WO1997027186A1

WO1997027186A1 - 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine used as medicine acting on the central nervous system

Info

Publication number: WO1997027186A1
Application number: PCT/EP1997/000187
Authority: WO
Inventors: Henning Böttcher; Joachim März; Gerd Bartoszyk; Hartmut Greiner; Jürgen Harting; Christoph Seyfried
Original assignee: MERCK Patent Gesellschaft mit beschränkter Haftung
Priority date: 1996-01-25
Filing date: 1997-01-17
Publication date: 1997-07-31
Also published as: AU715785B2; DE19602505A1; NO983439L; ZA97572B; HUP9900980A2; KR19990081970A; CN1209807A; SK99298A3; JP2000503972A; BR9707467A; AU1443297A; AR005549A1; NO983439D0; PL328228A1; EP0879234A1; CZ231898A3; CA2244136A1

Abstract

The invention concerns new 1-pyrazol-3-yl-ethyl-4-indol-3-piperidine derivatives of formula (I) where R1 is H or A; R2 is H, a phenyl substituted 1 to 3 times by Hal, NO¿2?, CON(R?4)¿2, SO2N(R4)2, cyanogen, A or R4-O; R3 is H, Hal, A, A-O-, amino, cyanogen, carboxamide, NO¿2?, SO2N(R?4)¿2; R4 is H or A; A is (C¿1?-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

l- (PYRAZOL-3-YL-ETHYL) -4- (INDOL-3-YL) -PIPERIDINE AS A MEDIUM INFLUENCING THE CENTRAL SYSTEM

The invention relates to new 1-pyrazol-3-yl-ethyl-4-indol-3-yl-piperidine derivatives of the formula I.

wherein

5 R ¹ H or A

R ² H, single to triple through Hal, N0 ₂ , CON (R ⁴ ) ₂ , S0 ₂ N (R ⁴ ) ₂ ,

Cyano, A or R ⁴ -0 substituted phenyl R ³ H, Hal, A, AO-, amino, cyan, carboxamide, N0 ₂ , S0 ₂ N (R ⁴ ) ₂ R ⁴ H or A, 0 R ⁵ H or A , A alkyl with 1-6 C atoms or a mono- to trisubstituted by fluorine-substituted alkyl with 1-6 C atoms Hal F, CI, Br or J

5 mean, and their salts, which have proven to be substances with pharmaceutically advantageous effects.

From the technical and patent literature a large number of Arzneimit¬ there shall be used to treat diseases that are approximations due to malfunction or STOE _Q of the central nervous system are caused, is known. The majority of these drugs, however, either have serious side effects or a relatively unspecific spectrum of activity.

₅ The invention was therefore based on the object of making available new compounds which, as medicaments, selectively act nerve system, but at the same time have few side effects and have no or only a very low dependency potential.

It was also an object of the invention to provide a process by which the corresponding compounds can be prepared in the highest possible yields and high purities.

These objects have been achieved by the present invention.

It has now been found that compounds of the formula I in which the radicals R ¹ - R ⁵ , A and Hal have the meanings indicated and their physiologically acceptable salts have a broad spectrum of valuable pharmacological properties. In particular, they show effects on the central nervous system, especially dopamine-stimulating (anti-Parkinson) and serotonin-agonistic and antagonistic effects. Specifically, the compounds of the formula I induce contralateral rotational behavior in Hemiparkinson rats (can be determined by the method of Ungerstedt et al., Brain Res. 24, (1970), 485-493). They inhibit the binding of tritiated dopamine agonists and antagonists to radial receptors (can be determined by the method of Schwarcz et al., J. Neurochemistry 34 (1980), 772-778 and Creese et al., European J. Pharmacol. 46 , (1977), 377-381) and the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol 140, (1987), 143-155). There are also changes in the DOPA accumulation in the striatum and the 5-HTP accumulation in the N. raphe (Seyfried et al., European J. Pharmacol. 160, (1989), 31-41). In addition, the compounds inhibit the tongue-jaw reflex in the anesthetized rat (ascertained based on the methods of Barnett et al., European J. Pharmacol. 21, 81973), 178-182, and of llhan et al., European J Pharmacol. 33, (1975), 61-64). There are also analgesic and hypotensive effects; Thus, in catheter-carrying, spontaneously hypertensive rats (strain SHR / Okamoto / NIH-MO-CHB-Kisslegg; method see Weeks and Jones, Proc. Soc. Exptl. Biol. Med. 104, (1960), 646-648) the di right measured blood pressure after oral administration of the compounds lowered.

The invention further relates to a process for the preparation of compounds of the given formula I and of their salts _r, characterized in that a compound of the formula II

wherein

R> 1, e R> 2. and "n ^ dr R-, 5 have the meanings given above and Z Hal, 0-S0 ₂ CH ₃ , 0-S0 ₂ CF ₃ , OSθ2-C ₆ H ₄ or O-SOrCeHs

means

with a compound of formula III

wherein

R ³ and R ^{4 have} the meanings given above,

implements, or that one

a compound of formula Ila n

wherein

R ¹ and R ^{2 have} the meanings given above, converted into an activated form, then reacted with a compound of the formula III under conditions known for the formation of peptide bonds and from the compound thus obtained forms the desired compound of the formula I by means of a reduction reaction,

and / or that compounds of the formula I are released as free bases by treatment with a strong base,

and / or that a base of the formula I is converted into the associated acid addition salt with an acid.

Compounds of formula I can have a chiral center.

Corresponding compounds of the formula I can occur in several enantiomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula 1.

Above and below, the radicals or parameters R ¹ to R ⁵ , A and Hal have the meanings given in the formulas I to III, unless expressly stated otherwise. If there are several groups of the same name in the molecule, they can assume different definitions independently of one another.

In the formulas above, group A has 1 to 6, preferably 1, 2, 3 or 4, carbon atoms. In particular, A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl. Group A furthermore represents a straight-chain or branched alkylene group having 1 to 6, in particular having 1 to 4, carbon atoms, preferably methylene or ethylene, but also, for. B. for ethylidene, trimethylene, -CH (CH ₃ ) CH ₂ -, -CH2CH (CH ₃ ) -, -C (CH ₃ ) ₂ -,

Propylidene, tetramethylene, -CH (CH ₃ HCH2) r, -CH ₂ -CH (CH ₃ ) -CH ₂ -, - (CH ₂ ) ₂ -CH (CH ₃ ) -, -C (CH ₃ ) rCH2-, -CH2-C (CH ₃ ) 2-, -CH (CH ₂ CH ₃ ) -CH _r , -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 ] -. However, this group can also be the corresponding mono- to trisubstituted by fluorine-substituted alkyl groups with 1 to 6 carbon atoms.

Accordingly, the group R ⁴ -0-, when R ^{4 is} A, in particular a straight-chain or branched alkylene group bonded via an oxygen atom and having 1 to 6, in particular 1 to 4, carbon atoms. AO is preferably methoxy, ethoxy, 1- or 2-propoxy, 1-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

A group denoted by phenyl is preferably an unsubstituted phenyl. A substituted phenyl group is preferably monosubstituted. However, such a phenyl group can also be substituted twice or three times, where the substituents can be identical or different. Preferred substituents are F, Cl, methoxy or OH. However, N0 ₂ , cyano, A or AO are also suitable as substituents, where A and AO- can have the meanings mentioned above.

In particular, a phenyl group is preferably o-, m-, p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, 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 corresponds to a halogen radical and can be fluorine, chlorine, bromine or iodine. It is particularly preferably fluorine or chlorine.

R ¹ is preferably a hydrogen or has the meanings of A.

R ² preferably represents hydrogen or one, two or three times by one Hal, A or R ⁴ -0-, where R ⁴ preferably has the meaning of A, but in particular also one, two or three phenyl substituted three times by C0N (R ⁴ ) ₂ or S0 ₂ N (R ⁴ ) ₂ .

R ³ is preferably a hydrogen, a radical with the meaning of A, in particular methyl or ethyl, or with the meaning of

R ⁴ -0, preferably methoxy or ethoxy. It particularly preferably has the meaning of a cyano, carboxamido or nitro group. In particular, it can also be an optionally substituted sulfonyl group. Possible substituents of this sulfonyl group are Hal, A, A substituted one to three times by Hal.

R ⁴ is preferably hydrogen, but may also have the meanings of A, in particular it is a methyl or ethyl radical.

Like R ^4, R ⁵ is preferably hydrogen, but may also have the meanings of A if appropriate, in particular it is a methyl or ethyl radical.

Among the compounds of the formula I, preference is given to those in which at least one of the radicals indicated has one of the preferred meanings indicated. Some groups of preferred compounds are those of the formulas Ia to Id, which correspond to the formula I, but in which in la R ^{1 represents} hydrogen or methyl;

in lb R ^{1 is} hydrogen or methyl and

R ^{2 is} hydrogen or a phenyl which is mono- to trisubstituted by Hal,

in Ic R ¹ methyl and

R ³ denotes hydrogen, fluorine, hydroxy, cyan, carboxamide, ethyl, methoxy or a trifluoromethylsulfonyloxy,

in Id R ¹ methyl and

R ^{4 represents} hydrogen or methyl.

The compounds of the formula I and also their starting compounds are prepared by methods known per se to the person skilled in the art, as are also described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag Stuttgart ), produced, under reaction conditions that are known and suitable for the reactions mentioned. In this case, use can also be made of variants which are known per se and are not mentioned here.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

Starting compounds for the preparation of compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis. Compounds of the formula I are preferably obtained by coupling reactions of the compounds of the formulas II or IIa known to those skilled in the art with those of the formula III, if appropriate after selective hydrogenation. If possible, the synthesis of compounds of the formula I is carried out in such a way that solvolysis to release the desired compound of the Formula I is superfluous, especially since compounds of this structure often behave unstably under such conditions.

Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formulas mentioned above, but instead of free amino and / or hydroxyl groups contain corresponding protected amino and or hydroxyl groups, preferably those which instead of an H atom , which is connected to an N atom, carry an amino protective group, in particular those which, instead of an HN group, carry an R'-N group, in which R 'is an amino protective group, and / or those which replace the H atoms of a hydroxy group carry a hydroxy protecting group, e.g. B. those who instead of a group -COOH a group -COOR "gene, wherein R" is a hydroxy protecting group.

Several - identical or different - protected amino and / or hydroxyl groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term “amino protecting group” is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction at another point in the Unsubstituted or substituted acyl, aryl (e.g. dinitrophenyl (DNP), aralkoxymethyl (e.g. benzoxymethyl (BOM)) or aralkyl groups (e.g. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical, but those with 1-20, in particular 1-8, are preferred The term “acyl group” is to be understood in the broadest sense in connection with the present process. It encompasses aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids derived acyl groups and especially alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenacetyl; Aroyl such as benzoyl or tolyl; Aryloxyalkanoyl such as phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl,

Ethoxycarbonyl; 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC). Preferred amino protecting groups are BOC, DNP and BOM, furthermore CBZ, benzyl and acetyl.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule. Typical for such groups are unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups.The nature and size of the hydroxy protecting groups is not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular, are preferred 1-10 carbon atoms, examples of hydroxy protecting groups include tert-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl protecting groups and acetyl, with benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the formula I which are to be used as starting materials can be prepared by the customary methods as described, for example, in US Pat. B. are described in the corresponding standard works and the relevant patent literature, for example by reacting compounds which correspond to formulas II and III, but at least one of these compounds carrying a protective group instead of an H atom.

The liberation of both the compounds of the formulas II, Ila or III and, if appropriate, of the compounds of the formula I from their functional derivatives succeeds, depending on the protection used. group - e.g. B. with strong acids, advantageously with trifluoroacetic acid or perchloric acid, but also with other strong inorganic 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, the presence of an additional Lö¬ solvent is possible, but not always necessary.

Suitable inert solvents are preferably organic, for example 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 and water. Mixtures of the abovementioned solvents are also suitable. Trifluoroacetic acid is preferably used in excess without the addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the elimination of protective groups are advantageously between about 0 and 50 ° C .; preferably one works between 15 and 30 ° C (room temperature).

The BOC group can e.g. B. preferably with 40% trifluoroacetic acid in dichloromethane or with about 3 to 5N HCl in dioxane at 15 to 60 ° C, the FMOC group with an about 5 to 20% solution of dimethylamine, diethylamine or piperidine in DMF at 15 to 50 ° C. The DNP group can be split off, e.g. B. also with an approximately 3 to 10% solution of 2-mercaptoethanol in DMF / water at 15 to 30 ° C.

Hydrogenolytically removable protective groups (e.g. BOM, CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, in particular z. B. alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is generally carried out at temperatures between 0 and about 100 ° C. and pressures between about 1 and 200 bar, preferably at 20 to 30 ° C. and 1 to 10 bar. A hydrogeno- CBZ group lysis is successful, for example. B. good at 5 to 10% Pd-C in methanol at 20 to 30 ° C.

Compounds of the formula I can preferably be obtained by reacting a pyrazole derivative of the formula II with a compound of the formula III. The methods known per se for N-alkylation of amines are expediently used.

The leaving group Z of the formula II is preferably Cl, Br, J, Cr to Ce-alkylsulfonyloxy, such as methane or ethanesulfonyloxy, Ci- to Cβ-fluoroalkylsulfonyloxy, such as trifluoromethanesulfonyloxy or Ce-Cio-arylsulfonyloxy such as benzene, p-toluene or 1- or 2-naphthalene sulfonyloxy.

The reaction succeeds in an inert solvent e.g. B. a halogenated hydrocarbon such as dichloromethane, trichloromethane or carbon tetrachloride, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile. Dimethyl sulfoxide, toluene or benzene are also suitable as solvents. However, mixtures of these solvents can also be used. This reaction can be carried out at temperatures between about -10 and 200 ° C., preferably between 0 and 120 ° C. The reaction is preferably carried out in the presence of an additional base, e.g. B. an alkali or alkaline earth metal hydroxide or carbonate such as sodium, potassium or calcium hydroxide, sodium, potassium or calcium carbonate. If the escape group Z is different from I, the addition of an iodide such as potassium iodide is recommended.

The starting materials of the formula II can be prepared by methods known from the literature.

The starting materials of the formula III can be prepared by methods generally known to the person skilled in the art, as are described in manuals on indole chemistry. Benzyl and BOC are preferred as protective groups of the piperidine nitrogen. In particular, These protective groups are added in order to introduce a substituent called R ⁴ , which is not equal to hydrogen, on the indole nitrogen. The latter reaction is particularly successful in the presence of a strong base, preferably from the group NaH, KH, KOC (CH ₃ ) ₃ or n-, sec- or tert-butyl lithium. The “amino protecting group” is then cleaved off using one of the methods described above.

Starting materials of the formula Ila can be prepared by methods known from the literature, in particular analogously to Example 5 below.

Coupling reactions of compounds of the general formula IIa with compounds of the general formula III can be carried out under conditions known for the formation of peptide bonds. Corresponding methods are described, for example, in "Amino acids, peptides, proteins", Jakubke, Hans-Dieter; Jeschkeit, Hans; Verlag Chemie, Weinheim (1982), but also in Wünsch E. (1974). "Synthesis of peptides", in: Houben-Weyl, "Methods of Organic Chemistry", Vol. 15, 1/2, (Ed., Müller, E.) Georg Thieme Verlag, Stuttgart. These methods include the azide method, the mixed anhydride method with carbonic acid half-ester Chlorides as anhydride formers, various methods of the activated esters and the carbodiimide method, and their modified form, the DCC additive method, from which the carbonyl compound obtained by the linkage reaction can be reduced by reducing the desired compound of the formula I. release suitable conditions.

This is particularly successful in the presence of a catalyst from the group of complex hydrides. This reaction is preferably carried out in a solvent from the ether group. Tetrahydrofuran is particularly preferably used as the solvent. In general, this reduction takes place under mild conditions at temperatures from -78 to + 66 ° C., preferably at room temperature. In particular, this reduction can also be carried out with sodium bis (2-methoxyethoxy) aluminum hydride (e.g. Vitride®). ren. For this purpose, this is used in excess. In this case, suitable ethers are preferred as solvents.

A base of the formula I can be converted into the associated acid addition salt using an acid. In particular, acids that provide physiologically acceptable salts are suitable for this reaction. So inorganic acids can be used, e.g. B. sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. b. Formic acid. Acetic acid, trifluoroacetic acid, propionic acid, pivalic acid, diethyl acetic 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, ethandisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. picrates, can be used for the isolation and / or purification of the compounds of formula I.

If desired, the free bases of the formula I can be liberated from their salts by treatment with strong bases, such as sodium or potassium hydroxide, sodium or potassium carbonate.

As already indicated above, the compounds of the formula I can contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are, for. B. optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, Malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid.

Enantiomer separation using a column filled with an optically active separating agent (eg dinitrobenzoyl-phenylglycine) is also advantageous. As a solvent is suitable for. B. a mixture of hexane / isopropanol / acetonitrile.

Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials (for example those of the formula II) which are already optically active.

The new compounds of formula I and their physiologically harmless salts can therefore be used as active pharmaceutical ingredients for anxiety agents, antidepressants, neuroleptics, anti-Parkinson agents and / or antihypertensives. They are useful for the treatment and prophylaxis of anxiety, for the treatment of panic attacks, schizophrenia, delusional obsessions, Alzheimer's disease, migraines, anorexia, bulimia, sleep disorders and drug abuse or for combating the consequences of cerebral infarction, but also for treatment extrapyramidal motor side effects of neuroleptics are suitable.

But they can also be used as intermediates for the production of others

Active pharmaceutical ingredients are used.

The compounds of the general formula I and their physiologically acceptable salts can therefore be used for the production of pharmaceutical preparations by combining them with the appropriate dose together with at least one carrier or auxiliary and, if desired, with one or more further active ingredients ¬ rungsform brings. The preparations thus obtained can be used as medicaments in human or veterinary medicine. Suitable carrier substances are organic or inorganic substances which are suitable for enteral (eg oral or rectal) or parenteral application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, poly- ethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatin, soy lecithin, carbohydrates such as lactose or starch, magnesium stearate, talc or cellulose.

Tablets, coated tablets,

Capsules, syrups, juices or drops. Of particular interest are coated tablets and capsules with enteric coatings or capsule shells. Suppositories are used for rectal application, solutions are used for parenteral application, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants.

The active compounds claimed according to the invention can also be lyophilized and the lyophilizates obtained, for. B. be used for the production of Injek¬ tion preparations.

The specified preparations can be sterilized and / or

Contain auxiliaries such as preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and / or flavorings. If desired, they can also contain one or more other active ingredients, e.g. B. one or more vitamins, diuretics, anti-inflammatory drugs.

The compounds of the formula I according to the invention are generally administered in analogy to other known preparations which are commercially available for the claimed indications, preferably in doses between about 1 mg and 50 mg, in particular between 5 and 30 mg, per dosage unit. The daily dosage is preferably between about 0.02 and 20 mg / kg, in particular 0.2 and 0.4 mg / kg body weight.

The specific dose for each individual patient depends, however, on a wide variety of factors, for example on the effectiveness of the special compound used, on the age, body weight, general state of health, gender, on the diet, on the time and route of administration, on the Elimination rate, drug combination and severity of each Disease to which the therapy applies. Oral application is preferred.

In the following examples are given which serve to illustrate the invention but do not limit the invention to the examples given.

All temperatures are given in ° C below.

Examples

example 1

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

144 g (2.57 mol) of KOH are dissolved in 1.6 l of methanol in a 2000 ml round-bottomed flask. 120 g (about 0.86 mol) of 7-ethyl indole and 161.4 g (about 0.86 mol) of 1-benzylpiperidin-4-one are then added to this solution. This reaction mixture is stirred under reflux conditions for 5 hours. Another 34.1 g (about 0.172 mol) of 1-benzyl-piperidin-4-one are added and the mixture is stirred under reflux conditions overnight. The reaction solution obtained is concentrated in vacuo, the product being obtained in crystalline form. This crude product is recrystallized from methanol.

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

Rf value 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 from Example 1 is dissolved in a solvent mixture consisting of 2 l of methanol and 0.5 l of glacial acetic acid and dissolved in Presence of a palla third. The catalyst is then filtered off and the solvent is distilled off in vacuo. The residue obtained is codistilled with toluene and dissolved in 1 liter of water. The pH of the solution is made alkaline by adding sodium hydroxide solution (32%). The crystals which precipitate out are separated off and dried.

Yield: 153.6 g of 7-ethyl-3- (4-piperidyl) indole (~ 95% of theory), mp. 189 ° C.

Example 3

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

495 ml of 90% strength sulfuric acid are heated to 130 ° C. in a 2 liter three-necked flask. 300 g of 3-acetyl-3,4-dihydro-6-methyl-pyran-2,4-dione (dehydrate acid) are added in small portions with stirring. Then stir for a while. After the reaction has taken place, the reaction mixture is poured onto about 1500 g of ice. The crystals formed are separated off. Yield: 192 g of 3,4-dihydro-6-methyl-pyran-2,4-dione (crude product) (85% of theory)

Example 4

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

191.6 g of 3,4-dihydro-6-methyl- ~ pyran-2,4-dione are dissolved in 800 ml of methanol. 190 g of NH ₂ NH ₂ .H ₂ O are added dropwise to this solution with stirring, the temperature rising to 70.degree. Following the reaction, the product formed is filtered off and processed further as a crude product.

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

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

105 g of 2- (5-methyl-3-pyrazolyl) acetic hydrazide and 720 ml of 2N

Sodium hydroxide solution is stirred together and heated under reflux conditions for 4 hours. The reaction solution thus obtained is then neutralized with hydrochloric acid. The reaction solution is then concentrated under vacuum. Precipitated crystals are separated and processed directly as a raw product.

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

Example 6

Ethyl 2- (5-methyl-3-pyrazolvn acetate

95 g of 2- (5-methyl-3-pyrazolyl) acetic acid and 660 g of ethanol are mixed in a 2 l flask with 74 ml of thionyl chloride and stirred for about 72 hours at room temperature and then left to stand for a further 48 hours. The reaction solution is concentrated under vacuum conditions. The residue obtained is taken up in a solvent mixture consisting of ethyl acetate / methanol in a ratio of 2: 1 and heated under reflux conditions, the product going into solution, but the by-product and common salt are not. The filtered mother liquor is concentrated in vacuo, the product being obtained 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) are suspended in 2 l of ethanol. 146.6 g of NaBH _{4 are} added in portions to this suspension with stirring. This reaction mixture is stirred for about 192 hours at room temperature. It will be about 150 ml of water and 65 ml of glacial acetic acid are added and the ethanol is distilled off. The pulpy residue obtained is taken up in ethyl acetate and extracted several times with water. The organic phase is dried, filtered and concentrated under vacuum conditions. Further product is separated from the aqueous phase by neutralizing and extracting 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 are suspended in 78 ml of toluene and heated to reflux. 59.5 g of phosphorus oxychloride are slowly added dropwise to this suspension over the course of 2 hours, a strongly exothermic reaction taking place. After the addition has ended, the mixture is heated under reflux for a further two hours. The reaction solution is then left to stand at room temperature for at least 12 hours. Then the pH of the solution is adjusted to 9 with sodium carbonate and extracted at least three times with ethyl acetate. The combined Essi ester phases are dried over magnesium sulfate, filtered off and the solvent is distilled off to dryness in vacuo. An oil is obtained as the residue which cannot be completely crystallized. This crude product is 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-pyrazolvn-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) are placed in a 250 ml round-bottomed flask -3-pyrazolyl) ethyl chloride (Example 8) placed in 125 ml of acetonitrile under reflux conditions for about 48 hours. The precipitate formed during this time is separated off. This is an unreacted starting material. The solvent of the reaction solution thus obtained is distilled off and the residue obtained is separated by chromatography (silica gel 60, ethyl acetate / methanol 3: 2). After concentration of the product-containing fraction, the reaction product is 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) Rf value: 0 , 28 (EssigesteπMethanol 2: 1), amorphous

Example 10

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

2.18 g (10 mmol) 5-fluoro-3- (4-piperidyl) indole, 3.10 g (16 mmol) 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide hydrochloride and 2.70 g (20 mmol) of 1-hydroxybenzotriazole are taken up in 100 ml of dichloromethane and stirred for 1 hour. 2.34 g (10 mmol) of 2- (3- (6-fiorphophenyl) -5-methyl-4-pyrazolyl) acetic acid are then added and the reaction solution thus obtained is stirred for about 72 hours. The reaction mixture thus obtained is extracted with sodium hydroxide solution and then dried over magnesium sulfate. After this solution has been filtered, the solvent is distilled off in vacuo. The crude product obtained in this way is not worked up but used directly in the next stage. 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-π- (2- (3- (4-fluorophenyn-5-methyl-4-pyrazolyl) ethyl) -4-piperidyQ-indole

6.5 g (10 mmol) of 5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) methylcarbonyl) -4-piperidyl) indole are dissolved in 100 ml of tetrahydrofuran dissolved and then mixed with 5 ml (25 mmole sodium bis (2-methoxyethoxy) aluminum hydride (Vitride ^® ). The reaction mixture thus obtained is stirred for two hours at room temperature. After the reaction has ended, excess sodium bis (2-methoxyethoxy ) Aluminum hydride is destroyed by adding water, resulting in a colorless mucus which is filtered off over kieselguhr and the solvent is distilled off in vacuo from the reaction solution thus obtained, giving 7.7 g of crude product which is purified by chromatography is (silica gel 60; It sigester / 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% of Theory)

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

Example 12

5-fluoro-1-methyl-3- (1-tert. Butyloxycarbonyl-4-piperidvπ-indole

0.9 g (30mmo!) Sodium hydride (80%) are suspended in 300 ml of tetrahydrofuran. With cooling, a solution consisting of 9.5 g of 5-fluoro-3- (1-tert.butyloxycarbonyl-4-piperidyl) indole and tetrahydrofuran is slowly added dropwise and the mixture is subsequently added for about an hour. stirs. Then 1.9 ml (30 mmol) of methyl iodide are added dropwise and the mixture is stirred for about two hours. The solution is concentrated in vacuo and the residue is taken up in ethyl acetate, extracted with water and then dried over magnesium sulfate. After filtering, the mixture is concentrated again in vacuo to the residue. The crude product thus obtained is purified by chromatography (silica gel 60; petroleum ether / ethyl acetate).

Yield: 6.7 g of 5-fluoro-1-methyl-3- (1-tert. Butyl oxy carbonyl -4-piperidyl) indole (~ 67% of theory); oil

Example 13

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

6.7 g (20 mmol) 5-fluoro-1-methyl -3- (1-tert. Butyloxycarbonyl-4-piperidyl) indole are stirred for one hour in 150 ml of a hydrochloric acid / ether mixture (strong Gas evolution). This solution is then concentrated in vacuo.

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

The following compounds were prepared analogously to Examples 9 or 11:

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, Rf 0.31, ethyl ether: methanol 2: 1 5-fluoro-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyl) indole, Rf 0.38, ethyl ether 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, EthyletheπMethanol 2: 1

5-fluoro-3- (1- (2- (3- (4-fluorophenyl) -5-methyl-4-pyrazolyl) -ethyl) -4-piperidyl) -indole, Rf 0.53, EthyletheπMethanol 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, EthyletheπMethanol 2: 1

6-methoxy-3- (1- (2- (5-methyl-3-pyrazolyl) ethyl) -4-piperidyi) 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

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 preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2 N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

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

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ P0 ₄ -2H ₂ θ, 28.48 g of Na ₂ HP0 ₄ 12H ₂ 0 and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in such a way that each tablet contains 10 mg of active ingredient. Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

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

Claims

1. 1-pyrazol-3-ylethyl-4-indol-3-yl-piperidine derivatives of the formula I.

wherein

R ¹ H or A

R ² H, phenyl mono- to trisubstituted by Hal, N0 ₂ , CON (R ⁴ ) ₂ , S0 ₂ N (R ⁴ ) ₂ , cyano, A or R ⁴

R ³ H, Hal, A, AO-, amino, cyan, carboxamide, N0 ₂ , S0 ₂ N (R ⁴ ) ₂

R ⁴ H or A,

R ⁵ H or A,

A alkyl with 1-6 C atoms or a mono- to trisubstituted by fluorine-substituted alkyl with 1 - 6 C atoms

Hal F, Cl, Br or J

mean, and their salts.

2. A compound according to claim 1 selected from the 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 -pyrazoiyl) -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.

3. Medicaments of the general formula I according to claim 1, and their physiologically tolerable salts.

4. Medicament according to claim 3 with serotonin agonistic and antagonistic effect.

5. Medicament according to claim 3 with dopamine-stimulating effect.

Process for the preparation of 1-pyrazol-3-ylethyl-4-indol-3-yl-piperidines of the formula I according to Claim 1 and salts thereof, characterized in that a compound of the formula II

wherein

R ¹ , R ² and R ^{5 have} the meanings given above and Z Hal, 0-S0 ₂ CH ₃₎ 0-S0 ₂ CF ₃ , OSO-rCe ^ or

0-S02-C ₆ H ₅

means with a compound of the formula

^{υ o} what

R ^{3 and} R ^{4 have the} meanings mentioned above,

implements, or that one

a compound of formula Ila

wherein

R ¹ and R ^{2 have} the meanings given above, is converted into an activated form, then is reacted with a compound of the formula III under conditions known for the formation of peptide bonds, and the desired compound is obtained from the compound thus obtained Formula I is formed by a reduction reaction

7. A process for the preparation of pharmaceutical preparations, characterized in that a compound of the formula I as claimed in claim 1 and / or one of its physiologically tolerable Salts together with at least one solid, liquid or semi-liquid carrier or auxiliary and optionally in combination with one or more other active ingredients in a suitable dosage form.

8. Pharmaceutical preparation, characterized by a content of at least one compound of the general formula I according to claim 1 and / or one of its physiologically acceptable salts.

9. Use of compounds of formula I according to claim 1 or of their physiologically acceptable salts in the manufacture of a medicament for the treatment of diseases.

10. Use according to claim 9 for the treatment of diseases caused by malfunctions and disorders of the central nervous system.