SK99298A3 - 1-(pyrazol-3-yl-ethyl)-4-(indol-3-yl)-piperidine used as medicine acting on the central nervous system - Google Patents

Abstract

The invention concerns new 1-pyrazol-3-yl-ethyl-4-indol-3-piperidine derivatives of formula (I) where R<1> is H or A; R<2> is H, a phenyl substituted 1 to 3 times by Hal, NO2, CON(R<4>)2, SO2N(R<4>)2, cyanogen, A or R<4>-O; R<3> is H, Hal, A, A-O-, amino, cyanogen, carboxamide, NO2, SO2N(R<4>)2; R<4> is H or A; A is (C1-C6)alkyl or (C1-C6)alkyl containing one to three times substituted by fluorine; Hal is F, Cl, Br or J. The invention also concerns the salts of said derivatives. It has been shown that these compounds have an interesting pharmaceutical activity.

Description

Technical field

The present invention relates to 1- (pyrazol-3-ylethyl) indol-3-yl) piperidine derivatives and their physiologically acceptable salts, which have good pharmacological properties with good tolerability and in particular act on the central nervous system and exhibit serotonin agonist and serotonin antagonistic action and dopamine stimulating The invention further relates to processes for their preparation and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

Numerous compounds are known to act on the central nervous system and medicaments for the treatment of diseases caused by malfunction and disorders of the central nervous system, but these compounds have undesirable side effects and a relatively non-specific spectrum of action. It is therefore an object of the present invention to provide novel compounds with valuable properties, particularly suitable for the manufacture of medicaments selectively acting on the central nervous system with low side effects and low addiction potential. It is also an object of the present invention to provide a process for the preparation of such compounds in as high a yield and high purity as possible. The invention solves these objects.

SUMMARY OF THE INVENTION

The present invention provides a 1- (pyrazol-3-ylethyl) -4 (indol-3-yl) piperidine derivative of the Formula I (I) wherein * R is hydrogen or A,

R ² is H, phenyl substituted by one to three groups from the group consisting of halogen, nitro, a group of the formula CON (R ⁴⁾ 2, SO 2 N (R ⁴⁾ 2, CN, A or R ⁴ -0-,

R ³ is hydrogen, halogen, A-Ο-, amino, cyano, carboxamide, nitro, general SO 2 N (R ⁴ ) 2,

R ⁴ is H or A,

R ( ⁵⁾ is hydrogen or A,

A (C1-C6) alkyl or (C1-C6) alkyl substituted by one to three fluorine atoms,

Hal is a fluorine, chlorine, bromine or iodine atom, and physiologically acceptable salts thereof, which have a pharmaceutically advantageous effect.

Surprisingly, it has been found that the derivatives of l- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine of formula I, wherein R ¹ to R ^5, A and Hal are as defined above, and physiologically acceptable acid addition acid salts have a wide range of valuable pharmacological properties. In particular, they act on the central nervous system and, in particular, show domapine stimulatory (anti-Parkinson's) and serotonin agonist and serotonin antagonist actions. The compounds of formula I induce a contralateral effect in hemiparkinsonian rats (as determined by the method of Ungerstedt et al., Brain Res.

24, p. 485-493 (1970). They inhibit the binding of tritiated dopamine agonists and antagonists to strier receptors (as determined by the method described by Schwarcz et al., J. Neurochemistry 34, 772-778, 1980 and Creesa et al. European J. Pharmacol. 46, 377-381). , 1977) and the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol. 140, 143-155, 1987). In addition, there is a change in DOPA accumulation in the striatum a

5-HTP accumulation in N.raphe (Seyfried et al. European J. Pharmacol. 160: 31-41 (1989)). In addition, they inhibit the reflex of the language of narcotized rats (detectable by the method of Barnett et al., European J. Pharmacol. 21, pp. 178-182 1973 and Ilhan et al., European J. Pharmacol. 33, pp. 61-64, 1975). In addition, they exhibit analgesic and blood pressure reducing effects; thus, in the case of catheters having awake, spontaneously hypertonic rats (SHR / Okamoto / NIH-MOCHB-Kisslegg strain; the method described by Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104, 646-648, 1960) decreases directly measured blood pressure after oral administration of a compound of formula I of the invention.

A process for the preparation of a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I wherein the individual symbols are as defined above is to react a compound of the formula II

wherein R ¹ , R ² and R ⁵ are as defined above and where is

Z is halogen, -O-SO ₂ CH ₃ , -O-SO ₂ CF ₃ , -OSO ₂ C ₈ H ₄ or -O-SO 4 -C 8 H 4, with a compound of formula III

(III) wherein R ³ and R ⁴ are as defined above, or the compound of formula IIa is converted

(IIa) wherein R ¹ and R ² are as defined above, to the activated form which is subsequently reacted with a compound of formula III under peptide bonding conditions and the compound thus obtained is reduced to give a compound of formula I, and / or the compound of formula I is reacted with a strong base to give the compound of formula I as the free base, and / or the base of the compound of formula I is reacted with an acid to provide an acid addition salt.

The compounds of formula I may have a chiral center. Therefore, they may be in different enantiomeric forms. The invention includes all such forms (e.g., D and L forms) as well as mixtures thereof (e.g., DL-forms).

In the general formulas, the individual symbols R ¹ to R ⁵ , A and Hal have the meanings given above, unless expressly stated otherwise. When a group in a molecule contains several substituents, the substituents may be the same or different.

The symbol A represents an alkyl group having 1 to 6, preferably 1, 2, 3 or 4 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, a pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl or 1-, 2-, 3 or 4-methylpentyl group. Further, A represents a straight-chain or branched alkylene group having 1 to 6 carbon atoms, in particular 1 to 4 carbon atoms, preferably a methylene group, an ethylene group, but also, for example, an ethylidene group, a trimethylene group of the formula -CH (CH ₃ ) CH _2- , -CH ₂ CH (CH ₃ ) -, -C (CH ₃ ) ₂ , a propylidene, tetramethylene group, a group of the formula -CH (CH ₃ ) - (CH ₂ ) ₂ -, -CH ₂ -CH (CH ₃₎ ) - (CH ₂ ) ₂ -, - (CH ₂ ) ₂ -CH (CH ₃ ) -, -C (CH ₃ ) ₂ -CH ₂ -, - (CH ₂ ) 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 ] -. A also represents an alkyl group having 1 to 6 carbon atoms substituted by one to three fluorine atoms.

Accordingly, R &lt; ⁴ &gt; is -O- in the case where R &^lt; ⁴ &gt; is A, especially a straight-chain alkylene group having 1 to 6, in particular 1 to 4 carbon atoms, bonded via an oxygen atom. Preferably, AO is methoxy, ethoxy, 1- or 2-propoxy, 1-butoxy, isobutoxy, sec-butoxy or tert-butoy.

The phenyl group is preferably an unsubstituted phenyl group. The substituted phenyl group preferably has one substituent. However, the phenyl group may also have two or three substituents, the substituents being the same or different.

Preferred substituents are fluorine, chlorine, methoxy or hydroxy. Possible substituents are, however, also nitro, cyano, A or A-Ο-, where A and A-O- are as defined above.

Preferably, the phenyl group is o-, m-, or p-fluorophenyl, o-, m-, or p-chlorophenyl, o-, m-, or p-methoxyphenyl, o-, m-, or p -etoxyfenylová.

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.

Hal is a halogen atom, which may be a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

Preferably

R ( ¹⁾ is hydrogen or A;

R @ ² is hydrogen, phenyl substituted by one, two or three halogen atoms, A or R @ ⁴ --O--, wherein R @ ⁴ is preferably A, in particular one, two or three groups of formula CON (R @ ⁴ ) 2 or SO 2 N (R ⁴ ) 2;

R @ ³ is hydrogen, A, especially methyl or ethyl, or R @ ⁴ --O-- preferably methoxy or ethoxy, particularly preferably cyano, carboxamide or nitro, in particular also optionally substituted sulfonyl, the possible substituents of this sulfonyl group being a halogen atom, group A or group A substituted with one, two or three halogen atoms;

R ⁴ is a hydrogen atom or alternatively an A group, in particular a methyl or ethyl group;

R ^5, similarly to R ^4, is a hydrogen atom or alternatively an A group, in particular a methyl or ethyl group.

Preferred are 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivatives of formula (I), wherein at least one of the symbols has the preferred meanings indicated above. Preference is given to groups of compounds of formulas Ia to Id which correspond to formula I, wherein in formula Ia represents

R ¹ is H or methyl;

Ib means

R ¹

R ² a hydrogen atom or a methyl or a hydrogen atom eh phenyl by one to three alkyl group and a substituovahalogénu,

Ic means

R ¹

R ³ a methyl group, a hydrogen, fluorine, hydroxy, cyano, carboxamide, ethyl, methoxy or a trifluoromethylsulfonyloxy group,

Id means

R ¹

R ^{4 is} methyl, hydrogen or a

methyl, the other symbols being as defined above.

1- (Pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivatives of formula (I) and starting materials for their preparation are prepared by known methods described in the literature (e.g., standard publications such as Houben-Weyl) , Methoden der Organischen Chemie, Georg-Thieme Verlag, Stuttgart) under the reaction conditions known and suitable for the above reactions. It is also possible to use known variants which are not described here in greater detail.

The starting materials can optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but the reaction mixture is immediately used to prepare compounds of formula I.

The starting materials for the preparation of the compounds of the formula I can be prepared by liberating them from their functional derivatives by solvolysis, in particular by hydrolysis or hydrogenolysis. The compounds of the formula I are preferably obtained by the coupling reactions of the compounds of the formula II or IIa and of the compounds of the formula III known to the person skilled in the art, optionally after selective hydrogenation. Preferably, the compounds of formula (I) are prepared such that solvolysis is unnecessary to release the desired compounds of formula (I), and moreover, compounds of this structure often behave unstable under such conditions.

The starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the above formulas, but instead have free amino or hydroxyl groups corresponding to protected amino or hydroxy groups, preferably compounds which have a protecting group instead of a hydrogen atom which is bonded to a nitrogen atom. amino, in particular compounds having an R'-N group instead of the HN group, wherein R 'is an amino protecting group and / or compounds having a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, for example compounds having a -COOH group instead -COOR, wherein R is a hydroxyl protecting group.

Several of the same or different amino-protecting groups and / or hydroxyl groups may be present in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

The term amino protecting group is well known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions, but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typically, such groups are unsubstituted or substituted acyl, aryl (e.g.

2,4-dinitrophenyl - DNP), aralkoxymethyl (e.g. benzyloxymethyl - BOM) or aralkyl (e.g. benzyl, 4-nitrobenzyl, triphenylmethyl). Since the amino-protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical. However, groups having 1 to 20, and in particular 1 to 8, carbon atoms are preferred. As used herein, the term acyl is always understood in its broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as, in particular, alkoxycarbonyl, aryloxycarbonyl and, in particular, aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkoxycarbonyl such as the benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC) groups. Preferred amino protecting groups are BOC, DNP and BOM, further CBZ, benzyl and acetyl.

The term hydroxy protecting group is also generally known and refers to groups which are suitable for protecting (blocking) the hydroxy group from chemical reactions but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typical of such groups are the above-mentioned unsubstituted or substituted aryl, aralkyl or acyl groups as well as alkyl groups. Since the hydroxyl protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical. However, groups having 1 to 20 and in particular 1 to 10 carbon atoms are preferred. Examples of hydroxyl protecting groups are tert-butyl, benzyl, p-nitrobenzyl, p-toluenesulfonyl and acetyl, with benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of formula I used as starting materials can be prepared by known methods, for example those described in standard chemical literature, including patent literature, for example by reacting compounds of formulas II and III, at least one of which has a protecting group instead of a hydrogen atom.

Depending on the protecting group used, the liberation of the compounds of formula II, IIa or III as well as the compounds of formula I from their functional derivatives is successful, for example with strong acids such as trifluoroacetic acid and perchloric acid but also with other strong inorganic acids such as hydrochloric acid. or sulfuric, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzenesulfonic acid or p-toluenesulfonic acid. It is possible, but not always necessary, to carry out the reaction in the presence of additional solvents.

Suitable inert solvents are, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be contemplated. Trifluoroacetic acid is preferably used in excess without addition of other solvents, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperature for the deprotection is expediently about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

For example, the BOC group may be preferably cleaved with 40% trifluoroacetic acid in dichloromethane or about 3-5% hydrochloric acid in dioxane at 15-30 ° C, while the FMOC group may be cleaved with a solution of dimethylamine, diethylamine or piperidine in dimethylformamide at about 5-20%. 15 to 50 ° C. Cleavage of the DNP group is also successful, for example, using an approximately 3-10% solution of 2-mercaptoethanol in dimethylformamide / water at a temperature of 15-30 ° C.

Hydrogenolytically removable protecting groups (e.g. BOM, CBZ or benzyl groups) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group, for example, performs well on 5-10% palladium on carbon in methanol at 20-30 ° C.

The compounds of formula I are preferably prepared by reacting a pyrazole derivative of formula II with a compound of formula III. Preferably, known methods of N-alkylation of amines are used.

The liberated Z moiety of formula (II) is preferably a chlorine, bromine, iodine, C1-C6 alkylsulfonyloxy, such as methanesulfonyloxy or ethanesulfonyloxy, fluoroalkylsulfonyloxy group having 1 to 6 carbon atoms, such as trifluoromethoxy, or trifluoromethoxy, such as trifluoromethoxy, such as benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or

2-naphthalenesulfonyloxy.

The reaction is carried out in an inert solvent such as halogenated hydrocarbons such as dichloromethane, trichloromethane or carbon tetrachloride, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide or dimethylacetamide, nitriles such as acetonitrile. Dimethylsulfoxide, toluene or benzol are also suitable as solvents. Mixtures of these solvents may also be used. This reaction is carried out at a temperature of about -10 to 200 ° C, preferably 0 to 120 ° C. The reaction is preferably carried out in the presence of an additional base such as alkali or alkaline earth metal hydroxides or carbonates such as sodium, potassium or calcium hydroxide or sodium, potassium or calcium carbonate. If the group released is a group other than an iodine atom, the addition of an iodide such as potassium iodide is recommended.

The starting materials of formula II are obtainable by methods known from the literature.

Starting materials of formula III are obtainable by methods known to those skilled in the art, as described, for example, in the indole chemistry manuals. Preferred piperidine nitrogen protecting groups are benzyl and BOC. More preferably, these protecting groups are introduced on a substituent referred to as R ⁴ , which is not equal to a hydrogen atom, on an indole nitrogen. This reaction is preferably carried out in the presence of a strong base and in particular the principle from the group consisting of lithium, sodium, potassium, Group KOC _{(CH3) 3,} and n-, sec-butyl lithium t. Subsequently, the amino protecting group is cleaved by one of the methods described above.

The starting materials of formula IIa are obtainable by methods known from the literature, in particular by analogous methods to those described in Example 5.

The coupling reaction of compounds of formula IIa with compounds of formula III can be carried out under conditions known to form peptide bonds. Corresponding methods are described, for example, in Aminosäuren, Peptide, Proteine, Jakubke Hans-Dieter; Jeschkeit Hans; Verlag Chemie, Weinheim 1982; but also in Wunsch E. 1974 Synthese von Peptiden in Houben-Weyl, Methoden der organischen Chemie, Volume 15, 1/2 (published by Muller E.) Georg Thieme Verlag, Stuttgart. Such methods include, for example, the azide process, the mixed anhydride process with carbonic acid polyesters chlorides as anhydride-forming compounds, various methods using activated esters and the carbodiimide process, as well as variations thereof, the DCC additive process. From these carbonyl compounds obtained by the coupling reactions, the desired compounds of formula I can be liberated by reduction under suitable conditions.

Such a reaction is particularly successful in the presence of a complex hydride catalyst. This reaction is preferably carried out in a solvent selected from the group consisting of ethers. Tetrahydrofuran is particularly preferred as the solvent. In general, the reaction is carried out under mild conditions at a temperature of -78 to 66 ° C, preferably at room temperature. In particular, this reduction can also be carried out with sodium 2-bis- (2-methoxyethoxy) aluminum hydride (such as Vitride ^R ). For this purpose, the reducing agent is used in excess. Ether is preferably used as the solvent in this case.

The base of formula (I) may be converted by acid into the appropriate acid addition salt, for example by reacting equivalent amounts of base and acid in an inert solvent such as ethanol and concentrating the reaction solution by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and ogranic acids may be used, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polycarboxylic, sulfonic acids or sulfuric acids such as formic, acetic, trifluoroacetic, propionic, pivalic, diethyl, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, ethanesulfonic, ethanesulfonic, ethanesulfonic, , 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid and naphthalenedisulfonic acid, and lauryl sulfuric acid. Salts with acids that are not physiologically harmless, for example picrates, can be used to isolate and / or purify the compounds of formula I.

The free bases of the formula I can optionally be liberated from their salts by treatment with a strong base, for example sodium or potassium hydroxide or carbonate.

As mentioned above, the compounds of formula I may contain one or more chiral centers and may therefore be in racemic or optically active form. Formula I includes all these forms as well as mixtures thereof. The racemates obtained can be separated into enantiomerically pure compounds by known methods, mechanically or chemically. Preferably, diastereomers are formed from racemic mixtures by reaction with an optically active resolving agent. Examples of such resolving agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic or lactic acid or various camphorsulfonic acids such as beta-camphorsulfonic acid.

Separation of the enantiomers by means of columns filled with optically active resolving agents (e.g. dinitrobenzoylphenylglycine) is also preferred. Hexane / isopropanol / acetonitrile is suitable for this purpose.

Naturally, it is also possible to obtain optically active compounds of the formula I by the above-mentioned methods using starting materials (e.g. compounds of the formula II) optically active.

The compounds of the formula I and their physiologically acceptable salts can be used as medicaments for anxiolytics, antidepressants, neuroleptics, anti-Parkinson's and / or antihypertensive agents. They are suitable for the treatment and prophylaxis of anxiety, panic attacks, schizophrenia, crazy urge, Alzheimer's disease, migraine, anorexia, bulimia, sleep disorders and drug abuse, or to combat the effects of cerebral infarction, but also to treat extrapyramidal motor neuroleptics. They can also be used as intermediates for the manufacture of other drug active substances.

The compounds of the formula I and their physiologically acceptable salts can therefore be used for the production of pharmaceutical compositions, in particular by non-chemical means. For this purpose, they can be converted into a suitable dosage form with at least one carrier or excipient and optionally in admixture with one or more other active substances. The compositions thus obtained can be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral or rectal) or parenteral administration and which do not react with compounds of the formula I, such as water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other glycerides fatty acids, gelatin, soybean lecithin, carbohydrates such as lactose or starches, magnesium stearate, talc or cellulose.

Tablets, dragees, capsules, syrups, juices or drops are particularly suitable for oral use. Particularly preferred are coated tablets and capsules with gastric acid resistant coatings or shells. Suppositories are suitable for rectal use, solutions for parenteral use, in particular oily or aqueous solutions, as well as suspensions, emulsions or implants.

The compounds of the invention may also be lyophilized and the lyophilizates obtained, for example, used for the preparation of injectables.

The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or flavoring agents. Alternatively, they may contain at least one other active ingredient, such as vitamins, diuretics and anti-inflammatory drugs.

The compounds of the formula I according to the invention are generally administered in doses similar to known commercial means for the above indications, preferably in an amount of 1 to 50 mg, in particular in an amount of 5 to 30 mg per dosage unit. The daily dose is preferably about 0.02 to 20 mg / kg body weight, in particular 0.2 to 0.4 mg / kg body weight.

The dose for each individual patient depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination, and severity of the disease. . Oral administration is preferred.

The invention is illustrated, but not limited, by the following examples. Percentages are by weight unless otherwise indicated. Temperatures are given in degrees Celsius.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

144 g (2.57 mol) of potassium hydroxide are dissolved in 1.6 l of methanol in a 2000 ml round-bottomed flask. 120 g (about 0.86 mol) of 7-ethylindole and 161.4 g (about 0.86 mol) of 1-benzylpiperidin-4-one are added to the solution. The reaction mixture was stirred for five hours under reflux conditions. Again, 34.1 g (about 0.172 mol) of 1-benzylpiperidin-4-one is added and stirred overnight under reflux conditions. The reaction solution obtained is concentrated in vacuo to give the product in crystalline form. The crude product was recrystallized from methanol.

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

Rf 0.35 (ethyl acetate / petroleum ether, 1: 1)

Example 2

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

The 7-ethyl-3- (1-benzyl-1,2,3,6-tetrahydro-4-pyridyl) indole obtained in Example 1 is dissolved in a solvent mixture consisting of 2 l of methanol and 0.5 l of glacial acetic acid in in the presence of palladium on carbon and hydrogenated. The catalyst was filtered off and the solvent was distilled off in vacuo. The residue is recrystallized from toluene and dissolved in 1 liter of water. The pH of the solution was made alkaline by the addition of sodium hydroxide (32%). The crystals formed are filtered off and dried.

Yield: 153.6 g of 7-ethyl-3- (4-piperidyl) indole (approximately 95% of theory). Melting point 189 ° C.

Example 3

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

In a three-necked flask containing 2000 ml, 495 ml of sulfuric acid (90%) was heated to 130 ° C. 300 g are added with stirring

3-acetyl-3,4-dihydro-6-methylpyran-2,4-dione (dehydrate acid) in small portions. It is stirred for some time. After completion of the reaction, the reaction mixture is poured onto approximately 1500 g of ice. The crystals formed are separated.

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

Example 4

2- (5-Methyl-3-pyrazolyl) acetic acid hydrazide

191.6 g of 3,4-dihydro-6-methylpyran-2,4-dione are dissolved in 800 ml of methanol. While stirring, 190 g of NH 4 NH 4 · H 2 O are added dropwise to the solution obtained, increasing the temperature to 70 ° C. The product formed in the reaction is filtered off and further processed as a crude product.

Yield: 193 g of 2- (5-methyl-3-pyrazolyl) acetic acid hydrazide (approximately 82% of theory). Mp 153-154 ° C.

Example 5

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

Stir 105 g of 2- (5-methyl-3-pyrazolyl) acetic acid hydrazide and 720 ml of 2N sodium hydroxide solution for four hours under reflux conditions. The reaction solution thus obtained is neutralized with hydrochloric acid. The reaction solution was concentrated in vacuo. The crystals obtained are collected and further used as a crude product.

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

Example 6

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

95 g of 2- (5-methyl-3-pyrazolyl) acetic acid and 660 g of ethanol in a 2000 ml flask are mixed with 74 ml of thionyl chloride, stirred for about 72 hours at room temperature and then left to stand for 48 hours. The reaction mixture was concentrated in vacuo. The residue is taken up in a solvent mixture consisting of ethyl acetate and methanol in a ratio of 2: 1, heated under reflux conditions to dissolve the product, but not the by-product and sodium chloride. The mother liquor obtained by filtration is concentrated in vacuo to give the product in crystalline form.

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

Example 7

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

100 g of ethyl 2- (5-methyl-3-pyrazolyl) acetate (crude product) is suspended in 2 liters of ethanol. With stirring, 146.6 g of sodium borohydride are added in portions to the suspension. The reaction mixture was stirred at room temperature for about 192 hours. Approximately 150 ml of water and 65 ml of glacial acetic acid are added and the ethanol is distilled off. The resulting slurry was taken up in ethyl acetate and extracted several times with water. The organic phase is dried, filtered and concentrated in vacuo. Further product is obtained from the aqueous phase by neutralization and extraction with ethyl acetate. Yield: 49 g of 2- (5-methyl-3-pyrazolyl) ethanol (approximately 75% of theory)

Example 8

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

49 g of 2- (5-methyl-3-pyrazolyl) ethanol are suspended in 78 ml of toluene and heated to reflux. 59.5 g of phosphorus oxychloride are slowly added to the suspension over two hours, during which a strongly exothermic reaction occurs. After the addition was complete, the mixture was refluxed for a further two hours. The reaction solution is allowed to stand at room temperature for at least 12 hours. The pH of the solution was adjusted to 9 with sodium carbonate and the reaction mixture was extracted at least three times with ethyl acetate. The combined ethyl acetate phases are dried over magnesium sulfate, filtered and the solvent is distilled off in vacuo. The oil obtained cannot crystallize fully. The crude product was purified by chromatography (silica gel, ethyl acetate / petroleum ether, 9: 1).

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

Example 9

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

In a 250 ml round-bottomed flask was charged 2.28 g (0.01 mol) of 7-ethyl-3- (4-piperidyl) indole (according to Example 2) and

1.44 g (0.01 mol) of 2- (5-methyl-3-pyrazolyl) ethyl chloride (according to Example 8) in 125 ml of acetonitrile and stirred under reflux conditions for about 48 hours. During this time, the precipitate formed is separated. It is an unreacted educt. The solvent from the obtained reaction solution was distilled off and the residue was chromatographed (silica gel, ethyl acetate / methanol, 3: 2). After concentration of the product-containing fraction, the reaction product precipitated as the oxalate, separated and dried. The yield is 1.3 g of 7-ethyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -

4-piperidylindole (29% of theory)

Rf: 0.28 (ethyl acetate / methanol, 2: 1) amorphous.

Example 10

5-Fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methyl) carbonyl) -4-piperidyl) indole

2.18 g (10 mmol) of 5-fluoro-3- (4-piperidyl) indole, 3.10 g (16 mmol) of 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide hydrochloride and 2.70 g (10 mmol) are collected. 20 mmol) of 1-hydroxybenzotriazole into 100 ml of dichloromethane and stirred for one hour. 2.34 g (10 mmol) of 2- (3- (6-fluorophenyl) -5-methyl-4-pyrazolyl) acetic acid are added and the reaction solution thus obtained is stirred for approximately 72 hours. The reaction mixture was extracted with sodium hydroxide solution and dried over magnesium sulfate. The solution is filtered and the solvent is distilled off in vacuo. The crude product obtained is not processed but used directly in the next step. Yield: 6.5 g of 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methyl) carbonyl) -4-piperidyl) indole (crude product).

Example 11

5-Fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -

4-piperidyl) indole

6.5 g (10 mmol) of 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methyl) carbonyl) -4-piperidyl) indole are dissolved. in 100 ml of tetrahydrofuran and treated with 5 ml (25 mmol) of sodium bis (2-methoxyethoxy aluminum hydride) (Vitride ^R ) and stirred for two hours at room temperature. Methoxyethoxy aluminum hydride is agitated by the addition of water to give a colorless slime which is filtered through diatomaceous earth and the solvent is distilled off in vacuo.

7.7 g of crude product which was purified by chromatography (silica gel 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 (approximately 40% of theory).

Similarly, 4-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -4-piperidyl) indole was also prepared.

Example 12

5-Fluoro-1-methyl-3- (1-tert-butyloxycarbonyl-4-piperidyl) indole

0.9 g (30 mmol) of sodium hydride (80%) is suspended in 300 ml of tetrahydrofuran. While cooling, a solution of 9.5 g of 5-fluoro-3- (1-tert-butyloxycarbonyl-4-piperidyl) indole and tetrahydrofuran is slowly added dropwise and stirred for about one hour. Finally, 1.9 ml (30 mmol) of methyl iodide are added dropwise and stirred for two hours. The solution is concentrated in vacuo, the residue is taken up in ethyl acetate, extracted with water and finally dried over magnesium sulphate. After filtration, it is concentrated in vacuo. The crude product obtained is purified by chromatography (silica gel 60, ethyl acetate / petroleum ether system).

Yield: 6.7 g of 5-fluoro-1-methyl-3- (1-tert-butyloxycarbonyl-

4-piperidyl) indole (about 67% of theory), oil.

Example 13

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

Stir 6.7 g (20 mmol) of 5-fluoro-1-methyl-3- (1-tert-butyloxycarbonyl-4-piperidyl) indole in 150 mL of hydrochloric acid / ether (vigorous gas evolution) for one hour. The solution was concentrated in vacuo.

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

Similar to Example 9 or 11, the following compounds are obtained:

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole-5-carbonitrile, m.p. 112-114 ° C;

3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole-5-carboxamide, m.p. 130-131.5 ° C;

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,

Rf 0.40 (ethyl ether: methanol, 2: 1),

4-Fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -

4-piperidyl) indole, Rf 0.52 (ethyl ether: methanol, 2: 1),

5-Fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) ethyl) -

4-piperidyl) indole, Rf 0.53 (ethyl ether: methanol, 2: 1),

5-fluoro-1-methyl-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, mp 223 ° C,

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

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

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

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

Rf 0.28 (ethyl acetate / 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 illustrate the pharmaceutical compositions of the present invention in more detail.

Example A

Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 n hydrochloric acid, sterile filtered, filled into injection ampoules, lyophilized under sterile conditions and sealed . Each ampoule contains 5 mg of active ingredient.

Example B suppositories

A mixture of 20 g of an active compound of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to solidify. Each suppository contains 20 mg of active ingredient.

Example C

solution

A solution of 1 g of an active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D

ointment

500 mg of an active compound of the formula I are mixed with

99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

Mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose,

1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are compressed in known manner into tablets, each tablet containing 10 mg of the active compound of the formula I.

Example F

dragee

Similar to Example E, tablets are compressed and coated in a known manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G

The capsules

2 kg of active ingredient of the formula I are filled into hard gelatine capsules, each capsule containing 20 mg of the active ingredient of the formula I.

Example H

ampoules

A solution of 1 kg of active compound of the formula I in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed. Each ampoule contains 10 mg of active ingredient.

Industrial usability

The 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative and its physiologically acceptable salts are useful for serotonin agonist and antagonist activity and for dopamine stimulant activity in the manufacture of pharmaceutical compositions for the treatment of diseases caused by malfunction and central nervous system disorders.

Claims (11)

PATENT CLAIMS A 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the general formula I wherein: R ^{@ 1} is hydrogen or A, R ² is H, phenyl substituted by one to three groups from the group consisting of halogen, nitro, a group of the formula CON (R ⁴⁾ 2, SO 2 N (R ⁴⁾ 2, CN, A or R ⁴ -0-, R ³ is hydrogen, halogen, A-Ο-, amino, cyano, carboxamide, nitro, general SO 2 N (R ⁴ ) 2, R ⁴ is H or A, R ( ⁵⁾ is hydrogen or A, A (C1-C6) alkyl or (C1-C6) alkyl substituted by one to three fluorine atoms, Hal is fluorine, chlorine, bromine or iodine, and salts thereof. 1- (Pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative according to claim 1, which is: 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 process for the preparation of a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I, wherein the individual symbols are as defined in claim 1 and the physiologically acceptable salts according to claim 1, characterized in that reacting a compound of formula (II) wherein R ¹ , R ² and R ⁵ are as defined above and where is Z is halogen, -O-SO ₂ CH ₃ , -O-SO ₂ CF ₃ , -OSO ₂ C ₆ H ₄ or -O-SO ₂ -C ₈ H ₅ , with a compound of formula III (III) wherein R ³ and R ⁴ is as defined above, a compound of formula IIa or is transformed (Ha) wherein R ¹ and R ² are as defined above, which are subsequently reacted with an activated form, a compound of formula III under peptide bonding conditions and thus obtained the compound is reduced to give a compound of formula I, and / or the compound of formula I is reacted with a strong base to give a compound of formula I as the free base, and / or the base of the compound of formula I is reacted with an acid to give an addition salt with acid. Medicament, characterized in that it contains, as active ingredient, a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1. Medicament according to claim 4 with a serotonin agonist and antagonist action, characterized in that it contains as active substance a 1- (pyrazol-3-ylethyl) -4 (indol-3-yl) piperidine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1. Medicament according to claim 4, characterized in that it contains, as active ingredient, a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I or a physiologically acceptable salt thereof according to the invention. of claim 1. A pharmaceutical composition comprising as active ingredient a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I and / or a physiologically acceptable salt thereof according to claim 1. A process for the manufacture of a pharmaceutical composition according to claim 7. The method of claim 7, wherein the 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1 is formulated in a suitable dosage form with at least one solid. a liquid or semi-liquid carrier or excipient and optionally together with at least one other active ingredient. Use of a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) -piperidine derivative of the formula I and / or a physiologically acceptable salt thereof according to claim 1 for the manufacture of a medicament for the treatment of diseases. Use of a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I and / or a physiologically acceptable salt thereof according to claim 1 for the manufacture of a medicament for the treatment of diseases caused by malfunction and central disorders of the nervous system. Pharmaceutical composition, characterized in that it contains, as active ingredient, a 1- (pyrazol-3-ylethyl) -4- (indol-3-yl) piperidine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1.