KR19990081970A - 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as a drug acting on the central nervous system - Google Patents

Abstract

The present invention is formula (I)

Formula I

(Wherein,

R ¹ is H or A,

R ² is H or phenyl mono- to tri-substituted with Hal, NO ₂ , CON (R ⁴ ) ₂ , SO ₂ N (R ⁴ ) ₂ , cyano, A or R ⁴ -O,

R ³ is H, Hal, A, AO-, amino, cyano, carboxamide, NO ₂ , SO ₂ N (R ⁴ ) ₂ ,

R ⁴ is H or A,

R ⁵ is H or A,

A is alkyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms mono- to trisubstituted with fluorine,

Hal is F, Cl, Br or I.)

Novel 1-pyrazol-3-ylethyl-4-indol-3-ylpiperidine derivatives thereof and salts thereof have been found to exhibit pharmaceutically useful actions.

Description

1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as a drug acting on the central nervous system

Numerous drugs for treating diseases caused by dysfunction or disease of the central nervous system are known in the technical literature and patent literature. However, most of these drugs have serious side effects or relatively nonspecific effects.

The present invention is formula (I)

(Wherein R ¹ is H or A,

R ² is H or phenyl mono- to tri-substituted with Hal, NO ₂ , CON (R ⁴ ) ₂ , SO ₂ N (R ⁴ ) ₂ , cyano, A or R ⁴ -O,

R ³ is H, Hal, A, AO-, amino, cyano, carboxamide, NO ₂ , SO ₂ N (R ⁴ ) ₂ ,

R ⁴ is H or A,

R ⁵ is H or A,

A is alkyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms mono- to trisubstituted with fluorine,

Hal is F, Cl, Br or I.)

It relates to a novel 1-pyrazol-3-ylethyl-4-indol-3-ylpiperidine derivatives and salts thereof, which have been identified as substances exhibiting a pharmaceutically useful action.

Accordingly, the present invention aims to produce useful new compounds which selectively act on the central nervous system as drugs and at the same time have little side effects, little or no dependence.

It is also an object of the present invention to provide an available method which can produce suitable compounds in the highest possible yields and purity.

This object can be achieved through the present invention.

It has now been found that compounds of formula (I) and their physiologically acceptable salts, wherein R ¹ to R ⁵ , A and Hal have the given meaning, have a wide range of useful pharmacological properties. Thus, they are particularly active in the central nervous system, in particular dopamine-stimulating (anti-Parkinson) and serotonin-agonistic and antagonistic. In particular, the compound of formula 1 induces contralateral pivoting behavior in Hemiparkinson rats (Ungerstedt et al., Brain Res. 24, (1970), detectable by the method of 485-493]. This compound binds tritiated dopamine agonists and antagonists to striatal receptors (Schwarcz et al., J. Neurochemistry 34, (1980), 772-). 778 and Creese et al., European J. Pharmacol. 46, (1977), 377-381), and the binding of tritium-labeled serotonin ligands to hippocampal receptors [Cossery et al., European J. Pharmacol 140, (1987), 143-155. In addition, the scale of DOPA in striatum and 5-HTP in n.raphe change [Seyfried et al., European J. Pharmacol. 160, (1989), 31-41. The compound also inhibits glossomaxillary reflex in anesthetized rats (Barnett et al., European J. Pharmacol. 21, 81973), 178-182, and Ilhan et al., European J. et al. Pharmacol. 33, (1975), 61-64. It also acts as analgesic and hypotension. Thus, spontaneous hypertensive rats with a conscious catheter (Strain SHR / Okamoto / NIH-MO-CHB-Kisslegg; method cf. Weeks and Jones, Proc. Soc.Exptl. Biol. Med. 104, (1960) , 646-648), blood pressure decreases when measured immediately after oral administration of the compound.

In addition, the present invention provides a compound of formula II:

Wherein R ¹ , R ² and R ⁵ are as defined above, Z is Hal, O-SO ₂ CH ₃ , O-SO ₂ CF ₃ , OSO ₂ -C ₆ H ₄ , or O- SO ₂ -C ₆ H ₅ )

A compound of formula III:

(Wherein R ³ and R ⁴ are the same as described above).

Or react with

Compounds of Formula IIa

(Wherein R ¹ and R ² are as described above) to the active form, and then reacted with the compound of formula III under known conditions to form peptide bonds, To form a compound of formula I,

And / or react with a strong base to liberate the compound of formula (I) as a free base, or

And / or converting a base of formula (I) to the relevant acid addition salt using an acid.

The compound of formula (I) may have a chiral center. Suitable compounds of formula (I) can occur in various enantiomeric forms. These forms (eg D- and L-forms) and mixtures thereof (eg DL-forms) are all included in Formula (I).

Above and below, the radicals or parameters R ¹ to R ⁵ , A and Hal have the meanings set forth in the formulas (I) to (III) unless stated otherwise. When there are several groups identically represented in a molecule, it can be considered that they are defined differently independently from each other.

In the formula, group A has 1 to 6 carbon atoms, preferably 1, 2, 3 or 4 carbon atoms. In particular, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, Preference is also given to 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl. Group A is also a linear or branched alkylene group having 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, with methylene or ethylene being preferred, for example ethylidene, trimethylene, -CH (CH ₃ ) CH ₂ -,- CH ₂ CH (CH ₃ ) —, —C (CH ₃ ) ₂ —, propylidene, tetramethylene, —CH (CH ₃ ) — (CH ₂ ) ₂ —, —CH ₂ —CH (CH ₃ ) —CH ₂ -,-(CH ₂ ) ₂ -CH (CH ₃ )-, -C (CH ₃ ) ₂ -CH _2- , -CH ₂ -C (CH ₃ ) _2- , -CH (CH ₂ CH ₃ ) -CH _2- , -CH ₂ CH (CH ₂ CH ₃ )-, -CH (CH ₂ CH ₂ CH ₃ )-, -C (CH ₃ ) (CH ₂ CH ₃ )-, -CH (CH ₃ ) CH (CH ₃ )-or -CH [CH (CH ₃ ) ₂ ]-is also preferred. However, as such a group, an alkyl group having 1 to 6 carbon atoms, which is mono- to tri-substituted with fluorine, is also possible.

Accordingly, when R ⁴ is A, the R ⁴ -O- group is a straight or branched chain alkylene group of 1 to 6 (particularly 1 to 4) carbon atoms, in particular bonded via an oxygen atom. AO is methoxy, ethoxy, 1- or 2-propoxy, 1-butoxy, isobutoxy, secondary-butoxy or tert-butoxy.

The group designated by phenyl is preferably unsubstituted phenyl. Substituted phenyl groups are preferably monosubstituted. However, such phenyl groups may be di- or trisubstituted and the substituents may be the same or different. Preferred substituents are F, Cl, methoxy and OH. However, NO ₂ , cyano, A or AO are also possible substituents, and A and AO- are the same as above.

In particular, the phenol groups are o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxy Phenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3-hydroxy-4-methoxyphenyl, 3-methoxy -4-hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3- or 3,4- Methylenedioxyphenyl is preferred.

Hal is a halogen radical and may be fluorine, chlorine, bromine or iodine. Especially fluorine or chlorine is preferable.

R ¹ is preferably hydrogen or A.

R ² is hydrogen or Hal, A or R ⁴ -O, preferably R ⁴ is A, preferably mono-, di- or tri-substituted phenyl, in particular CON (R ⁴ ) ₂ or SO in ₂ N (R ⁴⁾ ₂ days, or tri-substituted phenyl are also preferred.

R ³ is preferably a hydrogen, A, in particular a radical of methyl or ethyl or a radical of R ⁴ -O (in other words methoxy or ethoxy). Particular preference is given to cyano, carboxamide or nitro groups. In particular, optionally substituted sulfonyl groups are also possible. Substituents for these sulfonyl groups are Hal, A or A, which is mono- to tri-substituted by Hal.

R ⁴ is preferably hydrogen, optionally A, and is especially a methyl or ethyl radical.

R ⁵ is preferably hydrogen like R ⁴ , optionally A also possible, in particular a methyl or ethyl radical.

Among the compounds of the formula (I), preference is given to compounds in which one or more of the radicals mentioned above have the preferred meanings mentioned above. Some of the preferred compound groups can be represented by the following formulas Ia to Id corresponding to formula (I).

In la, R ¹ is hydrogen or methyl;

In lb, R ¹ is hydrogen or methyl and R ² is phenyl mono- to tri-substituted with hydrogen or Hal;

In Ic R ¹ is methyl and R ³ is hydrogen, fluorine, hydroxy, cyano, carboxamide, ethyl, methoxy or trifluoromethylsulfonyloxy;

In Id R ¹ is methyl and R ⁴ is hydrogen or methyl.

In addition, compounds of formula (I) and their starting materials are known to those skilled in the art described in, for example, Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart, etc. It is prepared under known reaction conditions suitable for the reaction by the prepared method. In this case, it is also possible to use known modified methods which are not mentioned here in detail.

If necessary, the starting materials may be reacted without separation from the reaction mixture, so that compounds of formula (I) are produced in situ.

Starting materials for the preparation of compounds of formula (I) can be obtained by solvolysis of the functional functional derivatives, in particular hydrolysis or hydrogenolysis, to liberate them. Compounds of formula (I) are preferably obtained by coupling reaction of compounds of formula (II) or (IIa) with compounds of formula (III) by methods known to those skilled in the art, if necessary after selective hydrogenation. In particular, compounds of formula (I) are often unstable under solvolysis conditions, so that, where possible, there is no need for solvolysis to favor the compounds of formula (I) which are desirable when synthesizing compounds of formula (I).

As starting materials for solvolysis or hydrogenolysis, starting materials corresponding to the above formulas, in addition to having the corresponding amino protecting group and / or hydroxy protecting group in place of the free amino group and / or the hydroxy group, are preferable, and especially to nitrogen atoms. Starting materials having amino protecting groups in place of the bonded hydrogen atoms, in particular starting materials having R'-N groups (R 'being amino protecting groups) in place of NH groups and / or having hydroxy protecting groups in place of H atoms of the hydroxy groups Preferred are starting materials (for example, starting materials having a group -COOR " (R " is a hydroxy protecting group) in which R " is a hydroxy protecting group in place of the -OOH group).

Within the molecule of the starting material, several (same or different) amino protecting groups and / or hydroxy protecting groups may be present. If these protectors differ, most can be removed selectively.

The term "amino protecting group" means a known group which is generally suitable for protecting (blocking) an amino group from a chemical reaction and is easy to remove after carrying out the desired chemical reaction in another part of the molecule. Typical examples include unsubstituted or substituted acyl, aryl [e.g. dinitrophenyl (DNP)], aralkoxymethyl [e.g. benzyloxymethyl (BOM)] or aralkyl groups (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino protecting group is removed after the desired reaction (or series of reactions), its nature and size are not critical; However, it is preferable that they are C1-C20, especially C1-C8. The term "acyl group" may be interpreted in the broadest sense with respect to the method of the invention. Acyl groups include acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, in particular alkoxycarbonyl groups, aryloxycarbonyl groups and especially aralkoxycarbonyl groups. Examples of this type of acyl group include alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluoyl; Aryloxyalkanoyl such as phenoxyacetyl; Such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodo-ethoxycarbonyl Alkoxycarbonyl; Aralkyloxycarbonyl such as benzyl-oxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, DNP and BOM, with CBZ, benzyl and acetyl being preferred.

The term "hydroxy protecting group" generally means a known group which is suitable for protecting the hydroxy group from chemical reactions and which is easy to remove after carrying out the desired chemical reaction in another part of the molecule. Typical examples include those unsubstituted or substituted aryl, aralkyl or acyl groups, with alkyl groups being preferred. Since hydroxy protecting groups are removed after the desired reaction or series of reactions, the nature and size are not critical; However, it is preferable that they are C1-C20, especially C1-C10. Examples of hydroxy protecting groups include tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl protecting groups and acetyl, with benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the formula (I) used as starting materials are the compounds corresponding to the formulas (II) and (III) as described in conventional methods such as, for example, in appropriate standard workbooks and related patent literatures (these compounds) At least one of which has a protecting group in place of a hydrogen atom).

When the compounds of formula (II), (IIa) or (III) and, if necessary, the compounds of formula (I) are all liberated (the free method depends on the protecting group used) in their functional derivatives, for example, strong acids, preferably trifluoro Roacetic acid or perchloric acid is used, or other inorganic strong acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, or sulfonic acids such as benzene- or p-toluenesulfonic acid. It is also possible to use additional solvents, but this is not necessary.

Suitable inert solvents are, for example, preferred are organic solvents such as carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), and methanol, ethanol or isopropanol. Alcohols such as water or water are also preferred. Also mixtures of the above solvents are possible. Trifluoroacetic acid is preferably used in excess without further use of other solvents, and perchloric acid is preferably used in a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. Removal reaction temperature of the protecting group is suitably in the temperature range of about 0 to about 50 ℃; In particular, it is preferable to perform reaction in the temperature range (room temperature) of about 15-30 degreeC.

The BOC group is preferably removed using, for example, 40% trifluoroacetic acid in dichloromethane or about 3 to 5N HCl in dioxane at a temperature of 15 to 60 ° C., while the FMOC group is at a temperature of 15 to 50 ° C. Preference is given to using about 5-20% solution of dimethylamine, diethylamine or piperidine in DMF. DNP groups can be removed using, for example, a solution of about 3-10% of 2-mercapto-ethanol in DMF / water at a temperature of 15-30 ° C.

Protecting groups (e.g., BOM, CBZ or benzyl) that can be removed by hydrogenolysis can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium on a support such as carbon). Can be. The solvent is suitable for this reaction, and in particular, alcohols such as methanol, ethanol, amides such as DMF, and the like can be used. Hydrolysis is generally carried out in the range of about 0 to 100 ° C. and in the range of about 1 to 200 bar of pressure, with 20 to 30 ° C. and 1 to 10 bar being particularly preferred. For example, CBZ groups can be readily hydrolyzed using 5-10% Pd-C in methanol at 20-30 °.

The compound of formula (I) is preferably obtained by reacting a pyrazole derivative of formula (II) with a compound of formula (III). Preference is given to using known methods for the N-alkylation of amines.

The leaving group Z in formula (II) is C ₁ -to C ₆ -alkylsulfonyloxy, benzene-, p-toluene-, or 1- or 2-naphthalenesulfone such as Cl, Br, I, ethane- or ethanesulfonyloxy Preference is given to C ₆ -to C ₁₀ -arylsulfonyloxy, such as fonyloxy.

The reaction is carried out in an inert solvent such as a halogenated hydrocarbon such as dichloromethane, trichloromethane or carbon tetrachloride, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, or a nitrile such as acetonitrile. Dimethyl sulfoxide, toluene or benzene are also suitable solvents. It is also possible to use mixtures of these solvents. This reaction can be carried out in a temperature range of about -10 to 200 ℃, preferably 0 to 120 ℃. The reaction is preferably carried out in the presence of additional bases, for example sodium, potassium or calcium hydroxides or hydroxides or carbonates of alkali or alkaline earth metals such as sodium, potassium or calcium carbonates. . If leaving group Z is not I, an iodide such as potassium iodide can be added.

Starting materials of formula (II) can be prepared according to methods known in the literature.

Starting materials of formula III can be prepared according to methods generally known to those skilled in the art, as described in the handbook on indole chemistry. Benzyl and BOC are preferred as protecting groups for piperidine nitrogen. Such protecting groups are particularly preferred when introducing R ⁴ substituents other than hydrogen on indole nitrogen. The latter reaction is particularly preferably carried out in the presence of a strong base, exactly in the presence of NaH, KH, KOC (CH ₃ ) ₃ , or n-, secondary- or tert-butyllithium. Thereafter, the "amino protecting group" is removed according to one of the above methods.

Starting materials of formula (IIa) can be prepared according to methods known in the literature, in particular in analogy to Example 5 below.

The coupling reaction of the compound of formula IIa with the compound of formula III can be carried out under known conditions to form peptide bonds. Corresponding methods are described, for example, in "Aminosauren, Peptide, Proteine" [Amino Acids, Peptides, Proteins], Jakubke, Hans-Dieter; Jeschkeit, Hans; Verlag Chemie, Weinheim (1982), Wunsch E. (1974), "Synthese von Peptiden" [Synthesis of Peptides] in: Houben-Weyl, "Methoden der organischen Chemie" [Methods of Organic Chemistry], Vol. 15, 1/2 (Ed., Muller, E.) Georg Thieme Verlag, Stuttgart. Such methods include, in particular, the azide method, mixed anhydride methods using chlorocarboxylic acid monoesters as anhydride-forming agents, various activated ester methods and carbodiimide methods, modified methods thereof, and DCC addition methods. Such carbonyl compounds obtained by the coupling reaction can be reduced under suitable conditions to favor the preferred compounds of formula (I).

In particular, this is done in the presence of a hydride group complex catalyst. This reaction is preferably carried out in a solvent of an ether group. Particular preference is given to using tetrahydrofuran as the solvent. Generally, this reduction is carried out under mild conditions at a temperature range of -78 to + 66 ° C, preferably at room temperature. In particular, this reduction can also be carried out using sodium bis (2-methoxy-ethoxy) aluminum hydride (eg Vitride ^(R) ). For this purpose, an excess of sodium bis (2-methoxy-ethoxy) aluminum hydride is used. At this time, suitable ether is preferred as a solvent.

Bases of formula (I) can be converted to the related acid addition salts using acids. In this reaction, any suitable acid that produces a physiologically acceptable salt can be used. Thus, for example, hydrochloric acid such as sulfuric acid, nitric acid, hydrochloric acid or bromic acid, phosphoric acid such as orthophosphoric acid, inorganic and organic acids such as sulfamic acid, in particular aliphatic, alicyclic, aromatic aliphatic, aromatic or heterocyclic mono- or poly Base carboxylic acid, sulfonic acid or sulfuric acid (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acid, lauryl sulfate) have. Salts of physiologically acceptable acids, such as picrates, can be used to isolate and / or purify the compound of formula (I).

If necessary, the salt of formula (I) can be treated with a strong base such as sodium or potassium hydroxide, or sodium or potassium carbonate to liberate the free base of formula (I).

As already pointed out above, the compounds of formula (I) may contain one or more chiral centers and therefore may exist in racemate or optically active form. The resulting racemates can be separated mechanically or chemically into enantiomers by known methods. It is preferred to react the racemic mixture with an optically active resolving agent to form diastereomers. Suitable splitting agents are optically active such as various optically active camphorsulfonic acids such as, for example, D- and L-type tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or β-camphorsulfonic acid. It is a mountain.

It is also desirable to separate enantiomers using a column packed with an optically active splitting agent (eg dinitrobenzoylphenyl-glycine). In this connection, suitable eluents include, for example, mixtures of hexane / isopropanol / acetonitrile.

It is of course also possible to obtain optically active compounds of the formula (I) according to the above method using already optically active starting materials (eg compounds of the formula (II)).

Thus, the novel compounds of formula (I) and their physiologically acceptable salts can be used as pharmaceutically active compounds of axiolytics, antidepressants, analgesics, anti-Parkinson's and / or antihypertensive agents. They are used to treat and prevent anxiety, panic attacks, schizophrenia, delusional obsessions, Alzheimer's disease, migraines, anorexia nervosa, anorexia nervosa, sleep disorders and drug abuse. Extrapyramidal Suitable for the treatment of motor side effects. However, it can also be used as an intermediate in the preparation of other pharmaceutically active compounds.

Thus, the compounds of formula (I) and their physiologically acceptable salts can be used in the manufacture of pharmaceutical preparations in the form of suitable dosage forms with one or more excipients or auxiliaries and, if necessary, with one or more other active compounds. The preparations thus obtained can be used as pharmaceutical preparations in human medicine or veterinary medicine. Possible excipients are organic or inorganic substances that are suitable for enteral (eg oral or rectal) or parenteral administration and do not react with the novel compounds, for example, water, vegetable oil, benzyl alcohol, polyethylene glycol, Carbohydrates such as glycerol triacetate and other fatty acid glycerides, gelatin, soya lecithin, lactose or starch, magnesium stearate, talc, or cellulose.

Tablets, coated tablets, capsules, syrups, juices or drops are especially used for oral administration. In particular, a capsule having a coated tablet and enteric skin or a capsule shell is preferable. Suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions and suspensions, emulsions or implants for parenteral administration.

The compounds according to the invention may be lyophilized and the resulting lyophilisate can be used, for example, in the production of injectables.

The formulation may be sterilized and / or may contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants and / or flavoring agents. If desired, it may contain one or more further active compounds, for example one or more vitamins, diuretics or anti-inflammatory agents.

The compounds of formula (I) according to the invention are generally administered similarly to other commercially available agents known for the treatment of the indications, preferably in the range of about 1 to 50 mg, in particular 5 to 30 mg per dosage unit. The daily dose is preferably in the range of about 0.02 to 20 per kg of body weight, particularly in the range of 0.2 to 0.4 mg.

However, the specific dosage of each patient may vary depending on a variety of factors, such as activity, age, weight, general health, sex, diet, time and route of administration, and rate of excretion, concomitant medications and the specific disease to be treated. Depends on the severity Oral administration is preferred.

The following are examples for explaining the present invention, and the present invention is not limited to the examples.

The temperatures listed below are all in degrees Celsius.

Example 1

7-ethyl-3- (1-benzyl-1,2,3,6-tetrahydro-4-pyridyl) indole

144 g (about 2.57 mol) of KOH was dissolved in 1.6 L of methanol in a 2000 ml round bottom flask. Then 120 g (about 0.86 mol) of 7-ethylindole and 161.4 g (about 0.86 mol) of 1-benzylpiperidin-4-one were added to the solution. The reaction mixture was stirred for 5 hours under reflux conditions. An additional 34.1 g (about 0.172 mol) of 1-benzylpiperidin-4-one was added and the mixture was stirred under reflux overnight. The resulting reaction solution was concentrated in vacuo to give the product in crystalline form. This crude product was recrystallized from methanol.

Yield: 224 g of 7-ethyl-3- (1-benzyl-1,2,3,6-tetrahydro-4-pyridyl) indole (-82% of theory)

R _f 0.35 (ethyl acetate / petroleum ether 1: 1)

Example 2

7-ethyl-3- (4-piperidyl) indole

7-ethyl-3- (1-benzyl-1,2,3,6-tetrahydro-4-pyridyl) indole obtained in Example 1 was dissolved in a solvent mixture comprising 2 L methanol and 0.5 L glacial acetic acid, The hydrogenation was carried out at 22 ° C. over 16 hours in the presence of a palladium catalyst (Pd-C 5%). The catalyst was then filtered off and the solvent was distilled off in vacuo. The obtained residue was distilled with toluene and dissolved in 1 L of water. Sodium hydroxide solution (32%) was added to make the pH of the solution alkaline. The precipitated crystals were separated and dried through the above method.

Yield: 153.6 g of 7-ethyl-3- (4-piperidyl) indole (-95% of theory)

M.p. 189 ℃

Example 3

6-Methyl-2H-pyran-2,4- (3H) -dione

495 ml of sulfuric acid (90%) were heated to 130 ° C. in a 2 L three neck flask. 300 g of 3-acetyl-3,4-dihydro-6-methylpyran-2,4-dione (dihydroacetic acid) was added in small portions with stirring. The mixture was then further stirred for several hours. After the reaction occurred, the reaction mixture was poured into about 1500 g of ice. The crystals formed were separated.

Yield: 192 g (crude) 3,4-dihydro-6-methylpyran-2,4-dione (85% of theory)

Example 4

2- (5-methyl-3-pyrazolyl) acethydrazide

191.6 g of 3,4-dihydro-6-methylpyran-2,4-dione was dissolved in 800 ml of methanol. 190 g of NH ₂ NH ₂ · H ₂ O was added dropwise while stirring this solution, and the temperature was raised to 70 ° C. After the reaction, the formed product was filtered and treated as a crude product.

Yield: 193 g of 2- (5-methyl-3-pyrazolyl) acethydrazide (82% of theory)

M.p .: 153-154 ℃

Example 5

2- (5-methyl-3-pyrazolyl) acetic acid

105 g of 2- (5-methyl-3-pyrazolyl) acethydrazide and 720 ml of 2N sodium hydroxide solution were mutually stirred and the mixture was heated under reflux for 4 hours. The reaction solution thus obtained was then neutralized with hydrochloric acid. Then the reaction solution was concentrated in vacuo. In this process, the precipitated crystals were separated and immediately treated as a crude product.

Yield: 202 g of 2- (5-methyl-3-pyrazolyl) acetic acid (crude)

Example 6

Ethyl 2- (5-methyl-3-pyrazolyl) acetate

95 g of 2- (5-methyl-3-pyrazolyl) acetic acid and 660 g of ethanol were treated with 74 ml of thionyl chloride in a 2 L flask, stirred at room temperature for about 72 hours and then left for an additional 48 hours. The reaction solution was concentrated in vacuo. The residue obtained was taken up in a solvent mixture consisting of ethyl acetate / methanol 2: 1 and heated under reflux conditions. The product was in solution by-product and not sodium chloride. The filtered mother liquor was concentrated in vacuo to give the product in crystalline form.

Yield: 141 g of ethyl 2- (5-methyl-3-pyrazolyl) acetate (crude)

Example 7

2- (5-methyl-3-pyrazolyl) ethanol

100 g of ethyl 2- (5-methyl-3-pyrazolyl) acetate (crude product) was suspended in 2 L of ethanol. While stirring the suspension, 146.6 g of NaBH _{4 was} added in small portions. The reaction mixture was stirred at rt for about 192 h. About 150 ml of water and about 65 ml of glacial acetic acid were added and ethanol was distilled off. The resulting doughy residue was taken up in ethyl acetate and extracted several times with water. The organic phase was dried, filtered and concentrated in vacuo. The aqueous phase was neutralized to separate the further product and extracted with ethyl acetate.

Yield: 49 g of 2- (5-methyl-3-pyrazolyl) ethanol (˜75% of theory)

Example 8

2- (5-methyl-3-pyrazolyl) ethyl chloride

49 g of 2- (5-methyl-3-pyrazolyl) ethanol were suspended in 78 ml of toluene and heated to reflux. 59.5 g of phosphorus oxychloride was slowly added to the suspension for 2 hours to cause an exothermic reaction. After the addition was complete, the mixture was heated at reflux for a further 2 hours. The reaction solution was then left at room temperature for about 12 hours. The pH of the solution was then adjusted to 9 using sodium carbonate and extracted three more times with ethyl acetate. The combined ethyl acetate phases were dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solvent was distilled off in vacuo to dryness. As a residue, an oil was obtained that did not fully crystallize. This crude product was purified by chromatography (silica gel 60; ethyl acetate / petroleum ether 9: 1).

Yield: 39.4 g of 2- (5-methyl-3-pyrazolyl) ethyl chloride (˜70% of theory)

Example 9

7-ethyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole

2.28 g (0.01 mol) of 7-ethyl-3- (4-piperidyl) indole (Example 2) and 1.44 g (0.01 mol) of 2 (5-methyl 3-pyrazolyl) ethyl chloride (Example 8) From the beginning was placed in 125 ml of acetonitrile in a 250 ml round bottom flask and stirred for about 48 hours under reflux conditions. The precipitate formed at this time was separated. This precipitate is the unreacted starting material. The residue obtained by distilling off the solvent of the reaction solution thus obtained was separated by chromatography (silica gel 60, ethyl acetate / methanol 3: 2). After concentrating the product-containing fractions, the reaction product was precipitated as oxalate, separated off and dried.

Yield: 1.3 g of 7-ethyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole oxalate (29% of theory)

R _f : 0.28 (ethyl acetate: methanol 2: 1), amorphous

Example 10

5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methylcarbonyl) -4-piperidyl) indole

2.18 g (10 mmol) of 5-fluoro-3- (4-piperidyl) -indole, 3.10 g (16 mmol) and 1- of 1-ethyl-3- (3'-dimethyl-aminopropyl) carbodiimide hydrochloride 2.70 g (20 mmol) of hydroxybenzotriazole was dissolved in 100 ml of dichloromethane and the mixture was stirred for 1 hour. Then, 2.34 g (10 mmol) of 2- (3- (6-fluorophenyl) -5-methyl-4-pyrazolyl) acetic acid was added, and the reaction solution obtained was stirred for about 72 hours. The reaction mixture thus obtained was extracted with sodium hydroxide solution and then dried over magnesium sulfate. After filtration of this solution, the solvent was distilled off in vacuo. The crude product thus obtained was used directly in the next step without finishing the reaction.

Yield: 6.5 g of 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methylcarbonyl) -4-piperidyl) indole Crude product)

Example 11

5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole

5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methylcarbonyl) -4-piperidyl) indole 6.5 g (10 mmol) Was dissolved in 100 ml of tetrahydrofuran and treated with 5 ml (25 mmol) of sodium bis (2-methoxyethoxy) aluminum hydride (Vitride ^(R) ). The reaction mixture thus obtained was stirred at room temperature for 2 hours. After completion of the reaction, excess sodium bis (2-methoxyethoxy) aluminum hydride was added to break down to form a colorless gelatinous mass and filtered through diatomaceous earth. The solvent was distilled off in vacuo from the reaction solution thus obtained to obtain 7.7 g of crude product, which was purified by chromatography (Escagel 60; ethyl acetate / petroleum ether 9: 1).

Yield: 1.7 g of 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole ~ 40%)

4-Fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole was similarly prepared.

Example 12

5-fluoro-1-methyl-3- (tert-butoxycarbonyl-4-piperidyl) indole

0.9 g (30 mmol) of sodium hydride (80%) was suspended in 300 ml of tetrahydrofuran. Then, a solution containing 9.55 g of 5-fluoro-3- (l-tert-butoxy-carbonyl-4-piperidyl) indole and tetrahydrofuran was cooled and slowly added dropwise, for about 1 hour. It was further stirred. Then 1.9 ml (30 mmol) methyl iodide was added dropwise and the mixture was further stirred for about 2 hours. The solution was concentrated in vacuo to dissolve the residue in ethyl acetate, extracted with water and dried over magnesium sulfate. After filtration, the residue was concentrated again in vacuo. The crude product thus obtained was purified by chromatography (silica gel 60; petroleum ether / ethyl acetate).

Yield: 6.7 g of 5-fluoro-1-methyl-3- (1 -tert-butoxy-carbonyl-4-piperidyl) indole (˜67% of theory); oil

Example 13

5-fluoro-1-methyl-3- (4-piperidyl) indole

6.7 g (20 mmol) of 5-fluoro-1-methyl-3- (1 -tert-butoxycarbonyl-4-piperidyl) indole was added to 150 ml of hydrochloric acid / ether mixture (gas generated significantly) for 1 hour. Stirred. This solution was then concentrated in vacuo.

Yield: 5.0 g of 5-fluoro-1-methyl-3- (4-piperidyl) indole (˜93% of theory)

Similar to Example 9 or 11, the following compounds were prepared:

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) -indole-5-carbonitrile

M.p. 112-114 ℃

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) -indole-5-carboxamide

M.p. 130-131.5 ℃

4-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.31, ethyl ether: methanol 2: 1

5-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.38, ethyl ether: methanol 2: 1

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.40, ethyl ether: methanol 2: 1

4-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.52, ethyl ether Methanol 2: 1

5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.53, ethyl ether Methanol 2: 1

5-fluoro-1-methyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, m.p. 223 ℃

6-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.62, ethyl ether: methanol 2: 1

6-methoxy-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.44, ethyl ether: methanol 2: 1

7-methoxy-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, R _f 0.30, ethyl ether: methanol 2: 1

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -1,2,3,6-tetrahydro-4-pyridyl) indole-5-carbonitrile

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -1,2,3,6-tetrahydro-4-pyridyl) indole-5-carboxamide

The following examples relate to pharmaceutical formulations.

Example A: Vials for Injection

A solution of 100 g of the active compound of formula (I) and 5 g of sodium diphosphate dissolved in 3 l of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterilized by filtration, filled into an injection vial, lyophilized under sterile conditions, and sealed. It was. Injectable vials containing 5 mg of the active compound were obtained.

Example B: Suppositories

A mixture of 20 g of the active compound of formula I and 100 g of soya lecithin and 1400 g of cocoa butter was poured into the mold and cooled. Suppositories containing 20 mg of the active compound were obtained.

Example C: Liquid

A solution was prepared by dissolving 1 g of the active compound of Formula I, 9.38 g of NaH ₂ PO ₄ · 2H ₂ O, 28.48 g of Na ₂ HPO ₄ · 12H ₂ O, and 0.1 g of benzalkonium chloride in 940 mL of secondary distilled water. The solution was adjusted to pH 6.8, adjusted to 1 L, and sterilized by radiation to prepare a solution.

Example D: Ointment

An ointment was prepared by mixing 500 mg of the active compound of formula I with 99.5 g of petrolatum under aseptic conditions.

Example E: Tablets

A mixture of 1 kg of active compound 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 was compressed in a conventional manner to prepare a tablet in which each tablet contains 10 mg of the active compound.

Example F: Tablets

Similar to Example E, tablets were compressed and then coated in a conventional manner using a coating consisting of sucrose, potato starch, talc, tragacanth and a colorant to prepare a tablet.

Example G: Capsule

2 kg of active compound of formula (I) were filled in hard gelatin capsules in a conventional manner such that each capsule contained 20 mg of active compound.

Example H: Ampoules

A solution of 1 kg of the active compound of formula (I) in 60 liters of secondary distilled water was sterilized by filtration and filled in an ampoule, lyophilized under sterile conditions, and aseptically sealed. An ampoule containing 10 mg of the active compound was obtained.

Claims (10)

1-pyrazol-3-ylethyl-4-indol-3-ylpiperidine derivatives of formula (I) and salts thereof. Formula I (Wherein, R ¹ is H or A, R ² is H or phenyl mono- to tri-substituted with Hal, NO ₂ , CON (R ⁴ ) ₂ , SO ₂ N (R ⁴ ) ₂ , cyano, A or R ⁴ -O, R ³ is H, Hal, A, AO-, amino, cyano, carboxamide, NO ₂ , SO ₂ N (R ⁴ ) ₂ , R ⁴ is H or A, R ⁵ is H or A, A is alkyl of 1 to 6 carbon atoms, or alkyl of 1 to 6 carbon atoms mono- to tri-substituted with fluorine, Hal is F, Cl, Br or I.) The compound of claim 1, wherein the compound is selected from the following group. 3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) -indole-5-carbonitrile, 3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) -indole-5-carboxamide, 4-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 5-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 4-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole, 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole, 5-fluoro-1-methyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 6-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 6-methoxy-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 7-methoxy-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 7-ethyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, 3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -1,2,3,6-tetrahydro-4-pyridyl) indole-5-carbonitrile, 3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -1,2,3,6-tetrahydro-4-pyridyl) indole-5-carboxamide. A drug of formula I according to claim 1 and a physiologically acceptable salt thereof. 4. A drug according to claim 3, which exhibits serotonin-agonistic and antagonistic action. The drug of claim 3, which exhibits dopamine-stimulating action. A compound of formula II: Formula II (Wherein, R ¹ , R ² and R ⁵ are as described above, Z is Hal, O-SO ₂ CH ₃ , O-SO ₂ CF ₃ , OSO ₂ -C ₆ H ₄ , or O-SO ₂ -C ₆ H ₅ ) A compound of formula III: Formula III (Wherein R ³ and R ⁴ are the same as described above). Or react with Compounds of Formula IIa Formula IIa (Wherein R ¹ and R ² are as defined above). Is converted to the active form, followed by reaction with a compound of formula III under known conditions to form peptide bonds, and from the resulting compound to form the desired compound of formula I via reduction reaction, or And / or react with a strong base to liberate the compound of formula (I) as a free base, or And / or 1-pyrazol-3-ylethyl-4-indol-3-ylpiperi of formula I according to claim 1, characterized in that the base of formula I is converted to the relevant acid addition salt using an acid. Process for the preparation of dine compounds and salts thereof. A compound of formula (I) according to claim 1 and / or a physiologically acceptable salt thereof is suitable in combination with one or more solid, liquid or semi-liquid excipients or auxiliaries, and if necessary in combination with one or more other active compounds Process for the preparation of a pharmaceutical formulation, characterized in that the dosage form. A pharmaceutical preparation characterized by containing at least one of the compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof. A compound of formula I according to claim 1, or a physiologically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disease. 10. A compound of formula (I) or a physiologically acceptable salt thereof according to claim 9 for use in the treatment of diseases caused by diseases of the central nervous system and diseases.