RU2211216C2 - Derivatives of amides and urea as inhibitors of reuptake of 5-ht and ligands of 5-ht1b/1d - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to novel derivatives of amides and urea of the formula (I): R¹-(CH₂)_n-(Y)_q-(Z)_r-CO-NH-R² (I) wherein R¹ means unsubstituted or substituted 3-indolyl, AO, Hal, CN; R² means: (Ia)

, (Ib)

or (Id)

; m = 1 or 2; n = 0, 1, 2, 3 or 4; Y means 2,4-cyclohexylene, 1,3-pyrrolidinylene, 1,4- piperazinylene or 1,4-piperidinylene ring that can be dehydrogenated partially also; Z means (CH₂)_nNH-,; q = 0 or 1; r = 0 or 1; R³ means A; R⁴ means AO-; Hal means F, Cl, Br, J; A means linear or branched C₁-C₆-alkyl under condition that q and r are not 0 simultaneously, and their physiologically acceptable salts also. Compounds of the formula (I) are antagonists of 5-HT1B/1D, elicit inhibitory effect with respect to reuptake of 5-HT and can be used in pharmaceutical composition in the effective dose. Compounds are prepared, for example, from compound of the formula (II): H₂N-R² and compound of the formula (III): R¹-(CH₂)_n-(Y)_q-(Z)_r-CO-L wherein L means Cl, Br, J, OH, OH-group modified functionally to confer to its reaction capacity [sic] or easily nucleophilically substituting removable group; R¹, R², n, Y, q, Z, r have values indicated above. EFFECT: valuable medicinal properties of compounds. 3 cl, 1 tbl, 11 ex

Description

m = 1 или 2,
n = 0, 1, 2, 3 либо 4,
Y обозначает 1,4-циклогексиленовое, 1,3-пирролидиниленовое, 1,4-пиперазиниленовое или 1,4-пиперидиниленовое кольцо, которое также может быть частично дегидрированным,
Z представляет собой (СН₂)_n или (CH₂)_nNH-,
q = 0 либо 1,
r = 0 или 1,
R³ обозначает А,
R⁴ представляет собой АО,
Hal обозначает F, C1, Вr или I,
А представляет собой неразветвленный или разветвленный алкил с 1-6 атомами углерода,
при условии, что q и r одновременно не равны 0,
а также к их физиологически приемлемым солям.This invention relates to derivatives of amides and urea of the formula I
R ¹ - (CH ₂ ) _n - (Y) _q - (Z) _r -CO-NH-R ² , (I)
in which R ¹ denotes 3-indolyl, unsubstituted or mono- or disubstituted A, AO, OH, Hal, CN, NO ₂ , NH ₂ , NHA, NA ₂ , COA, CONH ₂ , CONHA, CONA ₂ , CH ₂ OH, CH ₂ OA, CH ₂ NH ₂ , CH ₂ NHA, CH ₂ NA ₂ , COOH and / or COOA,
R ² represents

m = 1 or 2,
n = 0, 1, 2, 3 or 4,
Y represents a 1,4-cyclohexylene, 1,3-pyrrolidinyl, 1,4-piperazinyl or 1,4-piperidinyl ring, which may also be partially dehydrogenated,
Z represents (CH ₂ ) _n or (CH ₂ ) _n NH-,
q = 0 or 1,
r = 0 or 1,
R ³ is A,
R ⁴ represents AO,
Hal is F, C1, Br or I,
A represents a linear or branched alkyl with 1-6 carbon atoms,
provided that q and r are simultaneously not equal to 0,
as well as their physiologically acceptable salts.

 The aim of the present invention was to obtain new compounds with useful properties, in particular those that could be used for the manufacture of drugs.

It was found that the compounds of formula I and their physiologically acceptable acid addition salts have useful pharmacological properties and are well tolerated because they act on the central nervous system. Mostly, these compounds affect serotonergic transmission by inhibiting the secondary uptake of serotonin (5-HT) and having a high degree of affinity for 5-HT _{1B / 1D} receptors. Thanks to this combined action, they can be successfully used as antidepressants and tranquilizers.

The compounds possess 5-HT agonistic and antagonistic properties and also inhibit the secondary uptake of 5-HT. Inhibition of synaptosomatic uptake is used to demonstrate inhibition of 5-HT secondary uptake in vitro (Kong et al., Neuropsychopharmacology B (1993), 22-33). Ex vivo, this property is examined on mouse brain tissue according to the Waldmeier method (European J. Pharmacol. 46 (1997), 387-392). The degree of affinity for 5-HT _{1B / 1D} receptors can be determined, for example, by methods described by Peroutka et al. (Synapse 3 (1983), 61-66) and Hoyer et al. (European J. Pharmacol. 118 (1985), 1-12), and the presence of antagonistic properties in relation to 5-HT _{1B / 1D} can be established by the method of Choppin et al. (British Journal of Pharmacology, 114 (1995), 309-314).

Similar compounds also exhibiting an antagonistic [sic] effect on 5-HT _{1B / 1D} [sic] are described, for example, in patent application WO 97/14689 or WO 97/41802.

 Thus, the compounds of formula I both in veterinary medicine and in human medicine are suitable for the treatment of functional disorders of the central nervous system and inflammation. They can be used to prevent and eliminate the effects of cerebral infarction (cerebral apoplexy), such as stroke and ischemia of the brain, as well as for the treatment of extrapyramidal motor side effects of antipsychotics and trembling paralysis, for the active and symptomatic treatment of Alzheimer's disease, as well as for the treatment of lateral amyotrophic sclerosis. They can also be used as therapeutic agents for the treatment of injuries of the brain and spinal cord. In particular, however, they are suitable for use as pharmaceutical active compounds in the composition of tranquilizers, antidepressants, antipsychotics / antipsychotics, antihypertensive agents and / or for a positive effect on the disorder of obsessive states (RNS), anxiety states, panic attacks, psychoses, anorexia , delusions, agoraphobia, migraine, Alzheimer's disease, sleep disorders, inhibited dyskinesias, learning disabilities, age-related memory disorders, disorders related eating, such as bulimia, substance abuse and / or sexual dysfunction.

 In addition, they can be used to treat endocrine diseases, such as hyperprolactinemia, as well as for vasospasms, high blood pressure and gastrointestinal diseases.

 Further, they can be used as intermediates for the preparation of other pharmaceutical active compounds.

 This invention relates to derivatives of amides and urea of the formula I and their physiologically acceptable acid addition salts.

In particular, the present invention relates to compounds of formula I, which are selected from the group consisting of
a) N- [2- (3-fluoro-3-indolyl) ethyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea;
b) 4- (5-cyano-3-indolyl) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidine-1-carboxamide;
c) 4- (6-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidine-1-carboxamide;
d) 3- {1- [4-methoxy-3- (4-methyl-1-piperazinyl) phenylaminocarbonyl] -4-piperidyl} indole-5-carboxamide;
d) 4- (5-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidine-1-carboxamide;
e) 4- [2- (3-indolyl) ethyl] -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidine-1-carboxamide;
g) 4- (3-indolyl) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidin-1-carboxamide;
h) 4- (4-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] piperidine-1-carboxamide;
i) [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide of 4- (7-methoxyindol-3-yl) piperidin-1-carboxylic acid;
k) [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide of 4- [4- (5-fluoro-3-indolyl) butyl] piperazine-1-carboxylic acid;
k) [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide of 4- (5-cyanoindol-3-yl) -3,6-dihydro-2H-pyridin-1-carboxylic acid;
m) [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide of 3- (5-fluoroindol-3-yl) pyrrolidin-1-carboxylic acid;
m) [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide of 4- (5-fluoroindol-3-yl) cyclohexanecarboxylic acid;
o) N- [2- (5-hydroxy-3-indolyl) ethyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea;
p) N- {2- [4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea ;
p) N- [4- (5-cyano-3-indolyl) butyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea;
c) 4- [4- (5-cyano-3-indolyl) butyl] piperazine-1-carboxylic acid [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] amide;
t) (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide 4- (5-fluoroindol-3-yl) piperidine-1-carboxylic acid;
y) N- {2- [4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} - [2,3-dihydro-1-methylspiro (benzofuran) -3,4-piperidine] urea;
and their physiologically acceptable salts.

 Thus, this invention relates to compounds of formula I and a method for producing compounds of formula I according to claim 1.

The production method is characterized in that
a) a compound of formula II
H ₂ NR ² , (II)
in which R ² has one of the meanings indicated in claim 1 of the claims, is reacted with a compound of formula III
R ^l - (CH ₂ ) _n - (Y) _q - (Z) _r -CO-L, (III)
in which L is Cl, Br, I, OH, or another OH group, functionally modified to give it reactivity [sic], or an easily nucleophilically substituted leaving group, and
R ¹ , n, Y, q, Z and r have the meanings given in claim 1 of the claims, or
b) an amine component of the formula II
H ₂ NR ² , (II)
reacted with a component of formula IV
R ^l - (CH ₂ ) _n - (Y) _q - (Z) _r -H, (IV)
in which R ¹ , R ² , n, Y, q, Z and r have the indicated meanings,
while adding binders, such as N, N'-carbonyldiimidazole, diphosgene, triphosgene, or, alternatively, chloroformic acid esters and / or
c) the fact that one of the radicals R ¹ , R ³ and / or R ⁴ , if necessary, splitting, for example, an OA group to form an OH group and / or obtaining a CN, COOH or COOA group, is transferred to another radical R ¹ , R ³ and / or R ⁴ , and / or that, for example, the primary or secondary nitrogen atom is alkylated, and / or that the resulting base or acid of formula I is converted into one of its by treatment with an acid or base (her) salts.

The present invention also relates to drugs containing compounds of the formula I and their physiologically acceptable salts having an antagonistic [sic] effect on 5-HT _{1B / 1D} and inhibiting secondary uptake of 5-HT.

 This invention relates to compounds of formula I, their enantiomers and diastereomers, as well as their salts.

For all repeating radicals, such as, for example, A or R ³ , the condition of independence of their values from each other is fulfilled.

 The radical A is alkyl and has 1-6, preferably 1, 2, 3 or 4, in particular 1 or 2 C, carbon atoms. Thus, alkyl, in particular, means, for example, methyl, then ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, as well as pentyl, 1-, 2- or 3-methylbutyl, 1 , 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2 , 2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methoxypropyl, 1,1,2- or 1,2,2 trimethylpropyl.

 OA is preferably methoxy, as well as ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.

 NHA is preferably methylamino, further ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino.

NA _{2 is} preferably dimethylamino, then N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. Thus, CO-NHA is preferably N-methylcarbamoyl or N-ethylcarbamoyl; CO-NA ₂ is preferably N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl.

 Hal is preferably fluoro, chloro, bromo or iodo, in particular fluoro or chloro.

 n = 0, 1, 2, 3 or 4, in particular 0, 2 or 4.

Each of the radicals R ³ independently from each other denotes A, and these two radicals R ³ in the formula Ic may be identical or different from each other. Preferably, they are identical and, in a preferred embodiment, are, in particular, methyl.

 Y is preferably a 1,4-piperazinylene or 1,4-piperidinyl ring, which may also be partially dehydrogenated, in which case it is preferably a 1,4-substituted 3,6-dihydro-2H-pyridine ring, as well as 1, 3-pyrrolidinyl or 1,4-cyclohexylene ring.

R ¹ is preferably 2- or 3-indolyl, unsubstituted or mono- or disubstituted, in particular, monosubstituted Hal, CN, A, AO, CONH ₂ , CONHA, CONA ₂ , COOH, COOA, CH _{2 are} most preferred Ar, CH ₂ OAr and / or CH ₂ NA ₂ 3-indolyl.

The indole radical is preferably substituted at the 5-position, as well as at the 4-, 6- or 7-position. Thus, R ^{1 is} most preferably 3-indolyl, 5- or 6-methylindol-3-yl, 5- or 6-methoxyindol-3-yl, 5- or 6-hydroxyindol-3-yl, 4-, 5- either 6-fluoroindol-2-yl, 4-, 5- or 6-fluoroindol-3-yl, 5- or 6-cyanoindol-3-yl, 5- or 6-chloroindol-3-yl, 5- or 6- carboxyindol-3-yl, 5- or 6-methoxycarbonylindol-3-yl, 5- or 6-hydroxyindol-3-yl, 5- or 6-hydroxymethylindol-3-yl, 5- or 6-aminomethylindol-2-yl, 5- or 6-aminomethylindol-3-yl, as well as 5- or 6-bromoindol-3-yl, 5- or 6-ethylindol-3-yl, 5- or 6-isopropylindol-3-yl, 5- or 6 dimethylaminoindol-3-yl or 5- or 6-ethoxyindol-3-yl .

R ² is Ia, Ib, Ic or Id. The most preferred compounds are those containing, as R ² groups [sic] Ia, Ic or Id, m is preferably 1 or 2, in a preferred embodiment 2.

Z is (CH ₂ ) _n or (CH ₂ ) _n NH—, where n is preferably 2 or 4.

 Each of the variables q and r is equal to 0 or 1, provided that q and r cannot simultaneously be equal to 0.

 In the entire scope of this invention, the condition is satisfied that the radicals repeating in the molecule can be identical or different from each other, i.e. do not depend on each other.

Thus, the present invention relates, in particular, to compounds of the formula I, in which at least one of the aforementioned radicals has one of the above preferred meanings. Some preferred groups of compounds can be expressed by the following formulas I1-112 corresponding to formula Ia (radicals for which no detailed definition is given have the meanings indicated for formula Ia), where
in I1, R ² is a group (Ia);
in 12, R ² has the meaning given in II, R ⁴ is a methoxy radical, and R ³ is a methyl radical;
in I3, R ² is a group (Id);
in I4, R ² has the meaning indicated in I3, and the radical R ³ represents a methyl group,
in I5, R ³ is an Id or Ic group;
in I6 q = 1 and r = 0;
in I7, R ¹ is indol-3-yl monosubstituted by CN, F, OA, CONH ₂ or OH;
in I8 q = 0 and r = 1;
in I9 q and g have the meanings given in 16, a Z represents a 1,4-piperidinyl ring;
in I10, q and r are as defined in I6, and Y is a 1,4-cyclohexylene or 1,4-piperazinylene ring;
in I11, q and r have the meanings given in I8, an is 2 or 4;
in I12 q = r = 1.

 Otherwise, the compounds of formula I, as well as the starting materials used to prepare them, are prepared according to essentially known methods, such as those described in the literature (for example, in standard works, such as Houben-Weyl, Methoden der Organischen Chemie [Methods of organic chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), namely, under known reaction conditions suitable for carrying out the above reactions. In this case, you can also use the well-known essentially options, a detailed description of which is not given here.

 If desired, the starting materials used to carry out the claimed method can be obtained in situ, without isolating them from the reaction mixture, but directly involving in further reactions to obtain compounds of formula I. On the other hand, it is possible to carry out a stepwise reaction.

 In the compounds of formula III, the radical L is preferably Cl or Br; however, it can also be I, OH or, alternatively, an OH group functionally modified to give it reactivity [sic], in particular alkylsulfonyloxy with 1-6 (for example methanesulfonyloxy) or arylsulfonyloxy with 6-10 atoms carbon (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy) or, alternatively, trichloromethoxy, alkoxy, such as, for example, methoxy, ethoxy, propoxy or butoxy, as well as phenoxy.

 In a preferred embodiment, compounds of formula I can be prepared by reacting compounds of formula II with compounds of formula III.

 Typically, the starting materials of formulas II and III are known; unknown compounds of formulas II and III can be easily obtained analogously to those known.

 Compounds of formula III can also be prepared from known compounds by methods, for example, electrophilic substitution or, in some cases, nucleophilic substitution in the aromatic nucleus.

и др., J. Med. Chem. 1992, 35, 4020-4026 или Iyer и др., J. Chem. Soc. Parkin Trans. II, 1973, 872-878), которая, в случае необходимости, может быть дополнительно восстановлена и замещена.The appropriate starting material here is often the corresponding indole-3-alkanoic acid (which can be obtained analogously to Japp-Klingemann type Fischer indole synthesis, cf.

et al., J. Med. Chem. 1992, 35, 4020-4026 or Iyer et al., J. Chem. Soc. Parkin Trans. II, 1973, 872-878), which, if necessary, can be further restored and replaced.

The reaction of compounds II and III is carried out by alkylation or acylation of amines known from the literature. However, along with this, it is possible to conduct a reaction with these compounds in the presence of a solvent which does not change the soluble substance. Suitable solvents are, for example, hydrocarbons, such as benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, n-butanol [sic]; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-methylpyrrolidone; nitriles, such as acetonitrile, and also, if appropriate, mixtures of these solvents with each other or with water can be used. It may be desirable to add an acid acceptor, for example an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of alkali or alkaline earth metals, preferably potassium, sodium or calcium, or add an organic base such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of piperazine derivative of the formula II. Depending on the conditions used, the reaction time can range from several minutes to 14 days, and the reaction temperature is in the range of about 0-150 ^o C, usually 20-130 ^o C.

 Before carrying out this reaction, it may be necessary to protect other amino groups contained in the compound from alkylation or acylation, which is carried out by introducing suitable protective groups. The expression "amino group protecting group" is well known and refers to groups by which the amino group can be protected from chemical reactions and which are easily cleaved after carrying out the desired reaction in a different position in the molecule. Since such protective groups, as well as the processes of their introduction and cleavage are well known to specialists in this field from a variety of reference material and a number of textbooks, there is no need to describe them here in detail.

In addition, compounds of formula I can be obtained by introducing amines of formula II into a reaction with a component of formula IV containing the radical R ¹ .

Typically, the corresponding components are known or can be obtained by known methods, as already described. The preparation of compounds of formula II in which R ² is a radical Ia (piperazine derivatives) is also described, for example, by Clitherow JW et al. In J. Med. Chem. 1994, 37 (15), 2253-2257. Compounds of formula II in which R ² is Ib (piperidine derivatives) are also disclosed, for example, in WO 96/31508.

Spiro compounds of formula II, where R ² is Id, are disclosed in WO 96/19477, and compounds of formula II in which R ² is radical Ic are described in WO 95/26328.

 Compounds of the formulas [sic] II and IV are prepared [sic] using coupling agents, such as, for example, N, N'-carbonyldiimidazole, diphosgene or triphosgene, or, alternatively, chloroformic acid esters. This synthesis is carried out under normal acylation conditions, as already described. Preferably, this reaction takes place at room temperature using N, N-carbonyldiimidazole, triethylamine and acetonitrile as the solvent insoluble here.

In addition, it is possible to carry out some reduction using H ₂ gas in catalysis with transition metals such as Raney nickel or palladium. Thus, it is possible to replace, for example, Cl, Br, I, SH or, in some cases, also OH groups with hydrogen. Nitro groups can also be converted to NH ₂ groups by catalytic hydrogenation using Pd / H ₂ in methanol.

 Compounds corresponding to formula I, except that instead of one or more hydrogen atoms they contain one or more solvolysis group (s), can be subjected to solvolysis, preferably hydrolysis, to obtain compounds of formula I.

 In addition, a compound of formula I can be transferred to another compound of formula I by methods known per se

Compounds of formula I in which R ¹ is an indole radical substituted with CONH ₂ , CONHA or CONA ₂ can be obtained by partial hydrolysis of the corresponding substituted compounds of formula I as derivatives. Further, it is possible to hydrolyze the cyano-substituted compounds of formula I to acids and subsequent amidations of the latter using primary or secondary amines. The reaction of the free carboxylic acid with an amine is preferably carried out under the conditions of peptide synthesis. In a preferred embodiment, this reaction proceeds in the presence of a desiccant, for example carbodiimide, such as dicyclohexylcarbodiimide or N- (3-dimethylaminopropyl) -N-ethylcarbodiimide, then propane phosphonic anhydride (cf. Angew, Chem. 92, 129 (1980)), diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, nitrile, such like acetonitrile, at temperatures in the range of approx lysingly -10-40 ^o C, preferably 0-30 ^o C. Instead of an acid or amide in the reaction, you can also use reactive derivatives of these substances, for example those in which reactive groups in the intermediate stage are blocked by protective groups. Acids can also be used in the form of their activated esters, which are useful in situ, for example, by adding 1-hydroxybenzotriazole or N-hydroxysuccinimide.

However, it is most desirable to obtain nitriles by the reverse method, by dehydration starting from amides, for example using trichloroacetyl chloride / Et ₃ N [Synthesis (2), 184 (1935)] or POCl ₃ (J. Org. Chem. 2.6, 1003 ( 1961)).

 The resulting base of formula I can be converted using the acid into the corresponding acid addition salt. Suitable for this reaction are, in particular, acids that form physiologically acceptable salts. Thus, inorganic acids, for example sulfuric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, and further, organic acids, in particular aliphatic, alicyclic, araliphatic, can be used. , aromatic or heterocyclic monobasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, trimethylacetic acid lot, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic 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 acids, as well as lauryl sulfonic acid.

 If desired, the free bases of formula I can be liberated from their salts by treatment with strong bases, such as sodium or potassium hydroxide or carbonates, if other acid groups are absent in the molecule. In cases where the compounds of formula I have free acid groups, the salt can also be obtained by treatment with bases. Suitable bases are alkali metal hydroxides, alkaline earth metal hydroxides or organic bases in the form of primary, secondary or tertiary amines.

 In addition, the present invention relates to the use of compounds of formula I and / or their physiologically acceptable salts for the manufacture of pharmaceutical preparations, in particular by non-chemical means. In this regard, they can be appropriately dosed in combination with at least one solid, liquid and / or semi-liquid excipient or excipient and, if appropriate, one or more other (s) active (s) compound (s).

 Further, the present invention relates to compositions, in particular pharmaceutical preparations, containing at least one compound of formula I and / or one of its physiologically acceptable salts.

 These drugs can be used as drugs in human medicine and veterinary medicine. Acceptable excipients are organic or inorganic substances that can be administered enterally (e.g., orally), parenterally or topically and do not react with new compounds, e.g. water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, hydrocarbons such as lactose or starch, magnesium stearate, talc and petroleum jelly. Tablets, coated tablets, capsules, syrups, liquids, drops or suppositories are used, in particular, enteral, solutions, preferably oily or aqueous, as well as suspensions, emulsions or implants are used parenterally, and ointments, creams or powders are intended for topical application. New compounds can also be lyophilized and the resulting lyophilizates used, for example, in the manufacture of injectable preparations.

 The aforementioned preparations may be sterilized and / or include excipients, such as lubricants, antioxidants, stabilizers and / or surfactants, emulsifiers, salts, with which you can change the osmotic pressure, buffers, dyes, flavorings and / or flavorings. If desired, they may also contain one or more other active compounds, for example one or more vitamins.

 The compounds of formula I and their physiologically acceptable salts can be used in the treatment of humans or animals, as well as to eliminate diseases. They are useful for treating diseases of the central nervous system, such as stressful conditions, depression, anxiety, schizophrenia, diseases of the gastrointestinal tract, nausea, inhibited dyskinesias, parkinsonism and / or psychosis and side effects in the treatment of high blood pressure (for example, when α-methyldopa is used). In addition, these compounds can be used in endocrinology and gynecology, for example, in the treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome, unwanted postpartum lactation, as well as for the prevention and treatment of brain diseases (eg, migraine), in particular in geriatrics, like some ergot alkaloids.

 They can also be used, which is most preferred, as therapeutic agents for eliminating the effects of cerebral infarctions (brain apoplexy), such as stroke and cerebral ischemia, as well as for treating injuries to the brain and spinal cord.

 Nevertheless, in particular, they can be successfully used as pharmaceutical active compounds in the composition of tranquilizers, antidepressants, antipsychotics and / or for a positive effect on the obsessive state disorder (RNS), sleep disorders, inhibited dyskinesias, learning disabilities, age-related memory disorders, eating disorders, such as bulimia, and / or sexual dysfunction.

 In this case, the substances of this invention are typically used in a manner analogous to known preparations, preferably in an amount of about 0.1-500 mg, in particular 5-300 mg per dose. The daily dose is preferably about 0.01-250 mg / kg, in particular 0.02-100 mg / kg body weight.

 In this case, the substances of the present invention are typically used in amounts of about 1-500 mg, in particular 5-100 mg per dose. The daily dose is preferably about 0.02-10 mg / kg body weight. However, the dosage for each patient depends on a number of factors, for example, on the effectiveness of a particular compound used, age, body weight, general health and gender, diet, time and method of use, as well as the intensity of excretion, combination of drugs and the severity of the disease. Oral administration is preferred.

All the above and the following temperatures are given in ^o C. In the following examples, the expression "conventional treatment" means: if necessary, the solvent is removed, if necessary, water is added, if necessary, the pH of the mixture is stabilized in the range from 2 to 10, depending on the composition of the final product, the mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated, dried over sodium sulfate, filtered and concentrated, and finally, the precipitate is purified by silica chromatography barely and / or crystallization.

 Example 1

Аналогично получают следующие соединения:
дигидрохлорид 4-(3-индолил)-N-[4-метокси-3-(4-метил-1-пиперазинил)фенил] пиперидин-1-карбоксамида, т. пл. 204^oС;
[4-метокси-3-(N, N'-диметиламиноэтокси)фенил]амида 4-(5-фторо-1Н-индол-3-ил)пиперидин-1-карбоновой кислоты;
гидрохлорид [4-метокси-3-(4-метилпиперидин-1-ил)фенил] амида 4-(5-фторо-3-Н-индол-3-ил)пиперидин-1-карбоновой кислоты;
4-(5-циано-3-индолил)-N-[4-метокси-3-(4-метил-1-пиперазинил)фенил] пиперидин-1-карбоксамид, т. пл. 194-195^oС;
4-(6-фторо-3-индолил)-N-[4-метокси-3-(4-метил-1-пиперазинил)фенил] пиперидин-1-карбоксамид, т.пл. 135-137^oС;
3-(1-[4-метокси-3-(4-метил-1-пиперазинил)фениламинокарбонил] -4-пиперидил)индол-5-карбоксами, т. пл. 176-178^oС;
дигидрохлорид 4-(4-фторо-3-индолил)-N-[4-метокси-3-(4-метил-1-пиперазинил)фенил]пиперидин-1-карбоксамида, т. пл. >205^oС (разложение);
дигидрохлорид 4-(4-фторо-3-индолил)-N-[4-метокси-3-(4-метил-1-пиперидинил)фенил]пиперидин-1-карбоксамида;
[4-метокси-3-(4-метилпиперазин-1-ил)фенил] амид 4-(7-метокси-1H-индол-3-ил)пиперидин-1-карбоновой кислоты, т. пл. 219-222^oC;
4-[2-(3-индолил)этил]-N-[4-метокси-3-(4-метил-1-пиперазинил)фенил]пиперидин-1-карбоксамид,
т. пл. 200-202^oC;
4-[2-(3-индолил)этил] -N-[4-метокси-3-(N,N'-диметиламиноэтокси)фенил]пиперидин-1-карбоксамид;
4-[2-(3-индолил)этил]-N-[4-метокси-3-(4-метил-1-пиперидинил)фенил]пиперидин-1-карбоксамид;
[4-метокси-3-(4-метил-1-пиперазинил)фенил] амид 4-(5-циано-3-индолил)-3,6-дигидро-2Н-пиридин-1-карбоновой кислоты, т. пл. 223-225^oC;
дигидрохлорид [4-метокси-3-(4-метил-1-пиперазинил)фенил]амида 4-[4-(5-фтороиндол-2-ил)бутил] пиперазин-1-карбоновой кислоты, т. пл. >220^oC (разложение);
[4-метокси-3-(4-метил-1-пиперидинил)фенил] амид 3-(5-фтороиндол-3-ил)пирролидин-1-карбоновой кислоты, т. пл. 210-213^oC;
(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-(5-фтороиндол-3-ил)пиперидин-1-карбоновой кислоты;
[4-метокси-3-(4-метил-1-пиперазинил)фенил] амид 4-[4-(5-циано-3-индолил)бутил]пиперазин-1-карбоновой кислоты;
[4-метокси-3-(4-метил-1-пиперидинил)фенил] амид 4-[4-(5-циано-3-индолил)бутил]пиперазин-1-карбоновой кислоты;
[4-метокси-3-(N, N'-диметиламиноэтокси)фенил] амид 4-(5-циано-1Н-индол-3-ил)пиперидин-1-карбоновой кислоты;
[4-метокси-3-(N,N'-диметиламиноэтокси)фенил]амид 4-(3-индолил)пиперидин-1-карбоновой кислоты;
[4-метокси-3-(N, N'-диметиламиноэтокси)фенил] амид 4-[4-(5-фторо-1Н-индол-3-ил)бутил]пиперазин-1-карбоновой кислоты;
[4-метокси-3-(N, N'-диметиламиноэтокси)фенил] амид 4-[4-(5-циано-1Н-индол-3-ил)бутил]пиперазин-1-карбоновой кислоты;
(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-(5-циано-1Н-индол-3-ил)пиперидин-1-карбоновой кислоты

(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-(3-индолил)пиперидин-1-карбоновой кислоты;
(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-[4-(5-фторо-1H-индол-3-ил)бутил]пиперидин-1-карбоновой кислоты;
(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-[4-(5-циано-1Н-индол-3-ил)бутил]пиперидин-1-карбоновой кислоты;
(2,3-дигидро-1'-метилспиро(бензофуран)-3,4-пиперидин)амид 4-[3-(1H-индол-3-ил)пропил]пиперидин-1-карбоновой кислоты.Solution of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline dihydrochloride (2.55 g; 9 mmol), triethylamine (4.5 ml; 31.5 mmol) and N, N'-carbonyldiimidazole (1 6 g; 10 mmol) in 125 ml of acetonitrile was stirred at room temperature for 3 hours. A suspension of 2.0 g (9 mmol) of 5-fluoro-3-piperidin-4-yl-1H-indole and 1.3 ml (9 mmol) of triethylamine in 125 ml of acetonitrile was added to the mixture and stirred at room temperature for the following 12 hours. As a result of processing by the usual method, the precipitate is dissolved in acetone and using 1N. Hcl precipitates hydrochloride. By recrystallization from ethanol / diethyl ether, 4- (5-fluoro-1H-indol-3-yl) piperidine-1-carboxylic acid [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] hydrochloride is obtained

The following compounds are prepared analogously:
4- (3-indolyl) -N- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] piperidine-1-carboxamide dihydrochloride, mp. 204 ^o C;
[4-Methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] 4- (5-fluoro-1H-indol-3-yl) piperidine-1-carboxylic acid amide;
4- (5-fluoro-3-H-indol-3-yl) piperidine-1-carboxylic acid [4-methoxy-3- (4-methylpiperidin-1-yl) phenyl] amide hydrochloride;
4- (5-cyano-3-indolyl) -N- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] piperidine-1-carboxamide, mp 194-195 ^o C;
4- (6-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] piperidine-1-carboxamide, so pl. 135-137 ^o C;
3- (1- [4-methoxy-3- (4-methyl-1-piperazinyl) phenylaminocarbonyl] -4-piperidyl) indole-5-carboxy, mp 176-178 ^o C;
4- (4-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] piperidine-1-carboxamide dihydrochloride, mp. > 205 ^o C (decomposition);
4- (4-fluoro-3-indolyl) -N- [4-methoxy-3- (4-methyl-1-piperidinyl) phenyl] piperidine-1-carboxamide dihydrochloride;
[4-Methoxy-3- (4-methylpiperazin-1-yl) phenyl] 4- (7-methoxy-1H-indol-3-yl) piperidine-1-carboxylic acid amide, mp. 219-222 ^o C;
4- [2- (3-indolyl) ethyl] -N- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] piperidine-1-carboxamide,
t. pl. 200-202 ^o C;
4- [2- (3-indolyl) ethyl] -N- [4-methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] piperidine-1-carboxamide;
4- [2- (3-indolyl) ethyl] -N- [4-methoxy-3- (4-methyl-1-piperidinyl) phenyl] piperidine-1-carboxamide;
[4-Methoxy-3- (4-methyl-1-piperazinyl) phenyl] 4- (5-cyano-3-indolyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid amide, mp. 223-225 ^o C;
[4-Methoxy-3- (4-methyl-1-piperazinyl) phenyl] amide 4- [4- (5-fluoroindol-2-yl) butyl] piperazine-1-carboxylic acid dihydrochloride, mp. > 220 ^o C (decomposition);
[4-Methoxy-3- (4-methyl-1-piperidinyl) phenyl] amide 3- (5-fluoroindol-3-yl) pyrrolidin-1-carboxylic acid, mp. 210-213 ^o C;
4- (5-Fluoroindol-3-yl) piperidine-1-carboxylic acid (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide;
[4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] 4- [4- (5-cyano-3-indolyl) butyl] piperazine-1-carboxylic acid amide;
[4-methoxy-3- (4-methyl-1-piperidinyl) phenyl] 4- [4- (5-cyano-3-indolyl) butyl] piperazine-1-carboxylic acid amide;
[4-methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] 4- (5-cyano-1H-indol-3-yl) piperidine-1-carboxylic acid amide;
[4-methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] amide 4- (3-indolyl) piperidine-1-carboxylic acid;
[4-methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] amide 4- [4- (5-fluoro-1H-indol-3-yl) butyl] piperazine-1-carboxylic acid;
[4-methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] amide 4- [4- (5-cyano-1H-indol-3-yl) butyl] piperazine-1-carboxylic acid;
4- (5-cyano-1H-indol-3-yl) -piperidine-1-carboxylic acid (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide

4- (3-Indolyl) piperidine-1-carboxylic acid (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide;
(2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) 4- [4- (5-fluoro-1H-indol-3-yl) butyl] piperidine-1-carboxylic acid amide;
4- [4- (5-cyano-1H-indol-3-yl) butyl] piperidine-1-carboxylic acid (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide;
4- [3- (1H-indol-3-yl) propyl] piperidine-1-carboxylic acid (2,3-dihydro-1'-methylspiro (benzofuran) -3,4-piperidine) amide.

 Example 2

Аналогично получают следующие соединения:
N-[2-(5-гидрокси-3-индолил)этил] -N'-[4-метокси-3-(4-метил-1-пиперазинил)фенил]мочевину;
N-[4-(5-циано-3-индолил)бутил] -N'-[4-метокси-3-(4-метил-1-пиперазинил)фенил]мочевину;
N-[2-(5-фторо-3-индолил)этил] -N'-[4-метокси-3-(4-метил-1-пиперидинил)фенил]мочевину;
N-[2-(5-фторо-3-индолил)этил] -N'-[4-метокси-3-(N, N'-4-диметиламиноэтокси)фенил]мочевину;
N-{ 2-4-(6-фторо-3-индолил)пиперидин-1-ил] этил}-N'-[1'-метилпиперидин-3,4'-спиро-2,3-дигидробензофуран-5-ил]мочевину;
N-{ 2-[4-(6-фторо-3-индолил)пиперидин-1-ил] этил}-N'-[4-метокси-3-(4-метил-1-пиперазинил)фенил]мочевину, т. пл. 189-192 ^oC;
N-{ 2-[4-(6-фторо-3-индолил)пиперидин-1-ил] этил}-N'-[4-метокси-3-(4-метил-1-пиперидинил)фенил]мочевину;
N-{ 2-[4-(6-фторо-3-индолил)пиперидин-1-ил]этил}-N'-[4-метокси-3-(N,N'-4-диметиламиноэтокси)фенил]мочевину.Analogously to example 1, by reacting 1.17 g (4 mmol) of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline dihydrochloride, 2.0 ml (14 mmol) of triethylamine and 714 mg (4.4 mmol) of N , N'-carbonyldiimidazole in 35 ml of acetonitrile with 859 mg (4 mmol) of 5-fluorotriptamine hydrochloride and 1.1 ml (8 mmol) of triethylamine in 35 ml of acetonitrile, followed by recrystallization from ethyl acetate / petroleum ether, give N- [2- ( 5-fluoro-3-indolyl) ethyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea

The following compounds are prepared analogously:
N- [2- (5-hydroxy-3-indolyl) ethyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea;
N- [4- (5-cyano-3-indolyl) butyl] -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea;
N- [2- (5-fluoro-3-indolyl) ethyl] -N '- [4-methoxy-3- (4-methyl-1-piperidinyl) phenyl] urea;
N- [2- (5-fluoro-3-indolyl) ethyl] -N '- [4-methoxy-3- (N, N'-4-dimethylaminoethoxy) phenyl] urea;
N- {2-4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} -N '- [1'-methylpiperidin-3,4'-spiro-2,3-dihydrobenzofuran-5-yl urea;
N- {2- [4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} -N '- [4-methoxy-3- (4-methyl-1-piperazinyl) phenyl] urea, t pl. 189-192 ^o C;
N- {2- [4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} -N '- [4-methoxy-3- (4-methyl-1-piperidinyl) phenyl] urea;
N- {2- [4- (6-fluoro-3-indolyl) piperidin-1-yl] ethyl} -N '- [4-methoxy-3- (N, N'-4-dimethylaminoethoxy) phenyl] urea.

 Example 3

173 μl (1.2 mmol) of triethylamine and 230 mg (1.2 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride are added to a mixture of 314 mg (1.2 mmol) of 4- (5-fluoro- 1H-indol-3-yl) cyclohexanecarboxylic acid and 265 mg (1.2 mmol) of 4-methoxy-3- (4-methylpiperazin-1-yl) aniline in 40 ml of dichloromethane. First, this mixture was stirred at 0 ^{° C.} for one hour, and then at room temperature for 12 hours. The reaction mixture was concentrated, the residue was covered with ethyl acetate, and then the mixture was washed with a solution of water, 5% citric acid and saturated sodium hydrogen carbonate, dried and evaporated. Column chromatography separation yields [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] amide 4- (5-fluoro-1H-indol-3-yl) cyclohexanoic acid.

The following compounds are prepared analogously:
[4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] 4- (5-cyano-1H-indol-3-yl) cyclohexanoic acid amide,
[4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] 4- (6-fluoro-1H-indol-3-yl) cyclohexanoic acid amide,
[4-Methoxy-3- (4-methylpiperidin-1-yl) phenyl] amide 4- (5-fluoro-1H-indol-3-yl) cyclohexanoic acid,
[4-methoxy-3- (4-methylpiperidin-1-yl) phenyl] amide 4- (5-cyano-1H-indol-3-yl) cyclohexanoic acid,
[4-Methoxy-3- (4-methylpiperidin-1-yl) phenyl] amide 4- (6-fluoro-1H-indol-3-yl) cyclohexanoic acid,
[4-Methoxy-3- (N, N'-dimethylaminoethoxy) phenyl] amide 4- (5-fluoro-1H-indol-3-yl) cyclohexanoic acid,
2- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] acetamide,
2- [4- (5-fluoro-1H-indol-3-yl) piperidin-1-yl] -N- [3- (2-dimethylaminoethoxy) -4-methoxy-3-phenyl] acetamide,
2- [4- (1H-indol-3-yl) piperidin-1-yl] -N- [4-methoxy-3- (4-methylpiperazin-1-yl) phenyl] acetamide,
2- [4- (1H-indol-3-yl) piperidin-1-yl] -N- [3- (2-dimethylaminoethoxy-4-methoxy-3-phenyl] acetamide.

 The following examples relate to pharmaceuticals.

 Example A. Injection Vials.

 Using 2 n. hydrochloric acid, a pH of a solution of 100 g of the active compound of the formula I and 5 g of secondary sodium hydrogen phosphate in 3 l of double-distilled water is stabilized at 6.5, sterilized by filtration, poured into injection bottles, lyophilized and sterilely sealed. Each injection vial contains 5 mg of active compound.

 Example B. Suppositories.

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

 Example B. Solution.

A solution is prepared from 1 g of the active compound of the formula I, 9.38 g of NaH ₂ PO ₄ • 2H ₂ O, 28.48 g of NaH ₂ PO ₄ • 12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of twice distilled water. The pH of the solution is stabilized at around 6.8, supplemented to 1 liter and sterilized by radiation. This solution can be used in the form of eye drops.

 Example G. Ointment.

 500 mg of the active compound of formula I under aseptic conditions are mixed with 99.5 g of petrolatum.

 Example D. Tablets.

 A mixture of 1 kg of the active compound 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 conventionally compressed into tablets, each of which contains 10 mg of the active compound.

 Example E. Tablets with a shell.

 Analogously to Example D, tablets are pressed, after which they are coated in a conventional manner with a coating containing sucrose, potato starch, talc, tragacanth and dye.

 Example J. Capsules.

 2 kg of the active compound of the formula I are filled in the usual manner on hard gelatin capsules, each containing 20 mg of the active compound.

 Example 3. Ampoules.

 A solution of 1 kg of the active compound of formula I in 60 ml of twice distilled water is poured into ampoules, lyophilized under sterile conditions and sterilely sealed. Each ampoule contains 10 mg of active compound.

Claims (3)

1. Derivatives of amides and urea of the General formula I
R ¹ - (CH ₂ ) _n - (Y) _q - (Z) _r -CO-NH-R ² , (I)
in which R ¹ - 3-indolyl, unsubstituted or monosubstituted AO, Hal, CN, CONH ₂ ;
R ² represents

or

m is 1 or 2;
n is 0, 1, 2, 3 or 4;
Y is a 1,4-cyclohexylene, 1,3-pyrrolidinyl, 1,4-piperazinyl or 1,4-piperidinyl ring, which may also be partially dehydrogenated;
Z is (CH ₂ ) _n NH-;
q = 0 or 1;
r is 0 or 1;
R ³ - A;
R ⁴ is AO-;
Hal is F, Cl, Br or I;
And - unbranched or branched alkyl with 1-6 carbon atoms,
provided that q and r are simultaneously not equal to 0,
as well as their physiologically acceptable salts. 2. A method of obtaining compounds of formula I according to claim 1, characterized in that a) a compound of formula II
H ₂ NR ² , (II)
in which R ² has one of the meanings specified in paragraph 1 of the claims,
react with a compound of formula III
R ¹ - (CH ₂ ) _n - (Y) _q - (Z) _r -CO-L, (III)
in which L is Cl, Br, I, OH or OH group, functionally modified to give it reactivity [sic], or an easily nucleophilically substituted leaving group;
R ¹ , n, Y, q, Z and g have the meanings given in paragraph 1,
or with a component of formula IV
R ¹ - (CH ₂ ) _n - (Y) _q - (Z) _r -H, (IV)
in which R ¹ , R ² , n, Y, q, Z and r have the indicated meanings,
adding binder reagents, such as N, N'-carbonyldiimidazole, diphosgene, triphosgene or alternatively esters of chloroformic acid, and / or the resulting base or an acid of formula I by treatment with an acid or base is converted into one of his (her) salts. 3. A pharmaceutical preparation having antagonistic activity against 5-HT _{1b / D} and an inhibitory effect on secondary absorption of 5-HT, characterized in that it contains at least one compound of the general formula I and / or one of its physiologically acceptable salts in combination with at least one solid, liquid or semi-liquid excipients.

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