Derivatives of piperazine, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

The invention relates to piperazine derivatives of the formula I, in which R1denotes a substituted radicals CN or Hal indole-3-ilen residue, R2denotes unsubstituted 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl. Compounds are highly effective agonists 5-HT1Aand show inhibitory activity against reuptake of 5-HT. They can be used for treatment and prophylaxis of States of fear, depression, schizophrenia, neurosis, obsessions, to treat and deal with the consequences of stroke, in particular stroke and cerebral ischemia. Also described is a method of obtaining compounds and pharmaceutical composition thereof. 3 S. and 1 C.p. f-crystals, 1 PL.

The invention relates to piperazine derivatives of the formula I

< / BR>
in which R1denotes unsubstituted or one - or twofold substituted by the groups Hal, CN, A, AO, HE CONH2, CONHA, CONA2, COOH, COOA, CH2HE, CH2OA, CH2NH2CH2NHA and/or CH2NA2indole-3-ilen balance,

R2denotes unsubstituted or one - or twofold substituted by groups a, AO, HE, Hal, CN, NNHA, CH2PA2, COOH and/or cooa 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl, where Hal denotes F, Cl, Br or I and a denotes remotemachine or branched alkyl with 1-10 C-atoms which may be substituted by 1-5 F and/or Cl atoms, or cycloalkyl with 3-10 C-atoms,

and m denotes 2, 3 or 4,

and their physiologically acceptable salts.

The basis of the invention is to obtain new compounds with valuable properties, in particular such compounds, which could be used to manufacture medicines.

It has been found that the compounds of formula I and their physiologically acceptable acid additive salts have valuable pharmacological properties. The compounds of formula I act on serotonergic transmission. Due to the fact that these compounds inhibit the reuptake of serotonin, they are suitable primarily as antidepressants and anxiolytics. These compounds exhibit agonistic and antagonistic properties against serotonin. They inhibit the binding tretiranih ligands serotonin with hippocampally receptors (Cossery and other European Journ. Pharmacol. 140 (1987), pp. 143-155) and inhibit synaptic reverse zoom body and the accumulation of 5-HT (5-hydroxytryptamine) in different areas of the brain (Seyfried and others, European Journ. Pharmacol. 160 (1989), pp. 31-41). Antagonistic activity against 5-HT1Aconfirmed in vitro, for example, the inhibition caused by 8-OH-DPAT removal (termination) electroinductive ileal contractions in Guinea pigs (Fozard and Kiibinger, Br. Journ. Pharmacol. 86 (1985), R. 601). Confirmation antagonistic action against 5-HT1Aex vivo serve inhibition reduced under the action of 8-OH-DPAT to the accumulation of 5-NTR (Seyfried and others, European Journ. Pharmacol. 160 (1989), pp. 31-41) and antagonistic character induced by 8-OH-DPAT effects behavioral responses identified in test anxiety with recording ultrasonic vocalizations (DeVry. Psychpharmacol. 121 (1995), pp. 1-26). To confirm the inhibitory effect against serotonin reuptake ex vivo method used synaptic suppression of this capture (Wong and others, Neuropsychopharmacol. 8 (1993), pages 23-33) and antagonism towards p-chloroamphetamine (Fuller and others, Journ. Pharmacol. Exp. Ther. 212 (1980), pages 115-119). In addition, the observed analgesic and blood pressure-lowering effects.

Based on the foregoing proposed in the invention compounds can be used for the treatment of schizophrenia, disorders of cognitive abilities, state of fear, depression, nausea, Sanych memory impairment, psychosis, as well as to the positive impact on neurosis obsessive-compulsive disorder (obsessive-compulsive disorder, OCD) and disturbances in feeding behavior (e.g., bulimia). These compounds affect the Central nervous system, primarily for more agonistic activity against 5-HT1Aand the inhibitory effect on reuptake of 5-HT. Equally they can be used for the prevention and combat the effects of stroke (apoplexia cerebri), in particular stroke and cerebral ischemia, as well as for treatment extrapyramidal-motor side effects due to neuroleptic drugs (tranquilizers), and Parkinson's disease.

The compounds of formula I can be used both in veterinary medicine and in medicine for the treatment of functional disorders of the Central nervous system and inflammation. They are suitable for and is an symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. Effectively they can be used as therapeutic agents for the treatment of traumatic brain injuries and spinal injuries. In addition, they are suitable as active substances in which Oceania, neuroleptics, antihypertensives, and/or positive impact on neurosis obsessive-compulsive disorder, sleep disorders, slowed dyskinesia, a disorder in the learning process, age-related memory impairment, disturbance in feeding behavior, such as bulimia, and/or sexual disorders.

The object inventions are the compounds of formula I and their physiologically acceptable acid additive salt.

The object of the present invention are primarily compounds of formula I, selected from the group including

and) 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carbonitrile,

b) 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-5-Florinda,

in) 3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carbonitrile,

g) 3-{4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl} indole-5-carbonitrile,

and their physiologically acceptable salts.

For all residues, repeatedly present in the compounds, as, for example, And specify that their values do not depend on each other.

Balance And represents the alkyl has 1-10, preferably 1, 2, 3, 4, 5 or 6 and especially 1 or 2 C-atoms, so its main znacheniem.html, and 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-methylpropyl, 1,1,2 - or 1,2,2-trimethylpropyl, then vermeil, deformity, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoroethyl.

Cycloalkyl is a first, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-substituted.

OA represents preferably methoxy, and ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy. NHA is a preferred methylamino, then ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or tert-butylamino. NA2means preferably dimethylamino, then N-ethyl-N-methylamino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. On this basis, CO-NHA preferably denotes N-methylcarbamoyl or N-ethylcarbamate, a CO-NA2means preferably N,N-dimethylcarbamoyl or N,N-diethylcarbamoyl.

Hal represents fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, k represents 0 or 1, preferably 0, m hereafter the config or one - or twofold substituted, but above all, once substituted by a group of Hal, CN, A, AO, HE N2, CONHA, CONA2, COOH, COOA, CH2HE, CH2OA, CH2NH2CH2NHA and/or CH2NA22 - or 3-indolyl. Preferably indole residue in position 5, in position 6 or 7 substituted. The preferred values of R1are therefore the following: 2 - or 3-indolyl, 5 - or 6-methylindol-2-yl, 5 - or 6-methylindol-3-yl, 5 - or 6-methoxyindol-2-yl, 5 - or 6-methoxyindol-3-yl, 5 - or 6-hydroxyindole-2-yl, 5 - or 6-hydroxyindole-3-yl, 5 - or 6-Florinda-2-yl, 5 - or 6-Florinda-3-yl, 5 - or 6-laninga-2-yl, 5 - or 6-laninga-3-yl, 5 - or 6-Clorinda-2-yl, 5 - or 6-Clorinda-3-yl, 5 - or 6-carboxybenzoyl-2-yl, 5 - or 6-carboxybenzoyl-3-yl, 5 - or 6-methoxycarbonyl-2-yl, 5 - or 6-methoxycarbonylmethyl-3-yl, 5 - or 6-hydroxymethylene-2-yl, 5 - or 6-hydroxymethylene-3-yl, 5 - or 6-aminomethylphenol-2-yl, 5-or 6-aminomethylphenol-3-yl, 5 - or 6-bromoindole-2-yl, 5 - or 6-bromoindole-3-yl, 5 - or 6-ethylindole-2-yl, 5 - or 6-ethylindole-3-yl, 5 - or 6-cryptomaterial-2-yl, 5 - or 6-cryptomaterial-3-yl, 5 - or 6-isopropylindole-2-yl, 5 - or 6-isopropylindole-3-yl, 5 - or 6-dimethylaminoethyl-3-yl or 5 - or 6-dimethylaminoethyl-2-yl, 5 - or 6-taxiing-3-yl or 5 - is substituted by a group A, AO, HE, Hal, CN, NO2, NH2, NHA, NA2, COA, CONH2, CONHA, CONA2CH2OH, CH2OA, CH2NH2CH2NHA, CH2NA2, COOH and/or cooa 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl. Preferred as substituents of group a, AO, HE, Hal, CN, NH2, NHA, NA2or CH2HE. The preferred values of R2are therefore 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-yl, 7-hydroxy-2-oxo-2H-1-benzopyran-6-yl, 7-hydroxy-2-oxo-2H-1-benzopyran-4-yl, 7-fluoro-2-oxo-2H-1-benzopyran-6-yl, 7-fluoro-2-oxo-2H-1-benzopyran-4-yl, 5-fluoro-2-oxo-2H-1-benzopyran-6-yl, 6-fluoro - 2-oxo-2H-1-benzopyran-4-yl, 5-methyl-2-oxo-2H-1-benzopyran-4-yl, 7-methyl-2-oxo-2H-1-benzopyran-6-yl, 7-dimethylamino-2-oxo-2H-1-benzopyran-6-yl, 7-hydroxymethyl-2-oxo-2H-1-benzopyran-6-yl or 7-chloro-2-oxo-2H-1-benzopyran-6-yl.

For the invention is generally true that all residues, which can repeatedly be present in the molecule may be identical or different values, i.e., independently from each other.

In accordance with this object of the invention are such compounds of formula I in which at least one of these residues has one of the above preferred C is falling under formula I and where not deciphered more residues have the same value, as in the formula I, but there are some differences, namely:

in Ia R1denotes unsubstituted 3-indolyl;

in Ib R1in position 5 denotes a substituted 3-indolyl;

in the Ic k denotes 0, a m is 4;

in Id k denotes 1, and m is 3;

in Ie R has the meaning specified in Ib, and the Deputy is Hal, methoxycarbonyl, CN or carboxypropyl;

If R2denotes a 2-oxo-2H-1-benzopyran-6-yl;

in Ig R denotes a 2-oxo-2H-1-benzopyran-4-yl;

in Ih R2has the value specified in the If, but when in position 7 there is one Deputy;

in Ii R2has the value shown in Ig, but in position 7 there is one Deputy;

in Ij R2has the meaning specified in Ii, and the Deputy is Hal or HE.

The object of the invention is a method of obtaining derivatives of piperazine of the formula I and their salts. The method differs in that the compound of formula II

< / BR>
in which R2has the above meaning, is subjected to the interaction with the compound of the formula III

R1-(CH2)m-(CO)k-L, (III)

in which L denotes CL, Br, I, HE, OSOA, OCOPh, OSO2A, OSO2Ar, where Ar represents a phenyl or tolyl and the seat is returned leaving group, and R1, m and k have the meanings specified above,

or that by reductive amination of the compound of formula IV

R1-(CH2)m-1-CHO, (IV)

in which R1and m have the meanings indicated above is subjected to interaction with the compound of the formula II,

or that any compound falling within formula I, but instead of containing one or more hydrogen atoms of one or more recoverable groups and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent,

or that any compound falling within formula I, but instead of containing one or more hydrogen atoms of one or more solvolysis groups, is treated with a solvolysis agent,

and/or that under certain conditions the remainder R1and/or R2turn in the remainder R1and/or R2for example, by splitting OA-group with the formation of Oh-groups and/or by derivatization CN, COOH or cooa groups and/or by alkylation, for example, primary or secondary N-atom and/or by transformation of the received base or acid of formula I by treatment with acid or base in one of their salts.

The process poluchenii as Houben-Weyl, Methods der Organischen Chemie, published by Georg Thieme Verlag, Stuttgart; Organic Reactions, published by John Wiley & Sons, Inc., New York; DE-OS 4101686) when the conditions are known and suitable for the above exchange reactions. You can use these options, which in the present description are not mentioned in more detail.

Source materials required for carrying out the method, if necessary, can also be obtained in situ, not distinguishing them from the reaction mixture, and directly using the subsequent conversion into the compounds of formula I.

In the compound of formula III, the preferred value for the remainder of L is CL or Br, but it may be a first, HE or preferably reactionsare functionally modified IT group, primarily alkylsulfonate with 1-6 C-atoms (for example, methanesulfonate) or arylsulfonate with 6-10 C-atoms (for example, benzosulfimide, p-toluensulfonate, 1 - or 2-naphthalenesulfonate).

Source materials of formulas II and III, generally known; unknown same compounds of formulas II and III can be easily obtained analogously to known compounds.

Derivatives of piperazine of formula II for the most part ISV known methods. Thus, in particular, they can be obtained by the interaction of bis(2-chloroethyl)amine or chloride bis(2-chloroethyl)ammonium aminosilane benzopyranones connections.

Derivatives of indole of formula III is mostly known and partly also are commercially available products. In addition, these compounds can be obtained from known compounds by electrophilic, and in certain cases also by nucleophilic aromatic substitution. As a starting substance is used preferably corresponding indole-3-alanovoy acid (obtained analogously to the synthesis of indole Fisher (the type of the Japp-Klingemann), cf. etc., Journ. Med. Chem. 1992, 35, pages 4020-4026 or Iyer and others , Journ. Chem. Soc. Perkin Trans. II, 1973, pp. 872-878). Primary alcohols of the formula R1-(CH2)m-OH can be obtained, for example, the recovery of the corresponding carboxylic acids or their esters. By treatment with thionyl chloride, hydrogen bromide, tribromide phosphorus or any similar halogenosilanes receive the corresponding halides of the formula R2-(CH2)m-Hal. Appropriate sulfonylacetanilide can be obtained from alcohols interaction with the corresponding anhydrides of sulfonic acids.

1-(CH2)m-NH2can be obtained, for example, from halides using telemedcare or by restoring the corresponding NITRILES.

The interaction of the compounds of formulas II and III are carried out by the known methods used for alkylation, respectively acylation of amines. Components can be fused together in the absence of solvent under certain conditions in the tube or in an autoclave. But you can also make connections in the presence of a neutral solvent. As solvents are suitable, among others, for example, hydrocarbons, such as benzene, toluene, xylene; ketones, such as acetone, butanone; alcohols such as methanol, ethanol, isopropanol, n-butanol; ethers, such as tetrahydrofuran (THF) or dioxane; amides, such as dimethylformamide (DMF) or N-organic (N-MP); NITRILES, such as acetonitrile, while under certain conditions it is possible to use mixtures of these solvents among themselves or mixed with water. It may be appropriate to add acid binding agent, such as hydroxide, carbonate or bicarbonate of an alkaline or alkaline-earth metal, or any other salts of weak Kirichenko Foundation, such as triethylamine, dimethylaniline, pyridine or quinoline, or adding excess piperazine derivative of the formula II. Duration of response depending on the environment ranges from a few minutes up to 14 days, and the reaction temperature is in the range from approximately 0 to 150, usually from 20 to 130oC.

Under certain conditions prior to the implementation of this reaction is necessary before the process of alkylation or acylation to protect others contained amino groups, by introducing appropriate protective group. The concept of "aminosidine group" is well known and refers to groups that are capable of protecting the amino group from chemical reactions, but can be easily removed upon completion of the desired chemical reactions elsewhere in the molecule. As such protective groups, as well as methods for their introduction and removal are in principle known to the person skilled in the technical field of the numerous literary sources and textbooks, the need for a more detailed explanation disappears.

The compounds of formula I can be obtained, in addition, by reductive amination of compounds of the formula IV with compounds of the formula II. Educt of formula IV and II partially the tion can be performed in the presence of reducing agents, such as NaB3CN and NH(SLA)3.

Another possibility of obtaining the compounds of formula I is that forproduct that instead of hydrogen atoms contains one or more recoverable groups and/or one or more additional C-C and/or C-N-bonds is treated with a reducing agent, preferably at temperatures in the range from -80 to +250oWith the presence of at least one inert solvent. Recoverable (replaced by hydrogen) groups are primarily oxygen in a carbonyl group, hydroxyl, arylsulfonate (for example, p-toluensulfonate), N-benzazolyl, N-benzyl or O-benzyl.

In principle, compounds that contain only one or two or more of the above groups, respectively additional bonds, can be translated by a recovery in the compound of formula I, at the same time can recover the substituents in the group I contained in the initial connection. It is preferable to use the evolving hydrogen or complex hydrides of metals, in addition, it is possible to restore the wolf-Kishner, and also by means of gaseous hydrogen during the catalysis of periodoral, the latter can be formed, for example, by treating metals with weak acids or bases. For example, you can use a mixture of zinc with caustic lye or iron with acetic acid. Acceptable to use the sodium or other alkali metal dissolved in an alcohol, such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. In addition, there may be used aluminum alloy with Nickel in alkaline-aqueous solution, optionally with the addition of ethanol. For the formation of hydrogen is also suitable sodium amalgam or aluminum in aqueous-alcoholic or aqueous solution. The reaction can also be performed in a heterogeneous phase, it is reasonable to use water and benzene or toluene phase.

Along with these are particularly preferably used as reducing agents are complex metal hydrides, such as LiAlH4, NaBH4the hydride diisobutylaluminum or NaAl(OCH2CH2OCH3)2H2and DIBORANE, if necessary with the addition of catalysts, such as F3, AS3or LiBr. As solvents suitable for the above purposes are primarily ethers, in particular on the tee benzene. When restoring using NaB4preferred as solvents in the first place alcohols, such as methanol or ethanol, then water, and aqueous solutions of alcohols. The restoration of these methods is conducted preferably at temperatures in the range from -80 to +150, especially from about 0 to about 100oC.

In addition, some of the reactions on the restoration can be carried out using gaseous N2when catalysis by transition metals, such as Raney Nickel or Pd. With this technology, for example, Cl, Br, I, SH, and in certain cases, and the Oh-group can be replaced by hydrogen. Equally the nitro group by catalytic hydrogenation using Pd/H2in methanol to turn in NH2group.

Compounds falling within the principle under formula I, but instead of containing one or more H atoms of one or more solvolysis groups may be subjected to solvolysis and primarily hydrolysis of the obtained compounds of formula I.

In addition, one compound of formula I by known methods can be transformed into any other compound of formula I.

The compounds of formula I in which R1obousy substituted compounds of formula I by the partial hydrolysis. Another possibility is that lanzamiento the compounds of formula I first hydrolyzing to acids, which are then lidiruyut primary or secondary amines. Preferably the free carboxylic acid to expose the interaction with the amine under the conditions of peptide synthesis. This reaction is expedient to carry out preferably in the presence of a dehydration agent, such as carbodiimide, such as dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; these may also be used anhydride papapostolou acid (compare Angew. Chem. 92, 129 (1980)), diphenylphosphoryl or 2-ethoxy-N-etoxycarbonyl-1,2-dihydroquinoline in an inert solvent, for example in a halogenated hydrocarbon, such as dichloromethane, in a simple ether, such as THF or dioxane, in amide, such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures in the range of from approximately -10 to +40oC, preferably from 0 to 30oC. Instead of acid, respectively, instead of the amide in the reaction can be used as reactive derivatives of these substances, for example, those in which reactive groups are blocked at an intermediate stage protective groups. Acids can Ispolkom 1-hydroxybenzotriazole or N-hydroxysuccinimide. Thus, in particular, lanzamiento indole residues can hydrolyze to carboxyaniline or carboxamidotryptamine residues. But especially it is preferable to operate in the reverse sequence, i.e. to get the NITRILES due to removal of water from amides, for example, using trichloroacetamide/Et3N [see Synthesis (2), 184 (1985)] or l3(see Journ. Org. Chem. 26, 1003 (1961)).

Received under formula I, can be translated using acid to the corresponding acid additive salt. For the implementation of this reaction is suitable acids forming physiologically acceptable salt. Thus, in particular, it is possible to use inorganic acids, for example sulfuric acid, halogen acids such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, Sultanova acid, and also organic acids, specifically aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfo or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, encablossa acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalenamine and dissolvability, louisanna acid.

Free base of formula I can be liberated from their salts by treatment strong bases such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium, in cases where the molecule in the absence of other acid groups. In those cases where the compounds of formula I have free acid groups, by treatment with bases also can be used to form salts. As such grounds are suitable hydroxides of alkali and alkali-earth metals or organic bases as primary, secondary or tertiary amines.

The object of the invention is the use of compounds of the formula I and their physiologically acceptable salts for pharmaceutical compositions primarily non-chemical way. While one together with at least one solid, liquid and/or polozhitelnymi substances can be made appropriate dosage form.

Another object of the invention is the means, especially a pharmaceutical composition, containing in its composition at least one compound of the formula I and/or one of its physiologically acceptable salts. These compositions can be used as drugs in medicine and in veterinary medicine. As substances vehicles in them acceptable organic or inorganic substances suitable for enteral (for example oral), parenteral or local administration and not reacts with the new compounds, for example water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc, vaseline. For enteral introduction can be assigned primarily tablets, coated tablets, capsules, syrups, tinctures, drops or suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, further suspensions, emulsions or implants, for topical application can be assigned ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilizate be used, for example, for the manufacture of drugs for injection. Uxtv, as oiling agents, preservatives, stabilizers and/or wetting, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, colorants, flavorings and/or flavorings. Optionally, the composition can include several other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used in therapeutic applications for the treatment of humans and animals and to fight disease. They are suitable for the treatment of diseases of the Central nervous system, such as a state of tension, depression, fear, schizophrenia, disorders of gastrointestinal tract, nausea, slow dyskinesia, parkinsonism and/or psychosis, and to eliminate side effects in the treatment of hypertension (for example, -methyldopamine). In addition, the proposed connection can be used in endocrinology and gynaecology, for example for the treatment of acromegaly, hypogonadism, secondary amenorea, premenstrual syndrome, undesired puerperal (postpartum) lactation, in addition, for the prophylaxis and therapy of disorders related to cerebral vessels (e.g., migraine headaches), primarily as therapeutic agents to combat the effects of a stroke (apoplexia cerebri), in particular stroke and cerebral ischemia, and for the treatment of traumatic brain injuries and spinal injuries. But first of all they are suitable for use as active substances in such medicines as anxiolytics, antidepressants, tools, warning, psychotic state, and/or positive impact on neurosis obsessive-compulsive disorder (OCD), sleep disorders, slowed dyskinesia, a disorder in the learning process, age-related memory impairment, disturbance in feeding behavior, as, for example, bulimia, and/or sexual disorders.

Proposed in the invention substance prescribed as a rule, similar to known, commercially available products (such as bromocriptine, dihydroergocornine), preferably in dosages of from about 0.2 to 500 mg, especially from 0.2 to 50 mg per uniform dose. The daily dose is preferably from about 0.001 to 10 mg/kg weight of the patient. Low dosages are from about 0.2 to 500 mg, preferably from 0.2 to 50 mg per uniform dose. Low dosage (about 0.2-1 mg per uniform dose; approximately 0.001 to 0.005 mg/kg body weight) to designate this first of all the private dose. However, assigned to a particular patient dose depends on various factors, including the effectiveness of the applied compound, the patient's age, body weight, General state of health, sex, on the diet, on the time and method of administration, on the rate of excretion, combination of drugs and the severity of the corresponding disease, treatment is therapy. Preferably oral administration.

Under used in the following examples, the term "normal processing" we mean the following: if necessary, water is added, if necessary, depending on the structural characteristics of the final product set pH from 2 to 10, extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, evaporated and purified by chromatography on silica gel and/or by crystallization. Values of Rfwere determined using thin-layer chromatography on silica gel. The values of M++1 was identified by FAB-mass spectrometry (FAB means "the bombardment of accelerated atoms").

Example 1.

Dissolve 0,79 g (of 0.003 mole) of 4-(2-OK the N-1-benzopyrano] and 0.80 g (of 0.003 mole) of 3-(4-chlorobutyl)-5-caninde [which can be obtained by reduction of 3-(4-chlorobutanol)indole-5-carbonitrile] in 100 ml of acetonitrile, then add 0,50 ml (0,004 mol) of triethylamine and 1.20 ml (0,007 mole) of ethyldiethanolamine and stirred overnight on a steam bath. After the usual processing gain 3-{ 4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl]indole-5-carbonitrile, dihydrochloride, tPL284-285oC.

Similarly, get:

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-5-Florinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-5-chlorinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-5-methoxyindol,

3-(4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} -5-taxiing,

methyl ester 3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-6-Florinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-6-chlorinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}-6-methoxyindol,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl}-6-taxiing,

methyl ester 3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

3-{4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperidyl]butyl}-indole-6-carbonitridation analogously to example 1), of 7.70 g (0,033 mole) of 3-(4-chlorobutyl)-5-caninde (receipt see example 1), 6.7 g (of 0.066 mol) of triethylamine, and 11.3 ml of 0.066 mol) of ethyldiethanolamine and 55 ml of 1-methyl-2-pyrrolidone is stirred overnight at a bath temperature of 120-130oC. Then, the suspension is poured with stirring into 4 l of ice water, and after a long mixing receive crystal 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carbonitrile with tPL135-137oAnd in hydrochloride with tPL282-284oC.

Similarly, get:

3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}indole-5-carbonitrile, monohydrochloride, tPL287-290oWITH,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} -5-methoxyindol,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}-5-taxiing,

methyl ester 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} -6-methoxyindol,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}-6-taxiing,

methyl ester 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

3-{ 4-[4-(2-� (0,017 mole) of 4-(5-Florinda-3-yl)butyl ether methanesulfonate [produced by interaction of 4-(5-Florinda-3-yl)butanol (obtained by repair using a hydride layalina 4-(5-Florinda-3-yl)butane acid, which can be obtained by a reaction similar to the reaction of the Japp-Klingemann, THF) with the acid chloride of methansulfonate], 4.0 g (0,015 mol) of 4-(2-oxo-2H-1-benzopyran-6-yl)piperazine hydrochloride (getting analogously to example 1), 200 ml of acetonitrile and 10.0 ml of triethylamine is stirred for 30 h on the steam bath, thus exposing the components interact with each other. After the usual processing gain 3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}-5-Florinda, hydrochloride, tPL293-295oC.

Similarly, get:

3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-5-chlorinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-6-Florinda,

3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-6-chlorinda,

3-{ 4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole,

3-{ 4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-5-Florinda,

3-{ 4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-6-Florinda,

3-{ 4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-5-chlorinda,

3-{ 4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}-6-chlorinda.

Example 4.

A mixture of 0,0098 mole of 4-(5-methoxycarbonyl-2H-1-benzopyran-6-yl)piperazine is heated in acetonitrile for about 96 h on the steam bath. Then the reaction mixture is subjected to conventional processing and clean. In this way receive methyl ester 3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carboxylic acid.

Similarly, get:

methyl ester 3-{4-[4-(7-methyl-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{4-[4-(7-methyl-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

methyl ester 3-{ 4-[4-(7-cyan-2-OK the Piran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{4-[4-(7-methyl-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{4-[4-(7-methyl-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

methyl ester 3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid.

Example 5.

1.8 g methyl ester 3-{4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}indole-5-carboxylic acid is boiled for 1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid.

Similarly, get:

3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl}indole-6-carboxylic acid,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl}indole-5-carboxylic acid,

3-{ 4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl}indole-6-carboxylic acid,

3-{ 4-[4-(7-methyl-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-methyl-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carboxylic acid,

3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-5-carboxylic acid,

3-{ 4-[4-(1-benzopyran-6-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-6-yl)-1-pytrainer] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-methyl-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-methoxy-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-6-carboxylic acid,

3-{ 4-[4-(7-fluoro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-chloro-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-6-carboxylic acid,

3-{ 4-[4-(7-cyan-2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil] butyl} indole-6-carboxylic acid.

The following are examples of pharmaceutical compositions and technology of their preparation in the appropriate dosage forms.

Example: Vials for injection solutions

A solution of 100 g of the active substance of the formula I and 5 g of dinitrigenoxide in 3 l of double-distilled water using 2 N. hydrochloric acid set at pH 6.5, sterile filtered, filled flask, lyophilized in sterile sterile conditions and sealed. In each flask Sealy I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to harden. Each suppository contains 20 mg of active substance.

Example: Solution

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NH2RHO42H2Oh, 28,48 g Na2HPO412H2O and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. Then set to pH 6.8, adjusted to a volume of 1 l and sterilized by irradiation. This solution can be applied in the form of eye drops.

Example D: Ointment

When observing aseptic conditions prepare a mixture of 500 mg of the active substance of the formula I with 99.5 g of petroleum jelly.

Example D: Tablets

A mixture of 1 kg of active substance 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 tabletirujut by the conventional methods, receiving tablets, each containing 10 mg of active substance.

Example E: Bean

Analogously to example D is pressed tablets, which then according to standard technology is covered by a shell of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of active substance of the formula I according to conventional technology Isrotel the Example C: Ampoules

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

Were obtained the values of the IC50(concentration in mol/liter) for some typical representatives of compounds of formula I are presented in the table.

Presents experimental data demonstrate the inhibiting action against reuptake 5-HT, as well as act as agonists at 5-HT1Asome selected compounds claimed in the invention. The tests were carried out in accordance with the methods described earlier in this application. The results of the tests clearly demonstrate the value of the claimed compounds in terms of their potential use, especially as antidepressants and anxiolytics.

1. Derivatives of piperazine of the formula I

< / BR>
in which R1denotes a substituted radicals CN or Hal, indole-3-ilen balance,

R2denotes unsubstituted 2-oxo-2H-1-benzopyran-6-yl or 2-oxo-2H-1-benzopyran-4-Il,

where Hal denotes F, Cl, Br or I and m = 4,

as well as their Phi is CSR-2H-1-benzopyran-6-yl)-1-piperazinil]butyl}indole-5-carbonitrile,

b) 3-{ 4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil] butyl} -5-Florinda,

in) 3-{ 4-[4-(2-oxo-2H-1-benzopyran-4-yl)-1-piperazinil]butyl}indole-5-carbonitrile,

g) 3-{4-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-6-yl)-1-piperazinil]butyl} indole-5-carbonitrile,

and their physiologically acceptable salts.

3. The method of obtaining of piperazine derivatives of the formula I on p. 1 and their salts, which consists in the fact that the compound of formula II

< / BR>
in which R2has specified in paragraph 1 values, is subjected to the interaction with the compound of the formula III

R1-(CH2)m-(CO)k-L

in which R1has specified in paragraph 1 values

L denotes Cl, Br, J, OSO2A, A denotes alkyl, easy nucleophile substitutable leaving group,

k=0, m=4,

followed if necessary by turning the product into one of the salts.

4. The pharmaceutical composition inhibiting action on the reuptake of 5-HT, as well as possessing activity as agonists at 5-HT1A, characterized in that it contains at least one compound of General formula I and/or one of its physiologically acceptable salts.

 

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EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

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