,2,3,6-tetrahydro-pyridyl) -2-thia-butyl] -5. of methoxyindole-6-carboxylic acid, m.p. 168-171 ° C. Yield: 98%.

In a similar manner, the following compounds were prepared by saponification of the corresponding methyl or ethyl esters:

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -4-methoxyindole-6-carboxylic acid hydrochloride, m.p. 224-227 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxylic acid, m.p. 184-189 ° C 3- [4- (4- phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-6-carboxylic acid

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-7-carboxylic acid 3- [4- (4-phenyl-1,2,3,6) -tetrahydropyridyl) -2-thia-butyl] -5-hydroxyindole-6-carboxylic acid 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -7- Chloroindole-4-carboxylic acid 3- [4- (4- (m-hydroxy-phenyl) -1,2,3,6-tetrahydro-pyridyl) -2-thia-butyl] -indole-5-carboxylic acid 3- [4 - (4- (p-Hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxylic acid 3- [4- (3- (m-hydroxyphenyl)) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5-carboxylic acid 3- [4- (3- (m-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-Thia-butyl] -indole-5-carboxylic acid 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-5 3- [4- (3- (p-hydroxyphenyl) -1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -indole-6-carboxylic acid 3- [4- (4-phenyl) -piperidino) -2-thia-butyl] -indole-5-carboxylic acid

3- [4- (4-Phenyl-piperidino) -2-thia-butyl] -indole-6-carboxylic acid

3- [4- (4- (m-hydroxyphenyl) piperidino) -2-fia-butyl] indole-5-carboxylic acid 3- [4- (4- (m-hydroxyphenyl) piperidino) ) -2-Thia-butyl] -indole-6-carboxylic acid 3- [4- (4- (p-hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-5-carboxylic acid

3- [4- (4- (p-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-6-carboxylic acid

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-5-carboxylic acid

3-] 4- (3- (m-hydroxy-phenyl) -piperidino) -2-thia-butyl] -indole-6-carboxylic acid

3- [4- (3- (m-Hydroxy-phenyl) -piperidino) -2-thia-butyl] -7-chloro-indole-4-carboxylic acid 3- [4- (3- (p-hydroxy-phenyl) -piperidino) -2-thia-butyl] -7-chloro-indole-5-carboxylic acid 3- [4- (3- (p-hydroxyphenyl) -piperidino) -2-thia-butyl] -7-chloro- indole-6-carboxylic acid.

Example 23

In a similar manner to Example 1, the following compounds were prepared from the corresponding compounds of formulas II and III:

3- [3- (4-phenyl-1,2,3,6-tetrahydropyridyl) propyl] -4-hydroxymethylindole, m.p. 164-168 ° C 3- [4- (3- (m -methoxyphenyl) piperidino) butyl] -5-hydroxymethylindole, m.p. 98-100 ° C, 2-hydroxymethyl-3 - [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-methoxyindole, m.p.

146 ° C

2-hydroxymethyl-3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -6-methoxyindole, m.p. 120-122 ° C.

Methyl 3- [4- (4- (2-thienyl) -1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid, m.p. 110

113 ° C,

-10193304

Example 24

In a similar manner to Example 3, the following compounds were prepared starting from the corresponding oxocarboxylic acids:

3- [2- (4-phenyl-1,2,3,6-tetrahydropyridyl) ethyl] indole-6-carboxylic acid, m.p. 240 ° C.

3- [3- (4-phenyl-1,2,3,6-tetrahydropyridyl) -propyl] -indole-4-carboxylic acid, m.p. 268-271 ° C

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-hydroxyindole-6-carboxylic acid

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] ·

-6-hydroxy-indole-5-carboxylic acid

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia ·

butyl] -5-hydroxyindole-6-carboxylic acid, m.p. 231232 ° C.

3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) -2-thia-butyl] -6-hydroxyindole-5-carboxylic acid.

Example 25

3.9 g of 3- [4- (3- (m -methoxyphenyl) -piperidino) butyl] -5-hydroxymethylindole are suspended in 400 ml of toluene and 1.5 g of diisobutylaluminum hydride are added. dissolved in toluene and stirred with cooling, allowed to warm to room temperature and refluxed for 3 hours. After cooling and working up in the usual manner, the product is obtained in a yield of 3- [4- (3- (m-hydroxyphenyl) t-piperidino) butyl] -5-hydroxymethylindole, m.p. 94-95 ° C. : 44%.

The following examples illustrate the process for preparing the pharmaceutical compositions of the present invention.

The example

Tablet formulation kg 3 - [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxamide, 4 kg lactose,

1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are mixed according to the usual procedure and tablets are compressed. Each tablet contains 10 mg of active ingredient.

Compounds of Formula (I) wherein Y is a bond, 4 phenyl, 3-Z = hydrogen and

Substitutes for Ind

Example B

Drazsékészítmény

Tablets are prepared as described in Example A and then coated according to standard procedures with sucrose, potato starch, talc, tragacanth and coloring agent.

Example C

Capsule Composition kg of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] indole-5-carboxylic acid is filled in hard gelatin capsules according to the usual method. Each capsule contains 20 mg of active ingredient.

Example D

Ampoule composition kg of 3- [4- (4-phenyl-1,2,3,6-tetrahydropyridyl) butyl] -5-methoxyindole-6-carboxylic acid hydrochloride is dissolved in 60 liters of double-distilled water, filtered under sterile conditions into ampoules. fill, lyophilize and seal. The ampoules contain 10 mg of the active ingredient.

Similarly, compositions containing one or more of the compounds of formula (I), or salts thereof, may be prepared.

Pharmacological examination

Ligand binding capacity of the compounds of formula according to the invention (I) is tritiated spiperone were conducted rat striatal (striata) membrane preparation was tested (Creese et al, European J. Pharmacol, 46, jVÁn), 377-381) in each case 10 ^'7 mg / kg. The values in the following table express the ligand binding capacity in% relative to the control of 100%, where Z =

Effectiveness%,

2-CH0

2-C00C _a H ₅

4- CH ₂ OH 7 -CO ₂ NH ₂ .

6-CH ^ OH

5- CQ0H

5- CONH.,

6- C00H 6-COOCjHj6-CH ₂ OH 5-C000CH ₃

5- CH ₂ CH

6- CONH ₂

5-CH ₃ O-6-COOC ₂ Ϊ

7-Cl-4-COOCHj 2 -CH ₂ OH 5-CH ₃ O

27 34 Irish 10 H 17 11 11 Irish 26 You 7 II 38 -CIK-S-CHf-CH - 15 7 II 9 11 9 - <CH ₂ ) ₄ - 8 -ch ₂ -s-ch ₂ ch ₂ - 11 - (ch ₂ ) ₄ - 16 II 37

Claims (2)

PATENT CLAIMS A process for the preparation of an indole derivative of the Formula I wherein: Ind is hydroxymethyl or COW group substituted indol-3-yl group substituted with C1-4 alkoxy, hydroxy, fluorine, chlorine or bromine substituted one, ¹⁰ W is hydrogen, hydroxy, C 1-4 alkoxy, amino or N- (C 1-4 dialkyl), A is - (CH ₂ ) n - or -CH ₂ -S-CH ₂ -CH ₂ - 15 a group, n is 2, 3, 4 or 5, both Y are hydrogen or a C-C bond taken together, one of Z is Ar and the other of Z is hydrogen, and Ar is unsubstituted C1-4 alkoxy, or is monosubstituted by hydroxy phenyl or 2- or 3-thienyl ^25, and n is 2 or 3 only if simultaneously a hydroxy group or a COW group is indol-3-yl group 4, 5,6 or 7 - and physiologically acceptable salts thereof, characterized in that a) a compound of formula II in the formula (a) X ¹ is X or -NH ₂ , X represents a chlorine, bromine or iodine atom, a hydroxy group or a hydroxyl group which has been converted into a reactive group, and Ind and A have the meanings given above - ^{40 with} a compound of formula 11! X ² and X ³ can be the same or different and if 45 X '= NH ₂ , then they are always X, otherwise taken together as NH, Y and Z are as defined above; (b) a compound of formula (I) wherein A is -CH ₂ - in the group A is reduced to -CH ₂ , or a tetrahydro or hexahydropyridyl group Hydrogenating the pyridyl group in the compound of formula (I) containing 55 pyridyl groups to a tetra or hexahydropyridyl group, or c) hydrolyzing a compound of formula (I) having a cyano group in place of -COW to a -COOH or -CONH ₂ group or a compound of formula (I) in which the indole group is capable of being cleaved by nitrogen there is a protecting group, we are going to cut it off, d) for the preparation of thioethers of general formula (I), wherein: A is -CH ₂ -S-CH ₂ -CH ₂ - a compound of formula (V) - wherein R is C 1 -C 4 alkyl, or the two R groups taken together are - (CH ₂ ) _p - or -CH ₂ -CH ₂ -O-CH ₂ CH _{2 -} and p is 4 or 5, Ind is as defined above with a compound of formula (VI) Y and Z are as defined above - or a salt thereof, or e) for the preparation of compounds of formula I wherein the two Ys together represent a CC bond, a compound of formula VII: wherein one of E is -OH and the other E is hydrogen, and Ind, A and Z is as defined above - treated with a dehydrating agent and optionally cleaved to form the hydroxy group of the resulting compound of formula (I) and / or oxidized to -COOH and / or -COOH to -CHO and / or -COOH and / or the -COOH group or the ester group thereof is amidated to the carbamoyl group or the di-(C1-C4 alkyl) aminocarbonyl group and / or the acid amide or ester group is solvolized and / or a -COW group of the compound of formula (I) containing the resulting -COW group, wherein W is hydrogen, hydroxy or C 1 -C 4 alkoxy, the hydroxylmethyl group is reduced and / or the hydroxylmethyl group is oxidized to CHO or -COOH group and / or any of the compounds of formula 1.1 obtained above is physiologically acceptable. to an acid addition salt. A process for the preparation of a pharmaceutical composition comprising the pharmaceutically acceptable acid addition salt of an indole derivative of the formula (I), wherein Ind, A, Y and Z are as defined in claim 1, or a physiologically acceptable acid addition salt thereof. mixed with a carrier and / or excipient and formulated for administration.