3-intellipedia, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts. The compounds of formula I have an impact on the Central nervous system, in particular, have serotonin-agonistic or serotonin-antagonistic action. 4 C. and 1 C.p. f-crystals, 2 PL.

The invention relates to 3-intellipedia formula (I):

< / BR>
where R1, R2, R3and R4each independently of one another denotes H, A, OH, OA, F, Cl, Br, I, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA; or

R1and R2and R3and R4accordingly together also denote methylenedioxy-group;

R5denotes H or OH;

R6denotes H; or

R5and R6together also denote the connection;

A stands for Ala is

The basis of the invention is to obtain new compounds that can be used for the preparation of drugs.

It was found that the compounds of formula (I) and their physiologically acceptable salts accession acids have valuable pharmacological properties. So, in particular, they affect the Central nervous system, primarily possess serotonin-agonistic and serotonin-antagonistic activity. They inhibit the binding trithiolane serotonin ligands with hippocampal receptors (Cossery and others , European J. Pharmacol. 140 (1987), 143-155). In addition, when DOPA-accumulation in the striatum and 5-HTP-accumulation in N. raphe (Seyfried and others, European J. Pharmacol. 160 (1989), 31-41). Next, have analgesic and blood pressure-lowering activity; thus, in the case of containing the catheter, awake, patients spontaneously hypertension rats (Genus SHR/Okamoto/NIH-MO-CHB-Kißlegg; see method Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104 (1960), 646-648), directly measured blood pressure is reduced after oral administration of the compounds. Similarly, these compounds are suitable for the prevention and combat the effects of cerebral infarction (Apoplexia cerebri), as stroke and cerebral ischemia, and S="ptx2">

The compounds of formula (I) and their physiologically acceptable salts accession acids can therefore be used as biologically active substances for drugs such as anxiolytic, antidepressant and/or antihypertensive tools, and also as intermediate products for other biologically active substances for medicinal products.

The object of the invention are indole derivatives of formula (I) and their physiologically acceptable salts accession acids.

The remainder of "A" denotes alkyl with 1, 2, 3, 4, 5 or 6, in particular 1 or 2 C-atoms, preferably methyl, furthermore ethyl, n/a propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl; "OA" preferably denotes a methoxy group, hereinafter also referred to as ethoxy-, n-propoxy, isopropoxy, h-butoxy, isobutoxy-, Deut. -butoxy - or tert.-butoxy-group; "NHA" preferably denotes methylamino-group, then ethylamino, h-propylamino, isopropylamino, h-butylamino, isobutylamino-, Deut.butylamino - or tert. -butylamino group. "NA2" preferably denotes a dimethylamino group, then N-ethyl-N-methylamino, diethylamino-, di-n-propylamino-, di-isopropylamino - or di-n-butyl who etilcarbitol and CO-NA2preferably denotes N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

Indole residues are not substituted or mono - or doubly substituted. Preferably a single substitution, the substituents are preferably in position 5, further, however, can also be a 2-, 4-, 6 - or 7-position. If both indole-3-ilen residue substituted, the respective substituents may be the same or different. Similarly, the number of substituents of both indole residue may be different from each other.

Preferred substituents R1, R2, R3and R4in indole residues are, for example, CO2H, CO2CH3, OCH3, OH, O-CH2-O, F, CN or CONH2.

If indole system substituted in position 2, there is particularly preferably a substitution with "A".

The parameter "n" could mean 2, 3, 4, 5 or 6, preferably it represents 3 or 4.

R5and R6each preferably means hydrogen, but also can show a link.

Accordingly, the subject invention, in particular, are such compounds of formula (I) in which at least one of these residues is one of you who received the following formulas (Ia) - (Ih), which correspond to the formula (I) and where not specified more residues are indicated for formula (I) value, where, however:

in Ia: R2and R4denote H, and R1and R3are the same and each is in position 5 of the indole residue:

in Ib: R2and R4denote H and R1and R3each denotes COOH, COOA, CONH2, CONHA, CONH2or CN, and each is in position 5 of the indole residue;

Ic: R2and R4denote H and R1and R3each denotes OH, OA, F, Cl, Br, I or CF3and everyone is in position 5 of the indole residue;

in Id: R1and R2and R3and R4each along denotes methylendioxy-group;

Ie: R2, R4, R5and R6each denotes H;

If: R2and R4denote H, and R5and R6together represent a bond;

in Ig: R2, R4, R5and R6each represents H, and R1and R3are the same and denote F, CN, OA or CONH2;

in Ih: R2, R4, R5and R6each represents H, and R1and R3different from each other and each represents H, COOH, COOA, OCH3, OH, CN, CONH2, CONA or CONHA;

in Ii: R1

The subject invention further is a method for piperidinovyh derivatives of formula (I) and their salts, characterized in that the compound of formula (II):

< / BR>
where X1denotes X or NH2;

X denotes Cl, Br, I, OH or a reactive functionally converted to OH-group; and

R1, R2and n have the specified values

enter into interaction with the compound of the formula (III)

< / BR>
where X2and X3may be the same or different and, if X1= NH2each refers to X; otherwise, together represent NH; and

R3and R4have the specified values;

or the compound of formula (IV):

< / BR>
where R1, R2and n have the specified values,

enter into interaction with the indole of formula (V):

< / BR>
where R3and R4have the specified values;

or the compound of formula (I) in which R5denotes OH and R6denotes H; by dehydration converted into another compound of formula (I);

or appropriate are recoverable groups and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent; or corresponds to the formula (I) compound, which, however, instead of one or more hydrogen atoms contains one or more solvolysis groups, process solvolysis tool;

and/or the remainder R1, R2, R3and/or R4by esterification to complex ester, saponification, education simple ether cleavage of simple ether full or partial hydrolysis, or by alkylation turn into another (other) residue (remainder) R1, R2, R3and/or R4;

and/or received by a base or acid of the formula (I) by treatment with acid or base turn in one of their salts.

Obtaining compounds of formula (I), however, the exercise itself known in ways that are described in the literature (for example in standard works, as Houben-Weil, Methods of organic chemistry, ed. Georg-Thieme, Stuttgart; Organic reactions, John Wiley and Sons, Inc. New York; J. March. Adv. Org. Chem., 3rd ed., J. Wiley and Sons, (1985), namely under reaction conditions which are known and suitable for the specified interactions. You can also use themselves known here more not mentioned options.

Source homesteading mixture, and immediately injected into the interaction further, to obtain the compounds of formula (I).

In the indole derivatives of the formula (II) "X1" preferably denotes "X"; accordingly, in compounds of formula (II) X2and X3preferably together represent NH. The remainder of X preferably denotes chlorine or bromine; however, it can also indicate iodine, hydroxyl or reactive functionally modified OH group, in particular alkylsulfonate group with 1-6 (for example, methanesulfonate group) or arylsulfonate group with 6-10 C atoms (for example, benzosulfimide-, p-toluensulfonate-, 1 - or 2-naphthalenesulfonate-group).

Accordingly, the indole derivatives of formula (I) receive, in particular, by reacting 3-(chloroalkyl) or 3(bromoalkyl)- indoles with 3-piperid-4-yl-indoles, respectively where X2and X3together denote NH-group (below referred to as compounds of formula (IIIa).

Compounds of formulas (II) and in particular (III) partly known: unknown compounds of the formula (II) and (III) can be easily obtained analogously to known compounds.

Primary alcohols of the formula Ind-CnH2n-OH, and always denotes primer, by restoring the corresponding carboxylic acids or their esters. Treatment with thionyl chloride, bromoiodide, tribromide phosphorus and such halide compounds gives the corresponding halides of the formula Ind-CnH2n-Gal (Gal represents Br, Cl). Relevant sulfonyloxy-compounds derived from alcohols of the formula Ind-CnH2n-OH by entering into interaction with the corresponding anhydrides of sulfonic acids.

Iododerma the compounds of formula (I) Ind-CnH2nI get, for example, by exposure of potassium iodide to the corresponding ester p-toluenesulfonic acid. Amines of the formula Ind-CnH2n-NH2get, for example, of the halides with telemedcare or by restoring the corresponding NITRILES.

Derivatives of piperidine of formula (IIIa) for the most part known and are obtained, for example, by reacting secured in position 1 normal, itself known for protective amino group of the 4 groups of piperidine with indoles, which, if necessary, protected residues R3and/or R4. Preferably, these reactions are conducted under the influence of a catalyst, for example, acids. The resulting product ZAT the first degidratiruth to 1,2,5,6-tetrahydropyridine derivative, accordingly then to gidrirovanii.

The interaction of compounds of the formula (II) and (III) proceeds by methods known from the literature for electrophilic substitution of indoles. Components you can enter into interaction with each other without the presence of a solvent, if necessary in a sealed tube or in an autoclave. However, preferably the connection to enter into interaction in the presence of an indifferent solvent. As suitable solvents, for example hydrocarbons as benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols as methanol, ethanol, isopropanol, n-butanol; ethers, like tetrahydrofuran (THF) or dioxane; amides as dimethylformamide (DMF) or H-methyl-pyrrolidone; NITRILES like acetonitrile; if necessary, also mixtures of these solvents with one another or mixtures with water.

The reaction time depending on the applied conditions ranges from a few minutes up to 14 days; the reaction temperature is 0-150oC, usually 20-130oC.

In some cases, reactions may be favorable additive ciclofosfamida tools, such as hydroxide, carbonate or bicarbonate of alkali or alkaline earth metal, or another Slavka organic bases, as triethylamine, dimethylaniline, pyridine or quinoline. In other cases, the favorable the addition of catalytic amounts of acid, preferably an inorganic acid, such as HCl.

Further, the compound of formula (I) can be obtained by the fact that the compound of formula (IV) enter into interaction with the indole derivative of the formula (V).

The compounds of formula (IV), and in particular of the formula (V) are partly known; the unknown compounds can be easily obtained by analogy with the known. Thus, the compounds of formula (IV) can be easily obtained by interaction of Ind-CnH2n-NH2with 1.5-dihalogen-pentane-3-one, and halogen is preferably chlorine or bromine. Also, it is possible to obtain compounds of type (IV) by reacting Ind-CnH2n-Cl, Ind-CnH2n-Br or Ind-CnH2n-I with 4-piperidine.

The indoles of formula (V) can be obtained by various, in itself known syntheses of indole, for example, by indole synthesis, Fischer.

The interaction of compounds of formulas (IV) and (V) proceeds by methods known from the literature for the reactions of enamines with electrophilic components of the reaction. Components you can enter into interaction with each dragomirna or at elevated pressure, moreover, to increase the pressure of the supplied inert gas, such as nitrogen. However, you can also enter in the interaction of the compounds in the presence of an inert solvent. As solvents usable in the above case, the interaction of the compounds of formulas (II) and (III).

The optimal reaction time depending on the selected reaction conditions ranges from a few minutes up to 14 days; the reaction temperature is 0-150oC, usually 20-130oC.

Further it is possible to obtain the compound of formula (I) that forproduct that instead of hydrogen atoms contains one or more recoverable groups and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent, preferably at temperatures from -80oC to +250oC, in the presence of at least an inert solvent.

Recoverable (replaceable hydrogen groups are particularly oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example p-toluensulfonate), N-benzazolyl, N-benzyl or O-benzyl.

Fundamentally it is possible compounds that contain only one, or those who along with each other contain two or Bo the formula (I); at the same time can recover the substituents in the indole residues contained in the original connection. Preferably for this purpose use atomic hydrogen or complex hydrides of metals, then carry out the restoration of the wolf-Kizaru and restore using gaseous hydrogen at catalysis with transition metals.

The preferred source of nutrients for recovery correspond to the formula (VI):

< / BR>
where R7and R8denote H or, for example, arylsulfonate group and/or benzyl groups;

L represents CnH2nor relevant to the rest of the chain, where, however, one or more-CH2-groups are replaced by-CO-; and R1, R2, R3, R4, R5and R6have the specified values; where, however, R7and R8at the same time cannot denote H and L - CnH2n.

In the compounds of the formula (VI), L preferably denotes: -CO-(CH2)n-2-CO- [in particular-COCO-; -COCH2CO-; -CO-(CH2)2-CO-; -CO-(CH2)3-CO]; -(CH2)n-1CO [especially-CH2-CO-; -CH2CH2-CO-; -(CH2)3-CO-or -(CH2)4-CO-] ; further, for example, -CO-CH2C-(CH2)3-; -CH2CH2-CO-CH2CH2-; or -(CH2)3-CO-CH2-. The compounds of formula (VI) are obtained, for example, by reacting compounds of the formula (III) which, if necessary, before substituted in position 1, with a compound of formula (VII):

< / BR>
where R1, R2, R7L and X1have the above meanings, in the manner described above for the interaction of the compounds of formulas (II) and (III).

If the reductant is used atomic hydrogen, it is possible to obtain, for example, by treating metals with weak acids or bases. For example, you can apply a mixture of zinc with a solution of caustic alkali or iron with acetic acid. Also suitable application of sodium or other alkali metal in alcohol, as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. Next you can apply a Nickel alloy with aluminum in aqueous-alkaline solution, if necessary with the addition of ethanol. To obtain atomic hydrogen also suitable sodium amalgam or aluminum in aqueous-alcoholic or aqueous solution. The interaction can also be carried out in a heterogeneous phase, and appropriate use of water and benzene is ü complex metal hydrides, as LiAlH4, NaBH4diisobutylaluminium or NaAl(OCH2CH2OCH3)2H2and DIBORANE, if desirable, with the addition of catalysts, as BF3, AlCl3or LiBr. As solvents for this purpose are suitable in particular ethers like diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, as well as hydrocarbons like benzene. To restore using NaBH4suitable primarily alcohols as methanol or ethanol, then water, and aqueous alcohols as solvents. According to these methods restore preferably at temperatures from -80oC to +150oC, in particular at about 0-100oC.

Particularly preferably, you can restore-CO-group in amido acids (for example, those of formula (VI), where L denotes the group -(CH2)n-1using LiAlH4in THF at temperatures of about 0-66oC in CH2-group. At the same time, recovery can be chipped off in position 1 of the indole ring protective arylsulfonyl group. N-Benzyl group can be split by restoring using sodium in liquid ammonia.

Next, one or more spacecraft is using anhydrous hydrazine in absolute ethanol under pressure at temperatures of about 150-250oC. as the catalyst preferably used sodium alcoholate. Recovery is also possible to vary according to the method of Huang-Minlon, seeing the interaction with hydrazinehydrate in high-boiling, mixing with the water solvent as diethylene glycol or triethylene glycol, in the presence of alkali, as sodium hydroxide. The reaction mixture is usually boil for about 3-4 hours Then the water is distilled off and the resulting hydrazone decompose at temperatures down to nearly 200oC. Recovery of the wolf-Kizaru can be carried out at room temperature in dimethyl sulfoxide using hydrazine.

Moreover, certain recovery can be achieved by use of hydrogen gas at the catalytic effect of transition metals, such as Raney Nickel or palladium. Thus, for example, Cl, Br, I, SH or in certain cases also the OH-group can be replaced by hydrogen. Similarly, the nitro group by catalytic hydrogenation using Pd/H2methanol can be converted into NH2group.

Compounds which otherwise correspond to formula (I), however, instead of one or more H atoms contain one or more salvolini the substances for solvolysis get for example, by reacting the compounds of formula (IIIa) with the compounds which correspond to formula (II) (X1= X), but instead one or more H atoms contain one or more solvolysis groups. So, in particular 1-arylindole derivatives (corresponding to the formula (I), however, contains in position 1 of the indole residue acyl group, preferably alkanoyloxy, alkylsulfonyl or arylsulfonyl group, each with a number of carbon atoms up to 10, such as methane-, benzene - or p-toluene-sulfonyl) can hydrolyze to the corresponding, unsubstituted in position 1 of the indole ring, indole derivatives, for example, in an acid, preferably in a neutral or alkaline medium at temperatures 0-200oC. as a reason it is advisable to use sodium hydroxide, potassium or calcium; sodium carbonate or potassium, or ammonia. The solvent preferably used water; lower alcohols like methanol, ethanol; ethers like THF, dioxane; sulfones as tetramethylsilane; or mixtures thereof, particularly those containing water mixture. The hydrolysis may also occur during the processing of one water, in particular at the boiling point.

Further, the compound of formula (I) sa the crystals (I), where the indole system, replaced, for example, using COOA, CONH2, CONH2can be obtained by derivatization of the corresponding carboxy-indol-3-ilen compounds. Acids or their reactive derivatives, such as their galodamadruga or anhydrides, for example, you might atrificial to esters using the appropriate alcohol or alcoholate, in the application itself known methods or one of the many options. Next, acids, galodamadruga acids or esters can be lidirovat using primary or secondary, aliphatic or cyclic amines. Preferably the interaction of the free carboxylic acid with the amine under the conditions of peptide synthesis. This reaction is carried out preferably in the presence of dehydrating, such as a carbodiimide, as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N-ethyl-carbodiimide, then anhydride papapostolou acid (see Angew. Chemie., 92, 129 (1980)), diphenylphosphoryl or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example in a halogenated hydrocarbon like dichloromethane; simple ether as THF or dioxane; amide as DMF or dimethylacetamide, nitrile as acetonitrile; PR is built amide, can also be used in the reaction of the reactive derivatives of these substances, for example, those in which the reactive group of the intermediate is blocked by protective groups. Acid can also be used in the form of their activated esters, which are expedient receive in situ, for example, by adding 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Next, the cyan-substituted indole-3-ilen residues can hydrolyze to carboxy-indol-3-ilen, urea-indole-3-ilen residues.

The compounds of formula (I), in which the indole remains one - or twofold substituted O-alkyl, can be subjected to a cleavage reaction of simple ether, and form the corresponding hydroxy derivatives. For example, a simple ester group can be split by treatment with dimethyl sulfide complex with tribromide boron, for example, toluene, ethers like THF or dimethyl sulfoxide; or by melting together with the pyridine or bilingualised, preferably with pyridinecarboxamide, about 150-250oC.

The compounds of formula (I), if necessary, may contain an asymmetric center. So when you receive them they can obrazovyvalis the E. Resulting racemates, if it is desirable, in itself known methods, mechanically or chemically, can be divided into their optical antipodes. Preferably from a racemate by interacting with optically active separating means are formed diastereomers. As release agents are suitable, for example, optically active acids, such as D - or L-forms of tartaric acid, dibenzoyltartaric acid, diatsetilvinny acid, camphorsulfonic, almond acid, malic acid or lactic acid. Various forms of the diastereomers can be divided in itself known, for example, by fractional crystallization, and optically active compounds of formula (I) is in itself known, you can release it from the diastereomers.

The obtained base of formula I with acids can be converted to the corresponding salt accession acid. For this transformation is suitable acid, which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, halogen acids as hydrochloric acid or Hydrobromic acid, phosphoric acid, like phosphoric acid, nitric acid, sulfamic acid; geterotsiklicheskikh one - or polybasic carboxylic, sulfonic or sulfuric acids, as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, askorbinovaya acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine or disulfonate, louisanna acid.

Free base of formula (I), if desirable, can be free from their salts by treatment with strong bases like sodium hydroxide or potassium hydroxide, sodium carbonate or potassium, if the molecule contains no other acid groups. In those cases where the compounds of formula (I) contain free acid groups, by treatment with bases, you can also reach the salt formation. As a reason suitable the hydroxides of alkali metals, hydroxides of alkaline earth metals, or organic bases, in the form of Pani formula (I) and their physiologically acceptable salts for the preparation of pharmaceutical compositions in particular, non-chemical way. While their together with at least one carrier or auxiliary substance and, if necessary, in combination with one or more other biologically active substances brought to a suitable dosage forms.

The subject invention further funds are, in particular pharmaceutical compositions containing at least one compound of formula (I) and/or one of its physiologically acceptable salts. These compositions can be used as drugs in human medicine and veterinary medicine. As carriers take into account organic or inorganic substances which are suitable for intestinal (e.g. oral), parenteral or topical administration and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin; carbohydrate as lactose or starch; magnesium stearate, talc, vaseline. For intestinal use, in particular tablets, coated tablets, capsules, syrups, juices, drops or suppositories; for parenteral administration are solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants; for topicality you can use for example, for the preparation of drugs for injection.

These compositions can be sterilized and/or may contain auxiliary substances, as imparting lubricity agents, preservatives, stabilizers and/or wetting, emulsifying agents, salts for influencing the osmotic pressure, buffer substances, colorants, flavoring and/or aromatic substances. If desirable, they can also contain one or more other biologically active substances, for example one or more vitamins.

The compounds of formula (I) and their physiologically acceptable salts can be used in human or veterinary medicine. They are suitable for the treatment of extrapyramidal-motor side effects of antipsychotic agents, Central nervous system diseases, as a condition of tension, depression and/or psychosis, and side effects in the treatment of hypertension (for example, using a-Methyl-dopa). Further, the compounds may find application in endocrinology and gynaecology, for example, for the treatment of acromegaly, hypoplasia of the genital glands, secondary amenorrhoea, premenstrual syndrome, undesired puerperal lactation; then for prophylaxis and therapy of cerebral disorders (e.g. migraine), in the mswb (Apoplexia cerebri), as stroke and cerebral ischemia.

This proposed according to the invention substances, usually administered by analogy with the known, in the sale of drugs, for example, as Bromkriptin, Dihydroergocornine, preferably at doses of about 0.2 to 500 mg, in particular from 0.2 to 50 mg, dosing unit. The daily dose is preferably about 0.001 to 10 mg/kg of body weight. Low doses (approximately 0.2-1 mg per dosage unit of about 0.001 to 0.005 mg/kg body weight) when this is used in particular as a means of migraines; for the other indications, the preferred dosage of 10-50 mg per dosing unit. Special dose for each particular patient, however, depends on various factors, such as efficiency used a special connection on the age, body weight, General health, sex, cost, time and route of administration, rate of excretion, combination of drugs and the severity of the respective disease, which has implications for therapy. Preferably oral administration.

In the following examples, "conventional treatment" means add, if necessary, water, extracted with dichloromethane, separated, about what likehere and/or by crystallization. Temperature specified in theoC.

Example 1

1.2 g of 3-(4-Chlorobutyl)-5-methoxy-indole [obtained by reacting 5-methoxyindole 4-chlorobutyronitrile with the formation of 3-(4-chlorobutyryl)-5-methoxyindole and subsequent recovery using DIBORANE] and 1.0 g of 4-(indol-3-yl)-piperidine [obtained by reacting N-BOC-4-piperidone with indole followed by dehydration and hydrogenation of the resulting double bond, and by removal of the protective group] dissolve in 200 ml of acetonitrile and stirred for 8 h at room temperature. After conventional treatment get 3-/1-(4-(5-methoxyindol-3-yl)-butyl)-4-piperidyl)/-indole, hydrochloride. So pl. = 138-141oC (decomposition).

Similarly, by reacting methyl ester 3-(4-chlorobutyl)-indole-5-carboxylic acid 4-(5-methoxy-indol-3-yl)-piperidine get 3-/1-(4-(5-methoxycarbonylamino-3-yl)-butyl)-4-piperidyl)/-5-methoxyindol, hydrochloride; so pl. = 222-224oC;

3-(4-chlorobutyl)-indole with 4-(5-methoxyindol-3-yl)-piperidine get 3-/1-(4-indol-3-yl)-butyl)-4-piperidyl)/-5-methoxyindol, hydrochloride; so pl. = 213-216oC;

(3-(4-chlorobutyl)-5-methoxyindole 4-(5,6-methylenedioxyphenol-3-yl)-piperidine get 3-/1-(4-(5-methoxyindol-3-yl) - the 4-(5-methoxyindol-3-yl)-piperidine get 3-/1-(4-(5-methoxyindol-3-yl)-butyl)-4-piperidyl/-5-methoxyindol;

(3-(4-chlorobutyl)-indole with 4-(3-indolyl)-piperidine get 3-/1-(indol-3-yl)-butyl)-4-piperidyl/-indole;

(3-(4-chlorobutyl)-5-methoxyindole 4-(5-hydroxyindole-3-yl)-piperidine get 3-/1-(4-(5-methoxy-indol-3-yl)-butyl)-4-piperidyl/-5-hydroxyindole; so pl. = 203-204oC;

(3-(4-chlorobutyl)-5-caninde 4-(5-carbamimidoyl-3-yl)-piperidine get 3-/1-(4-cyan-indol-3-yl)-butyl)-4-piperidyl/-indol-5-carboxamid, hemihydrate; so pl. = 227-228oC;

(3-(4-chlorobutyl)-5-caninde 4-(5-laninga-3-yl)-piperidine get 3-/1-(4-(5-cyan-indol-3-yl)-butyl)-4-piperidyl/-5-laninga, dihydrate; so pl. = 95-101oC;

(3-(4-chlorobutyl)-5-methoxycarbonylamino 4-(5-carbarnoyl-indol-3-yl)-butyl)-4-piperidyl/-indol-5-carboxamid, hydrate: so pl. = 228-231oC;

(3-(4-chlorobutyl)-indole-5-carboxamide with 4-(5-carbamimidoyl-3-yl)-piperidine get 3-/1-(4-(5-carbarnoyl-indol-3-yl)-butyl)-4-piperidyl/-indol-5-carboxamid, trihydrochloride, so pl. = 202-203oC;

(3-(4-chlorobutyl)-5-farindola 4-(5-Florinda-3-yl)-piperidine get 3-/1-(4-(5-the fluorine-indol-3-yl)-butyl)-4-piperidyl/-5-Florinda;

methyl ester 3-(4-chlorobutyl)-indole-5-carboxylic acid 4-(5-methoxycarbonylamino-3-yl)-piperidine get methyl ester 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-get bution 3-/1-(4-(5-carbarnoyl-indol-3-yl)-butyl)-4-piperidyl/-5-laninga.

Example 2

0.8 g of Methyl ether 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)- butyl)-4-piperidyl/-indole-5-carboxylic acid [obtained according to example 1] boiled for 0.5 h with 100 ml of 2n. the ethanol solution of KOH, process as usual and get 3-/1-(4-(5-carboxy-indol-3-yl)-butyl)-4-piperidyl/-indole-5-carboxylic acid.

Similarly, by saponification of the corresponding complex ester, based on

from 3-/1-(4-(5-methoxycarbonylamino-3-yl)-butyl)-4-piperidyl/-5 - methoxy-indole get 3-/1-(4-(5-carboxyla-3-yl)-butyl)-4 - piperidyl/-5-methoxy-indole, hydrochloride hydrate; so pl. 248oC (decomposition);

from 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-butyl)-4-piperidyl/- indole-5-carboxamide get 3-/1-(4-(5-carboxy-indol-3-yl)-butyl)- 4-piperidyl/-5-carboxamide, hydrochloride; so pl. 282-285oC.

Example 3

Analogously to example 1, from 3-(3-chloropropyl)-5-methoxyindole [obtained by reacting 5-methoxyindole with 3-chloro-propionylcarnitine with 3-(3-chloropropionyl)-5-methoxyindole and subsequent recovery using DIBORANE] and 1.0 g of 4-(indol-3-yl)-piperidine [produced by interaction of N-BOC-4-piperidone with indole, followed by dehydration and hydrogenation of the resulting double)-4-piperidyl/-indole.

Similarly, by reacting methyl ester 3-(3-chlorpropyl)-indole-5-carboxylic acid 4-(5-methoxy-indol-3-yl)-piperidine get 3-/1-(3-(5-methoxycarbonylamino-3-yl)-propyl)-4-piperidyl/-5-methoxy-indole;

3-(3-chlorpropyl)-indole with 4-(5-methoxyindol-3-yl)-piperidine get 3-/1-(3-(indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindol, hydrochloride;

3-(3-chloropropyl)-5-methoxyindole 4-(5,6-methylenedioxyphenol-3-yl)-piperidine get 3-/1-(3-(5-methoxyindol-3-yl)-propyl)-4-piperidyl/-5,6-methylenedioxy-indole;

3-(3-chloropropyl)-5-methoxyindole 4-(5-methoxyindol-3-yl)-piperidine get 3-/1-(3-(5-methoxy-indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindol;

3-(3-chlorpropyl)-indole with 4-(3-indolyl)-piperidine get 3-/1-(3-(indol-3-yl)-propyl)-4-piperidyl/-indole;

3-(3-chloropropyl)-5-methoxyindole 4-(5-hydroxyindole-3-yl)-piperidine get 3-/1-(3-(5-methoxy-indol-3-yl)-propyl)-4-piperidyl/-5-hydroxyindole;

3-(3-chloropropyl)-5-caninde 4-(5-carbamimidoyl-3-yl)-piperidine get 3-/1-(3-(5-cyan-indol-3-yl)-propyl)-4-piperidyl/-indol-5-carboxamide;

3-(3-chloropropyl)-5-caninde 4-(5-laninga-3-yl)-piperidine get 3-/1-(3-(5-cyan-indol-3-yl)-propyl)-4-piperidyl/-5-tsianina;

3-(3-chloropropyl)-5-methoxycarbonyl-5 - carboxamide; so pl. = 195-196oC;

3-(3-chlorpropyl)-indole-5-carboxamide with 4-(5-carbamimidoyl-3-yl)-piperidine get 3-/1-(3-(5-carbarnoyl-indol-3-yl)-propyl)-4-piperidyl/-indol-5-carboxamid, sesquihydrate-isopropanolate, so pl. = 102-105oC (decomposition);

3-(3-chloropropyl)-5-farindola 4-(5-Florinda-3-yl)-piperidine get 3-/1-(3-(5-the fluorine-indol-3-yl)-propyl)-4-piperidyl/-5-Florinda, hydrochloride, hemihydrate, so pl. 164-165oC;

3-(3-chloropropyl)-5-farindola 4-(6-Florinda-3-yl)-piperidine get 3-/1-(3-(5-the fluorine-indol-3-yl)-propyl)-4-piperidyl/-6-fluoro-indole, hydrochloride, hydrate, so pl. 174-178oC;

3-(3-chloropropyl)-5-farindola with 4-(4-Florinda-3-yl)-piperidine get 3-/1-(3-(5-the fluorine-indol-3-yl)-propyl)-4-piperidyl/-4-Florinda, hydrochloride, T. pl. 269-270oC;

methyl ester 3-(3-chlorpropyl)-indole-5-carboxylic acid 4-(5-methoxycarbonylamino-3-yl)-piperidine get methyl ester 3-/1-(3-(5-methoxycarbonyl-indol-3-yl)-propyl)-4-piperidyl/-indole-5 - carboxylic acid;

3-(3-chlorpropyl)-indole-5-carboxamide with 4-(5-laninga-3-yl)-piperidine get 3-/1-(3-(5-carbarnoyl-indol-3-yl)-propyl)-4-piperidyl/-5-laninga, hydrate, so pl. 102-104oC (decomposition);

Example 4

Analogously to example 2, by saponification of methyl ester which, get 3-/1-(3-(5-carboxy-indol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic acid.

Similarly, by saponification of the corresponding complex ester based on

from 3-/1-(3-(5-methoxycarbonylamino-3-yl)-propyl)-4-piperidyl/-5 - methoxy-indole get 3-/1-(3-(5-carboxyla-3-yl)-propyl)-4 - piperidyl/-5-methoxy-indole;

from methyl ester 3-/1-(3-(5-methoxyindol-3-yl)-propyl)-4 - piperidyl/-indole-5-carboxylic acid get 3-/1-(3-(5-methoxyindol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic acid;

from methyl ester 3-/1-(3-(6-methoxyindol-3-yl)-propyl)-4 - piperidyl/-indole-5-carboxylic acid get 3-/1-(3-(6-methoxyindol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic acid;

from methyl ester 3-/1-(3-(4-methoxyindol-3-yl)-propyl)-4 - piperidyl/-indole-5-carboxylic acid get 3-/1-(3-(4-methoxyindol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic acid;

from 3-/1-(3-(5-methoxycarbonyl-indol-3-yl)-propyl)-4 - piperidyl/-indole-5-carboxamide get 3-/1-(3-(5-carboxy-indol-3-yl)-propyl)-4-piperidyl/-indol-5-carboxamide, hydrochloride, T. pl. 278-280oC.

Example 5

2.1 g of 3-/1-(5-Methoxy-indol-3-yl)-butyl)-4-piperidyl/-indole-5-carboxylic acid are suspended in 100 ml of N-methylpyrrolidine. Then add 3.2 g of 2-ha solution is passed up to the saturation dried gaseous NH3and again stirred for 10 hours After conventional treatment get 3-/1-(4-(5-methoxy-indol-3-yl)-butyl)-4-piperidyl/-indol-5 - carboxamide.

Similarly, by following amidation of carboxylic acids with 2-chloro-1-methyl-pyridinemethanol:

from 3-/1-(4-(6-methoxyindol-3-yl)-butyl)-4-piperidyl/-indole-5-carboxylic acid get 3-/1-(4-(6-methoxyindol-3-yl)-butyl)-4-piperidyl/- indol-5-carboxamide;

from 3-/1-(4-(4-methoxyindol-3-yl)-butyl)-4-piperidyl/-indole-5-carboxylic acid get 3-/1-(4-(4-methoxyindol-3-yl)-butyl)-4-piperidyl/- indol-5-carboxamide;

from 3-/1-(3-(5-carboxy-indol-3-yl)-propyl)-4-piperidyl/-indole-5 - carboxylic acid get 3-/1-(3-(5-carbarnoyl-indol-3-yl)-propyl)-4 - piperidyl/-indol-5-carboxamide;

3-/1-(3-carboxy-indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindole get 3-/1-(3-(5-carbamimidoyl-3-yl)-propyl)-4-piperidyl/-5-methoxy-indole;

from 3-/1-(3-(5-methoxyindol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic

acid get 3-/1-(3-(5-methoxyindol-3-yl)-propyl)-4-piperidyl/- indol-5-carboxamide;

from 3-/1-(3-(6-methoxyindol-3-yl)-propyl)-4-piperidyl/-indole-5-carboxylic acid get 3-/1-(3-(6-methoxyindol-3-yl)-propyl)-4-piperidyl/- indol-5-carboxamide;

from 3-/1-(3-(4-IU is Idil/- indol-5-carboxamide.

Example 6

A solution of 3.9 g 3-/1-(4-(5-carboxy-indol-3-yl)-butyl)-4-piperidyl/- indole-5-carboxylic acid in 250 ml of DMF is mixed with 1 g of N-methylmorpholine. With stirring a solution of two equivalents of tert.-of butylamine in 5 ml of DMF, 1.3 g of 1-hydroxybenzotriazole and a solution of 1.9 g of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride in 20 ml of DMF. Stirred for 16 h at room temperature and the filtrate is evaporated. After conventional treatment get 3-/1-(4-(5-N-tert.-butylcarbamoyl-indol-3-yl)-butyl)-4-piperidyl/- indol-5-N-tert.butyl-carboxamide.

Similarly, by reacting with tert.-- butylamine, on

from 3-/1-(4-(5-carboxyla-3-yl)-butyl)-4-piperidyl/-5-methoxyindole get 3-/1-(4-(5-N-tert. -butylcarbamoyl-3-yl)-butyl)-4 - piperidyl/-5-methoxy-indole;

from 3-/1-(4-(5-carboxy-indol-3-yl)-butyl)-4-piperidyl/-indole-5 - carboxamide get 3-/1-(4-(5-N-tert.-butylcarbamoyl-3-yl)- butyl)-4-piperidyl/-indol-5-carboxamide;

from 3-/1-(3-(5-carboxy-indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindole get 3-/1-(3-(5-N-tert. -butylcarbamoyl-3-yl)-propyl)-4 - piperidyl/-5-methoxy-indole.

Example 7

A mixture of 1.6 g of 3-/1-(4-(indol-3-yl)-butyl)-4-piperidyl/-5-methoxyindole [obtained according to example 1], 1 is ndol-3-yl)-butyl)-4-piperidyl/-5-hydroxyindole; so pl. 178-180oC.

In a similar way:

from 3-/1-(4-(5-methoxy-indol-3-yl)-butyl)-4-piperidyl/-indole get 3-/1-(4-(5-hydroxy-indol-3-yl)-butyl)-4-piperidyl/-indole;

from 3-/1-(4-(5-methoxy-indol-3-yl)-butyl)-4-piperidyl/-5-methoxyindole get 3-/1-(4-(5-hydroxy-indol-3-yl)-butyl)-4-piperidyl/-5-hydroxyindole;

from 3-/1-(4-(6-methoxy-indol-3-yl)-butyl)-4-piperidyl/-5-hydroxyindole get 3-/1-(4-(6-hydroxy-indol-3-yl)-butyl)-4-piperidyl/-5-hydroxyindole;

3-/1-(3-(indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindole get 3-/1-(3-(indol-3-yl)-propyl)-4-piperidyl/-5-hydroxyindole;

from 3-/1-(3-(5-methoxy-indol-3-yl)-propyl)-4-piperidyl/-5-methoxyindole get 3-/1-(3-(5-hydroxy-indol-3-yl)-propyl)-4-piperidyl/-5-hydroxyindole.

Example 8

To a suspension of 0.6 g of sociallyengaged in 20 ml of THF, with stirring and at room temperature was added dropwise a solution of 3.6 g 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-butyl)-4-piperidyl/- indole in 40 ml of THF. Then stirred for another hour at 25oC, add 20 ml of dilute sodium hydroxide solution, filtered and the filtrate treated as usual. Get 3-/1-(4-(5-hydroxymethylene-3-yl)-butyl)-4-piperidyl/-indole.

Similarly by vosstanovlenie-3-yl)-butyl)-4 - piperidyl/-5-methoxy-indole;

methyl ester 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-butyl)- 4-piperidyl/-5-carboxylic acid get 3-/1-(4-(5-hydroxymethyl-indol-3-yl)-butyl)-4-piperidyl/-5-hydroxymethylene;

3-/1-(3-(5-methoxycarbonylamino-3-yl)-propyl)-4-piperidyl/-5 - methoxyindole get 3-/1-(3-(5-hydroxymethylene-3-yl)-propyl)-4 - piperidyl/-5-methoxy-indole;

3-/1-(3-(5-methoxycarbonyl-indol-3-yl)-propyl)-4-piperidyl/- indole-5-carboxamide get 3-/1-(3-(5-hydroxymethylene-3-yl)- propyl)-4-piperidyl/-indol-5-carboxamide.

Example 9

Boiling a solution of 2.5 g 3-/1-(4-(5-carboxyla-3-yl)-butyl)-4 - piperidyl/-5-farindola in 50 ml of absolute methanol for 2 h miss gaseous hydrogen chloride. Then boil the next hour, process as usual and get 3-/1-(4-(5-methoxy-carbanilide - 3-yl)-butyl)-4-piperidyl/-5-fluoro-indole.

Example 10

Analogously to example 1, by reacting 3-(4-chlorobutyl)-indole [obtained by reacting indole with 4-chlorobutyryl-chloride with the formation of 3-(4-chlorobutyryl)-indole and subsequent recovery using DIBORANE] 4-(indol-3-yl)-1,2,5,6-tetrahydropyridine [produced by interaction of N-BOC-4-piperidone with indole and subsequent dehydration and removal of the protective) /indole, hydrochloride, T. pl. 190-192oC.

Similarly, by interaction

methyl ester 3-(4-chlorobutyl)-indole-5-carboxylic acid 4-(5-methoxy-indol-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-methoxycarbonylamino-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine - 4-yl)/-5-methoxyindol;

3-(4-chlorobutyl)-indole with 4-(5-methoxyindol-3-yl)-1,2,5,6 - tetrahydropyridine get 3-/1-(4-(indol-3-yl)-butyl)-(1,2,5,6 - tetrahydropyridine-4-yl)/-5-methoxyindol;

3-(4-chlorobutyl)-5-methoxyindole 4-(5,6-methylenedioxyphenol-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-methoxyindol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl)/- 5,6-methylenedioxyphenol;

3-(4-chlorobutyl)-5-methoxyindole 4-(5-methoxyindol-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-methoxyindol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl)/- 5-methoxyindol;

3-(4-chlorobutyl)-indole with 4-(3-indolyl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(indol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl)-indole;

3-(4-chlorobutyl)-5-methoxyindole 4-(5-hydroxyindole-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-methoxy-indol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl)/- 5-hydroxyindole;

3-(4-chlorobutyl)-5-caninde 4-(5-carbamimidoyl-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-cyan-indol-3-yl)-buta what rehydrogenation get 3-/1-(4-(5-laninga-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl)/- 5-tsianina;

3-(4-chlorobutyl)-5-methoxycarbonylamino 4-(5-carbarnoyl-indol-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine - 4-yl)-indol-5-carboxamide;

3-(4-chlorobutyl)-indole-5-carboxamide with 4-(5-carbarnoyl-indol-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-carbarnoyl-indol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine-4-yl) - indol-5-carboxamide;

3-(4-chlorobutyl)-5-farindola 4-(5-Florinda-3-yl)-1,2,5,6 - tetrahydropyridine get 3-/1-(4-(5-the fluorine-indol-3-yl)-butyl)- (1,2,5,6-tetrahydropyridine-4-yl)/-5-fluoro-indole;

methyl ester 3-(4-chlorobutyl)-indole-5-carboxylic acid 4-(5-methoxycarbonylamino-3-yl)-1,2,5,6-tetrahydropyridine get methyl ester 3-/1-(4-(5-methoxycarbonyl-indol-3-yl)-butyl)- (1,2,5,6-tetrahydropyridine-4-yl)-indole-5-carboxylic acid;

3-(4-chlorobutyl)-indole-5-carboxamide with 4-(5-laninga-3-yl)-1,2,5,6-tetrahydropyridine get 3-/1-(4-(5-carbarnoyl-indol-3-yl)-butyl)-(1,2,5,6-tetrahydropyridine - 4-yl)/-5-cyan-indole.

Example 11

Analogously to example 1, from 3-(2-chloroethyl)-2-methyl-5-methoxyindole [obtained by reacting 2-methyl-5-methoxyindole with 2 chloroacetylation with the formation of 3-(2-chloroacetyl)-2-methyl-5-methoxyindole and subsequent recovery through d is I, subsequent dehydration and hydrogenation of the resulting double bond and removal of the protective group] after conventional treatment, get 3-/1-(2-(2-methyl-5-methoxy-indol-3-yl)-ethyl)-4-piperidyl/-5-Florinda, hydrochloride. Rf= 0,31.

Similarly, by interaction

3-(2-chloroethyl)-indole with 4-(5-fluoro-indol-3-yl)-piperidine get 3-/1-(2-(indol-3-yl)-ethyl)-4-piperidyl/-5-Florinda, hydrochloride, Rf= 0,20;

3-(2-chloroethyl)-indole with 4-(4-fluoro-indol-3-yl)-piperidine get 3-/1-(2-(indol-3-yl)-ethyl)-4-piperidyl/-4-Florinda, hydrochloride, T. pl. 297oC;

3-(2-chloroethyl)-2-methyl-5-methoxyindole with 4-(4-fluoro-indol-3-yl)-piperidine get 3-/1-(2-(2-methyl-5-methoxy-indol-3-yl)-ethyl)-4-piperidyl/-4-Florinda, hydrochloride, T. pl. 215oC;

3-(2-chloroethyl)-indole with 4-(5-methoxy-indol-3-yl)-piperidine get 3-/1-(2-(indol-3-yl)-ethyl)-4-piperidyl/-5-methoxy-indole;

3-(2-chloroethyl)-2-methyl-5-methoxyindole with 4-(4-methoxy-indol-3-yl)-piperidine get 3-/1-(2-methyl-5-methoxy-indol-3-yl)-ethyl)-4-piperidyl/-4-methoxy-indole.

Example 12

0.4 g of 3-/1-((5-fluoro-indol-3-indol-3-yl)-methylcarbamoyl)-4 - piperidyl/-5-torindel [obtained by reacting 5-farindola with 2 chloroacetylation with the formation of 3-(2-chloracetic the temperature drops mixed with 1.3 equivalents of NaAl(OCH2CH2OCH3)2H2dissolved in 10 ml of toluene. Stirred for 2 h at room temperature, then treated as usual and get 3-/1-(2-(5-the fluorine-indol-3-yl)-ethyl)-4-piperidyl/-5-Florinda, hydrochloride, Rf= 0,27.

Similarly, by restoring using NaAl(OCH2CH2OCH3)2H2;

from 3-/1-(2-(5-the fluorine-indol-3-yl)-ethylcarboxyl)-4-piperidyl/-4-fluoro-indole get 3-/1-(3-(5-the fluorine-indol-3-yl)-propyl)-4-piperidyl/-4-fluoro-indole;

3-/1-(5-fluoro-indol-3-yl)-methylcarbamoyl)-4-piperidyl/-4-farindola get 3-/1-(2-(5-the fluorine-indol-3-yl)-ethyl)-4-piperidyl/-4-Florinda, hydrochloride; so pl. 260oC.

Pharmacological data

Determined the binding trithiolane ligands hippocampally receptors serotonin-1A according to the method described Cossery with the staff. in the journal European J. Pharmacol., 140, pp. 143-155 (1987) in the presence of some compounds of formula I. the Data IC50in table 1, the value of the IC50given in nm/L.

< / BR>
Table 1 data indicate the affinity of the compounds according to the invention to the receptor of the Central nervous system, which reflects the potential impact to serotoninergicheskoi transmission (agonistic and/the tion of dopamine antagonists and agonists, as well as linking spiperone and ADTN to D2-receptor in the rat striatum was determined by the method described Schwarcz with the staff. in the journal of Neuro-Chemistry, 34, 772-778 (1980) and Cossery with the staff. in the journal European J. Pharmacol., 46, pp. 337-381 (1977). Determined the size of the IC50some compounds of formula I, the values of the IC50in nmol/l data are shown in table 2.

< / BR>
The following examples relate to pharmaceutical compositions:

Example A: Preparation for injections

A solution of 100 g of biologically active substances of the formula (I) and 5 g of dinitrigenoxide in 3 l of double-distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, the solution is sterile filtered, poured into glass containers for preparations for injection, lyophilizer in sterile sterile conditions and closed. Each glass container of medicine for injection contains 5 mg of biologically active substances.

Example B: Candles

Melt a mixture of 20 g of biologically active substances of the formula (I) and 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and cooled. Each suppository contains 20 mg of biologically active substances.

Example: Solution

Prepare a solution of 1 g of biologically active substances of the formula (I), 9,38 g of NaH is. Set pH to 6.8, made up to a total volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

Mix 500 mg of biologically active substances of the formula (I) with 99.5 g of vaseline under aseptic conditions.

Example D: Tablets

A mixture of 1 kg of biologically active substances of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate as usual pressed into tablets such that each tablet contains 10 mg of biologically active substances.

Example E: Bean

Analogously to example D is pressed tablets, which are then applied a coating of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of biologically active substances of the formula (I) in the usual way bring into hard gelatin capsules so that each capsule contains 20 mg of biologically active substances.

Example C: Ampoules

A solution of 1 kg of biologically active substances of formula I in 60 l of double-distilled water is sterile filtered, filled them ampoules, lyophilizer in sterile sterile conditions and closed. Each ampoule contains 10 mg of biologically active substances is dependent from each other denotes H, And, HE, OA, F, Cl, Br, Z, CN, CF3, COOH, CONH2, CONHA, CONA2or cooa, or R1and R2and R3and R4accordingly together also denote methylenedioxy;

R5denotes H or HE;

R6denotes H; or

R5and R6together also denote the connection;

And denotes alkyl with 1 to 6 C-atoms;

n denotes 2, 3, 4, 5 or 6,

and their physiologically acceptable salts.

2. 3-Intellipedia formula I on p. 1 representing: ) 3-(1-(3-(5-carbarnoyl-3-indolyl)-propyl)-piperid-4-yl)-indole-5-carboxamide; b) 3-(1-(3-(5-carbarnoyl-3-indolyl)-propyl)-piperid-4-yl)-indole-5-carbonitrile; ) 3-(1-(4-(5-methoxycarbonyl-3-indolyl)-butyl)-piperid-4-yl)-5-methoxy-indole; d) 3-(1-(3-(5-etoxycarbonyl-3-indolyl)-propyl)-piperid-4-yl)-indole-5-carboxamide; d) 3-(1-(4-(5-cyan-3-indolyl)-butyl)-piperid-4-yl)-indole-5-carbonitrile, and their physiologically acceptable salts.

3. The method of obtaining 3-intellipedia formula I or their physiologically acceptable salts, characterized in that the compound of formula II

< / BR>
where X1denotes X or NH2;

X denotes Cl, Br, J, OH or a reactive functionally modified HE-group;

R1, R2and n have shown what may be the same or different and denote X if X1= NH2in case, if X1denotes X, X2and X3indicate along NH-group;

R3and R4are specified in paragraph 1 values

followed, if necessary, by saponification of the resulting product and translation, if necessary, the obtained base or acid with acid or base in one of their salts.

4. Pharmaceutical composition having serotonin-agonistic and/or serotonin-antagonistic activity, characterized in that it contains as active substance at least one compound of formula I under item 1 and/or one of its physiologically acceptable salt in an effective amount, optionally together with conventional additives.

5. A method of obtaining a pharmaceutical composition, characterized in that the compound of formula I under item 1 and/or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary substance is brought to a suitable dosage forms.

 

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