Derivatives of 1-(n-phenyliminomethyl)piperazine and pharmaceutical composition

 

(57) Abstract:

The invention relates to derivatives of 1-(N-phenyliminomethyl)piperazine of the formula I, where R is H, alkyl -, cycloalkyl-substituted cycloalkyl-WITH or monocyclic heteroaryl-CO; R1Is h or lower alkyl; R2- halogen, alkoxy, phenoxy, NO2, CN, acyl, NH2, NH(acyl), alkyl-SO2NH, alkoxycarbonyl, NH2WITH, (alkyl)NHCO (alkyl)2NCO, (acyl)NHCO, CF3or polyporaceae; benzyl or mono - or bicyclic aryl, or heteroaryl, all of which are optionally substituted. Compounds active against 5-HT1Areceptors and are useful for the treatment of neuromuscular dysfunction of the lower urinary tract. Also described pharmaceutical composition based on compounds I. 2 C. and 5 C.p. f-crystals, 9 PL.

This invention relates to derivatives of 1-(N-phenyliminomethyl)piperazine, substituted in position 2 of the phenyl ring, containing their pharmaceutical compositions and to uses of such derivatives and compositions.

In mammals urination is a complex process that requires the integrated action of the bladder, the internal and external sphincter, the muscles of the IOM sphincter, in the Autonomous centers of the spinal cord and Central nervous system at the level relevant to varolii bridge center urination (PMC) in the brain stem (Pons varolii) under the control of the cerebral cortex (De Groat, Neurobiology of Incontinence, Ciba Foundation Symposium 151: 27, 1990). Urination is the result of contraction of the muscles of the sphincter, which consists of interwoven fibers smooth muscle, under parasympathetic autonomic control of the sacral spinal cord. Simple reflex emptying (voiding) is formed sensory nerves that perceive pain, temperature and tension that goes from the bladder to the sacral spinal cord. However, sensory tracts from the bladder reaches also PMC, leading to the generation of nerve impulses, which usually inhibit the sacral spinal reflex arc, controlling the emptying of the bladder. Thus, the urine is initiated voluntary suppression of cortical inhibition of this reflex arc and relaxation of the muscles of your pelvic floor and external sphincter. Finally, the muscle is the sphincter is reduced and the emptying of the bladder.

Abnormalities of the lower urinary tract, such is Ascania, nycturia and the urge to urinate and may be caused by cystitis, prostatitis or benign prostate hypertrophy (national Department of standardization) (which affects approximately 70% of older men) or neurological disorders. Syndrome urinary incontinence include stress incontinence (during coughing or other efforts), incontinence associated with urge for urination, and urinary incontinence due to overflow of the bladder (the paradoxical Isuzu). Enuresis is called involuntary emission of urine at night or during sleep.

Earlier treatment of neuromuscular dysfunction of the lower urinary tract included the introduction of compounds that act directly on the muscles of the bladder, such as flavoxate, antispasmodic drug (Ruffman, J. Int. Med. Res., 16:317, 1988), also active against PMC (Guarneri et al., Drugs of Today 30:9, 1994), or anticholinergic compounds, such as oxybutynin (Andersson, Drugs, 35:477, 1988). The antagonists1-adrenergic receptors to ensure national Department of standardization is also normal, but based on a different mechanism of action (Lepor, Urology, 42:483, 1993). However, treatments that involve direct inhibition of the muscles of the pelvis (including muscle-simate tachycardia and dry mouth (Andersson, Drugs, 35:477, 1988). Thus, it would be useful if they were available compounds that act through peripheral or Central nervous system, for example, to influence the sacral spinal reflex arc and/or pathway inhibition PMC thus, to restore the normal functioning of the mechanism of urination.

1-(N-Phenyl-N-cyclohexylcarbonyl-2-amino-ethyl)-4-(2-methoxyphenyl)piperazine (compound A)

< / BR>
described in GB 2263110, and States that he is an antagonist of 5-HT1-receptor. Also revealed that it can be used for the treatment of disorders of the Central nervous system, for example, as an anxiolytic agent (tranquilizer) in the treatment of anxiety.

The compounds of this invention, described below, are structurally different compounds And, as in position 2 aniline rings are new Deputy. Other differences between the compounds of this invention and the compounds described in GB 2263110 are substitution in the aromatic ring at position 4 piperazinovogo ring. These structural variations are not described and not assumed by the patent GB 2263110, in particular, compounds that can be used to Ulu is passed, than the connection And, in pharmacological tests that predict their activity in relation to lower urinary tract, in particular, against incontinence of urine.

Other compounds that were found by the authors of this invention are useful in the methods of the present invention, for example in the treatment of disorders of the urinary tract, described in US 4205173, EP 711757, DE 2405441, US 3472854, Chem. Pharm. Bull., 33:1826-1835 (1985) and J. Med. Chem., 7:721-725 (1964), which are incorporated here by reference.

In one aspect this invention relates to the use of compounds of General formula I

< / BR>
where R denotes cycloalkylcarbonyl, substituted cycloalkylcarbonyl or monocyclic heteroarylboronic group having 5-7 ring atoms,

R1denotes a hydrogen atom or a lower alkyl group,

R2denotes a halogen atom or alkoxy, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulfonyl, alkoxycarbonyl, carbarnoyl, allylcarbamate, dialkylamino, arylcarbamoyl, trifluoromethyl or polyporales and

In denotes a mono - or bicyclic (C6-C12)-aryl group, a monocyclic heteroaryl group having 5-7 ring atoms, a bicyclic, heteroaryl is substituted, to obtain medicines for treating neuromuscular dysfunction of the lower urinary tract of a mammal.

In another aspect the invention relates to compounds of General formula I (shown above), where R denotes cycloalkylcarbonyl, substituted cycloalkylcarbonyl or monocyclic heteroarylboronic group having 5-7 ring atoms,

R1denotes a hydrogen atom or a lower alkyl group,

R2denotes a halogen atom or an alkoxy group, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulfonyl, alkoxycarbonyl, carbarnoyl, allylcarbamate, dialkylamino, arylcarbamoyl, trifluoromethyl or polyporales and

In denotes a mono - or bicyclic (C6-C12)-aryl group, a monocyclic heteroaryl group having 5-7 ring atoms, a bicyclic heteroaryl group having 9-12 ring atoms, or benzyl group, each of which may be substituted or unsubstituted, provided that, if In denotes alkoxy-substituted aryl group, this alkoxygroup must be in position 2 aryl rings.

The invention also includes the enantiomers, diastereomers, N-oxides,soedinenii, having the same type of activity (hereinafter sometimes referred to as "active metabolites").

This invention further relates to pharmaceutical compositions containing a compound of the formula I or an enantiomer, diastereoisomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

As used in the description in the definition of R, cycloalkylcarbonyl includes cyclohexylcarbonyl, substituted cycloalkylcarbonyl includes cyclohexylcarbonyl, substituted alkyl or aryl group, and a monocyclic heteroaryl radicals contain one or more heteroatoms (such as oxygen, nitrogen and sulfur). Monocyclic heteroarylboronic has the same definition as monocyclic heteroaryl, but also contains a carbonyl group attached to a carbon atom of the ring.

As used in the description in the definition, examples, mono - or bicyclic (C6-C12)-aryl groups are phenyl and naphthyl. Preferred substituents for the aryl radicals include lower alkyl, lower alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), lower halogenoalkane (afripolitan in the description in the definition, monocyclic heteroaryl radical has the same meaning as R above, and bicyclic heteroaryl radical denotes a bicyclic aromatic radical containing one or more heteroatoms (e.g. nitrogen, oxygen, sulfur) and 9-12 ring atoms.

Preferred substituents for the benzyl groups are alkyl, alkoxy, halogen, nitro, cyano, amido, amino, alkylamino, acylamino, alkylsulfonyl or acyl.

Preferred substituents for b are optionally substituted monocyclic aryl and bicyclic heteroaryl. The most preferred substituents for b are alkoxyphenyl and monoisostearate bicyclic heteroaryl.

R preferably denotes cyclohexylcarbonyl, 1-methylcyclohexylamine, 1-phenylcyclohexylamine, 3-fullcarbon, 3-thienylboronic, 4-pyridylcarbonyl, 3-pyridylcarbonyl or 2-pyrazinecarboxamide.

R1preferably denotes a hydrogen atom or methyl group.

R2preferably denotes an iodine atom or methoxy, phenoxy, nitro, cyano, acetyl, amino, acetamido, acetoxymethyl, carbarnoyl, ethylcarbitol, dimethylcarbamoyl, cyclohexyl 2-methoxyphenyl, 2.5-dichlorobenzyl or 4-indolyl.

The compounds of this invention are useful for the treatment of neuromuscular dysfunction of the lower urinary tract, including (without limitation) dysuria, incontinence and enuresis. They can be used to facilitate at least one of these dysfunctions, as the urge to urinate, increased frequency of urination, incontinence, leakage of urine, enuresis, dysuria, urinary retention and difficulty in emptying the bladder.

The compounds of this invention are useful for blocking serotonergic 5-HT1receptors and, as a result of this inhibitory activity for the treatment of disorders of the Central nervous system, due to serotonergic dysfunction, such as anxiety, depression, hypertension, disturbance of a cycle of sleep/wakefulness, eating disorders, sexual function and cognitive abilities mammals, in particular humans.

All patents, patent applications and literature sources are given in the description, are included as references in their entirety. In the event of any inconsistency will prevail this description, including definitions.

This invention includes pharmaceutical compositions containing the bottom of the urinary tract such as dysuria, urinary incontinence, enuresis, etc. includes Dysuria urinary frequency, nycturia (nocturnal polyuria), urination and difficulty in emptying the bladder, i.e., discarding suboptimal volume during urination.

Symptoms of incontinence include stress incontinence (during coughing or other efforts), incontinence associated with urge for urination, and urinary incontinence due to overflow of the bladder (the paradoxical Isuzu). Enuresis is called involuntary emission of urine at night or during sleep.

Without claims on theory the inventors believe that the introduction of antagonists of 5-HT1Areceptors of this invention prevents unwanted activity of the sacral reflex arc and/or cortical mechanisms that control urination. Thus, it is expected that a large range of neuromuscular dysfunctions of the lower urinary tract can be treated with compounds of this invention.

"Effective amount" of a compound for the treatment associated with urination disorder is a number that results in a measurable relief of at least od what about the disorder can be easily determined by empirical methods, well-known experts in this field, for example by establishing a matrix of dosages and frequencies of administration and a comparison group of experimental units or subjects with each position in the matrix. The exact amount that must be administered will vary depending on the condition and severity of the disorder and physical condition of the patient. Measurable weakening any symptom or parameter can be determined by a physician with expertise in this area or reported by the patient to the doctor. It should be clear that any clinically or statistically significant reduction or relief of any symptom or parameter of disorders of the urinary tract is within the scope of this invention. Clinically meaningful reduction or relief means perceived by the patient and/or physician relief.

For example, one patient may suffer from several symptoms of dysuria simultaneously, such as, for example, urination and excessive frequency of urination, any or both of which may be reduced using the methods of the present invention. In case of any reduction in incontinence frequency or volume of unwanted discharge of urine is considered as a beneficial effect of these methods l is physiologically acceptable carrier, such as, for example, phosphate buffered saline or deionized water. The pharmaceutical composition may also contain fillers, including preservatives and stabilizers, which are well known in this field. These compounds can be prepared in the form of a solid oral or separarely dosage units, such as, for example, tablets, capsules, powders and suppositories, and may additionally include fillers, including without limitation lubricating substance (substances), plasticizer (plasticizer), dye (dyes), amplifier (amplifiers) absorption, bactericide (bactericides), etc.

Methods of administration include oral and enteral, intravenous, intramuscular, subcutaneous, percutaneous, TRANS-mucosal (including rectal and buccal) and the introduction of inhalation. Preferably use the oral or dermal route of administration (i.e., using solid or liquid oral compositions or skin patches, respectively).

The amount of administered agent may be in the range between ~0.01 and ~ 25 mg/kg / day, preferably between ~0.1 and ~10 mg/kg / day and most preferably between ~0.2 and ~5 mg/kg / day. Must be ponat which is an effective treatment for this disorder, as such an effective amount can be achieved by the introduction of multiple doses of such pharmaceutical compositions.

In a preferred embodiment of the present invention compounds are prepared in the form of capsules or tablets, each of which preferably contains 50-200 mg of the compounds of the invention, and most preferably are introduced to the patient at a total daily dose of 50-400 mg, preferably 150-250 mg and most preferably about 200 mg to facilitate urinary incontinence and disorders amenable to treatment with the ligands of the receptor 5-HT1A.

Methods, tables and examples below are for a more complete description of the preferred variants of the present invention and demonstrate its benefits and applicability without limitation whatever way the scope of the invention.

THE SYNTHESIS OF COMPOUNDS OF THE INVENTION

The compounds of this invention can be obtained by methods illustrated in the following diagrams reactions, or using their modifications using readily available starting materials, reagents and methods of synthesis are well known to specialists in this field.

Unless otherwise indicated, the substituents of the compounds and Probab synthesis of compounds of formula I is depicted in Scheme I.

Ortho-substituted anilines of the formula II (Y-NH2) alkylate 1,-disubstituted alkanes (Z) to obtain the product III. The reaction is carried out in an inert organic solvent, preferably a polar aprotic solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dioxane, tetrahydrofuran (THF), acetone, acetonitrile, or chlorinated solvents such as dichloromethane, chloroform, 1,2-dichloroethane, or proton solvent such as n-butanol (n-VION). The reaction is usually carried out at 0-120oWith the presence of a proton acceptor, such as triethylamine (Et3N), diisopropylethylamine or etc., and optionally in the presence of potassium iodide.

In compounds of formula Z, X and X1can be C1, Br, I, aryl or alkylsulfonyl. Intermediate products of the formula III used in the alkylation of suitable derivatives of piperazine IV with obtaining compounds of formula X.

The alkylation can be carried out in a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane, or in a polar aprotic solvent such as DMF, THF, acetone, acetonitrile, or in proton polar solvent, such as n-VION, etc. or apolar solvent, such Et3N, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, etc., and optionally in the presence of potassium iodide.

Piperazines of formula IV, which are not commercially available, can be obtained by reaction of the appropriate B-NH2-derivatives (which can usually be easily obtained by reduction of the corresponding IN-NO2-derivatives) with bis-(2-chloroethyl)amine or bis-(2-hydroxyethyl)amine in the presence of excess hydrogen chloride. These reactions can be carried out in aprotic solvents such as dimethylformamide, diglyme (dimethyl ether of diethylene glycol), or toluene, at a temperature between 40oC and the boiling point of the solvent, usually in the presence of a base such as potassium carbonate, cesium carbonate, or etc., and optionally in the presence of potassium iodide.

The compounds of formula V can be appropriately obtained from compounds V as starting compounds in which X represents COO-lower alkyl and n denotes n-1. Conventional recovery methods (for example, the use of Li-dealuminated or other hydrides of metal complexes) gives the corresponding compound V in which X represents CH2HE and n is n-1, which can byto above. Source esters can be obtained by the nucleophilic substitution of monosubstituted piperazine suitable for 2-halogenated.

Alternative methods of producing compounds of formula V are suitable alkylation monosubstituted derivatives of piperazine compound of the formula X-CH(R1)(CH2)n-1CH2-OPrG or X-(CH2)nCH(R1)-X, where X denotes a leaving group, n is above a certain value and PrG denotes a protective group (for example, O-tetrahydropyranyl), which can be removed after alkylation of the piperazine.

Another method for the synthesis of intermediate compounds of formula III includes the use of raw materials with structure II (Y is halogen). These source materials interact with compounds of formula Z, where X and X1represent, respectively, the NH2and HE. This alkylation reaction is carried out in an aprotic solvent such as DMF, toluene, or proton polar solvent, such as n-VION and so on, when 40-140oWith usually using one equivalent or an excess of the reagent of formula Z (X=NH2as the proton acceptor, as described in G. Doleschall et al., Tetrahedron, 32, 57-64 (1976). Received aminoalcohols fo the formation of intermediate products of the formula III (X1=CL), or with alkyl - or arylsulfonate with the formation of the corresponding sulfonylation. These reactions are carried out in an aprotic solvent, such as chloroform, DMF, pyridine, etc. at a temperature between 50oC and the boiling point of the solvent.

The compounds of formula X can also be obtained by alkylation of compounds of formula II (Y=NH2) intermediate products of the formula V in which R1and n are as defined above meanings and X is a halogen atom such as chlorine or bromine, or a leaving group, such as methanesulfonate - or p-toluensulfonate.

These reactions can be carried out without solvent or in an aprotic solvent such as dichloromethane, chloroform, DMF, THF, acetone, acetonitrile, or in proton solvent such as n-butanol, and so on, when 0-160oWith not necessarily in the presence of a proton acceptor, such as Et3N, potassium carbonate, cesium carbonate, 4-dimethylaminopyridine, etc., and optionally in the presence of potassium iodide.

The compounds of formula I, where R2CN can also be obtained from compounds of the formula I, in which R2- CONH2, reactions of dehydration. P2O5, l5, RH3R and such can bihydrate can be carried out in a chlorinated solvent, such as dichloromethane, chloroform, carbon tetrachloride, or in an aprotic solvent such as DMF, toluene, etc. at a temperature between 40oC and the boiling point of the solvent, optionally in the presence of a base such as Et3N

Alternative compounds of formula X can be obtained by AllYouNeed intermediates of formula V (X=NH2) the starting material of formula II (Y= Cl, Br, F, I or tripterocalyx). These reactions can be carried out using the same solvents and conditions, which are described above, or using catalysis palladium complex compound (Synlett, p. 329 (1996)).

The compounds of formula X acelerou to obtain compound I by reaction of c with a suitable allelochemical R Hal in which R' is cycloalkylcarbonyl or monocyclic heteroarylboronic and Hal is a halogen atom. This reaction can be carried out in aprotic solvents such as dichloromethane, chloroform, 1,2-dichloroethane, DMF, acetone, acetonitrile, toluene, etc. at 0-100oWith not necessarily in the presence of an organic base as a proton acceptor, such as Et3N, diisopropylethylamine (DIPEA), 4-dimethylaminopyridine and the like.

Alternative soedineniya, can be used for the synthesis of compounds of formula I in which R2- CN, CONH2THE PINES3or SOON3by reaction with reagents such as trimethylsilyltriflate and tert-utility (J. Org. Chem., 55, 3114 (1990)), the lithium cyanide and tetrakis(triphenylphosphine)palladium(0) (EP 711757), carbon monoxide methanol and palladium diacetate, in the presence of 1,3-diphenylthiophene (J. Org. Chem., 59, 6683 (1994)). Such reactions can be carried out in a polar or apolar solvent, such as THF, toluene, benzene, DMSO and the like.

Another method of synthesis of compounds of formula I in which R1- N, shown in Scheme 2.

Ortho-substituted halogenases formula II (Y is halogen) is used to arilirovaniya protected aminoacetaldehyde formula VII (X = NH2) to obtain the corresponding protected arylaminoquinolines formula VIII. This reaction can be carried out in an aprotic solvent such as pyridine, DMF, toluene, or similar, when 40-120oWith not necessarily in the presence of a base such as Et3N, or with the use of palladium complex catalysts as described above.

Another way of obtaining the intermediate compounds of the formula VIII is the alkylation of compounds of formula II (Y=NH2) EIT experts in the field. The compounds of formula VIII are stable and free from the protective groups by standard methods before use in the next stage.

The aldehydes of formula VIII', obtained by removing the protective groups of compounds of formula VIII can communicate without extracting with N-substituted piperazines IV under reducing conditions to form compounds of formula XI. These reactions can be carried out in polar solvents, such as methanol, ethanol, or in chlorinated solvents such as dichloromethane, chloroform and the like, using borohydride alkali metals, such as NaBH4and NaBH3CN, N(SLA)3or using complexes Baranov, such as NR3-Py, optionally in the presence of an acid promoter, such as acetic acid, at 10-100oC.

The compounds of formula XI can be etilirovany R Hal obtaining compounds of the formula I carrying out reactions in the same conditions described above for end-stage Scheme 1. Alternative intermediate products of the formula VIII can be etilirovany R Hal obtaining compounds of formula IX using the same conditions described above.

Intermediate p is the group in the final stage of obtaining the corresponding aldehydes (IX'), which can interact with the appropriate N-substituted-piperazines of formula IV using borohydride alkali metals, such as NaBH4and NaBH3CN or Na(SLA)3not necessarily in the presence of catalytic amounts of acetic acid or containing titanium catalyst, such as tetraisopropoxide titanium, to form compounds of formula I. These reactions can be carried out in a chlorinated solvent such as dichloromethane or chloroform, or in polar aprotic solvents, such as methanol or ethanol, at 10-100oC.

Example 1.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A mixture of 3.03 g of 2-chloro-1-nitrobenzene, to 4.52 g of 1-(2-amino-ethyl)-4-(2-methoxyphenyl)-piperazine and 3,18 g of anhydrous potassium carbonate in 30 ml of n-butanol was stirred for 32 hours at the boil under reflux. After cooling, the mixture was poured into water, then extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. The crude product obtained by evaporation of the solvent, was purified flash chromatography (ethyl acetate: petroleum ether 4:6) and the residue obtained after evaporation of the solvent, was dissolved in dipiperidino. So pl. 117-118oC.

1H-NMR (CDC13, ): 8,50 ((CL, 1H, NH), 8,19 (d, 1H, aniline H3), was 7.45 (DD, 1H, aniline H5), 7,08-of 6.78 (m, 5H, h6 aniline and SN metoksifenilny ring), 6,63 (DD, 1H, aniline H4), 3,86 (s, 3H, och3), 3,40 (dt, 2H, ), 3,27 totaling 3.04 (m, 4H, piperazine protons), 2,80-2,62 (m, 6N, and piperazine protons).

Cyclohexylcarbodiimide (0,98 ml) and triethylamine (1,03 ml) were added sequentially to a solution containing 2.1 g of the compound obtained as described above and 15 ml of 1,2-dichloroethane. The mixture was stirred for 16 h at boiling under reflux. After that it was cooled, diluted with chloroform, washed with 1 N. sodium hydroxide and water. The organic phase was dried over anhydrous sodium sulfate and the crude product obtained after evaporation of the solvent, was purified flash chromatography (ethyl acetate: petroleum ether 1:1) and then were led out of cyclohexane with getting to 1.79 g (65%) specified in the connection header.

1H-NMR (CDC13, ): of 8.04 (d, 1H, H3 nitroaniline ring), 7,65-7,47 (m, 3H, H4,5,6 nitroaniline ring), 7,10 to 6.75 (m, 4H, CH metoksifenilny ring), 4,15-to 3.92 (m, 1H ), 3,83 (s, 3H, och3), 3,70-to 3.50 (m, 1H ), 3,10-2,80 (m, 4H, piperazine protons), 2,80-to 2.40 (m, 6N, piperazine protons ), 2,10-0,75 (m, 11N, the proton is nogitaclue, so pl. 183-187o(Acetone: diethyl ether);

nanomeasurement, so pl. 150-153oC (acetone);

monoethanolamine hydrate, so pl. 136-140oC.

Example 2.

1-[N-(2-Trifloromethyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A solution of 2.09 g of 2-triphtalocyaninine and 3.15 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-piperazine in 20 ml of n-butanol was stirred at 100oC for 2 hours Then the mixture was cooled, diluted with water, podslushivaet 2 N. sodium hydroxide and was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, was evaporated to dryness and the crude product was purified flash chromatography (ethyl acetate: petroleum ether 3: 7) and then was led from ethanol to obtain 0.55 g (12%) 1-[N-(2-trifloromethyl)-2-amino-ethyl] -4-(2-methoxyphenyl-piperazine. The melting point of 69.5-71oC.

1H-NMR (CDC13, ): 8,02-a 7.85 (W, 1H, NH), 7,43-7,27 (m, 2H, CH aniline), 7,03-to 6.80 (m, 4H, CH metoksifenilny ring), 6,72 (DD, 1H, CH aniline), to 6.57 (t, 1H, CH aniline), 3,86 (s, 3H, och3), 3,43 is 3.23 (m, 2H, ), 3,23-3,03 (m, 4H, piperazine protons), 2,85-2,60 (m, 6N piperazine protons ).

Specified in the title compound was obtained according to the method described in the second stage of Example 1 is isano above, used instead of 1-[N-(2-nitrophenyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine and 4-dimethylaminopyridine was used instead of triethylamine, and the mixture was boiled for 1.5 h under reflux. The crude material was purified flash chromatography (ethyl acetate: petroleum ether 4: 6). Yield 44%.

1H-NMR (CDC13, ): of 7.48-7,25 (m, 4H, CH cryptomaterial ring), 7,02-for 6.81 (m, 4H, CH metoksifenilny ring), 4,40-4,20 (m, 1H, ), of 3.84 (s, 3H, och3), 3,36-3,18 (m, 1H ), 3,10-2,90 (m, 4H, piperazine protons), 2,75 at 2.45 (m, 6N, piperazine protons ), 2,03 and 1.80 (m, 1H, SNA(Oh)), a 1.75-to 0.80 (m, 10H, cyclohexyl protons).

Example 3.

1-[N-(2-Phenoxyphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine

Acting as described in the first stage of Example 2, but using 2-phenoxyimino instead of 2-triphtalocyaninine received crude 1-[N-(2-phenoxyphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine. It was purified flash chromatography (ethyl acetate). The residue was dissolved in ethanol, the solution was acidified using 2 n solution of hydrogen chloride in ethanol and then added diethyl ether to obtain 45% of 1-[N-(2-phenoxyphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine. NS after filtration. The point of plaul the 6,85 (m, M, aromatic), to 6.80 (DD, 1H, aromatic), 6,63 (t, 1H, aromatic), of 3.78 (s, 3H, och3), the 3.65-3,00 (m, N, piperazine protons ).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-phenoxyphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine, and the mixture was heated for 2.5 h under reflux. The crude material was purified flash chromatography (ethyl acetate: petroleum ether 7:3). Yield 32%.

1H-NMR (CDC13, ): 7,40-7,20 (m, 4H, aromatic), 7,10 (t, 2H, aromatic), 7,05-to 6.80 (m, 7H, aromatic), 4,21-a 4.03 (m, 1H ), 3,83 (s, 3H, och3), 3,55 is 3.40 (m, 1H ), 3,10-of 2.93 (m, 4H, piperazine protons), of 2,75 2,50 (m, 6N, piperazine protons ), 2,25-2,05 (m, 1H, SNA(O)), 1,80-to 0.80 (m, 10H, cyclohexyl protons).

Example 4.

1-[N-(2-Itfeel)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-(2-Itfeel)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that 2-iodoaniline used instead of 2-triphtalocyaninine and that the heating assistir 1:4). Yield 37%.

1H-NMR (CDC13, ): the 7.65 (DD, 1H, aniline H3), 7,20 (DD, 1H, aniline H5), 7,07-to 6.80 (m, 4H, CH metoksifenilny ring), 6,55 (DD, 1H, aniline H4), of 6.45 (DD, 1H, N6 aniline), 5,15-5,03 (W, 1H, NH), a 3.87 (s, 3H, och3), 3,30 was 3.05 (m, 6N, piperazine protons ), 2,83-to 2.65 (m, 6N, piperazine protons ).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-itfeel)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine, and the mixture was heated for 7 hours under reflux. The yield was 73%.

1H-NMR (CDC13, ): of 8.95 (DD, 1H, H3 idfamilia ring), 7,45-7,35 (m, 2H, CH idfamilia ring), 7,15-to 6.80 (m, 5H, CH metoksifenilny ring and the remaining SN idfamilia ring), 4,53-4,37 (m, 1H, ), of 3.84 (s, 3H, och3), 3,20-2,95 (m, 5H, protons of piperazine), 2.77-to of 2.50 (m, 7H, protons of piperazine and SNA(O)), 1,90-to 0.80 (m, 10H, cyclohexyl protons).

Example 5.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(4-indolyl)piperazine

Mixture of 0.49 g of N-(2-chloroethyl)-2-nitroaniline, obtained in accordance with the method described by G. R. Ramage et al., in J. Informatica, boiled under reflux with stirring in a nitrogen atmosphere for 2.5 hours After cooling at room temperature the mixture was poured into water and was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (ethyl acetate: petroleum ether 3:7) to obtain 0.35 g (40%) 1-[N-(2-nitrophenyl)-2-amino-ethyl]-4-(4-indolyl)piperazine.

1H-NMR (CDC13, ): 8,60-8,45 (W, 1H, NH aniline), 8,18 (DD, 1H, aniline H3), 8,20-8,10 (W, 1H, NH of indole), the 7.43 (TD, 1H, H5 aniline), 7,20-7,05 (m, 3H, H3,6,7 indole), 6,85 (DD, 1H, aniline H4), 6,70-to 6.57 (m, 2H, N6 aniline and H5 indole), of 6.50 (t, 1H, H2 indole), 3,45 (2N, ), 3,35-of 3.25 (m, 4H, piperazine protons), 3,85-2,70 (m, 6N, and piperazine protons).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-itfeel)-2-amino-ethyl] -4-(4-indolyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine, and the mixture of formamide was heated for 5 h under reflux. The crude material was purified flash chromatography (ethyl acetate: petroleum ether 7:3, then used only the ethyl acetate and in the end only 7,65 was 7.45 (m, 3H, H4,5,6 nitroaniline ring), 7,20-7,00 (m, 3H, H3,6,7 indole), 6,55 (DD, 1H, H5 indole), of 6.50 (t, 1H, H2 indole), 4,15-3,95 (m, 1H, ), 3,70-3,55 (m, 1H, ), 3,25-2,95 (m, 4H, piperazine protons), 2,75 at 2.45 (m, 7H,) CHC(O), piperazine protons), 2,10-to 0.80 (m, 10H, cyclohexyl protons).

Example 6.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2,5-dichlorobenzyl)-piperazine

2.5-DICHLOROSILANE (2,01 g) was added to a mixture of 1.94 g of 1-ethoxycarbonylpyrimidine and 3.45 g of anhydrous potassium carbonate in 20 ml of dimethylformamide and stirred at room temperature under nitrogen atmosphere. After 24 h stirring at the same temperature, the reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase, which was dried over anhydrous sodium sulfate, was evaporated to dryness in vacuum. The oily residue was purified flash chromatography (petroleum ether : ethyl acetate 85:15) to give 2 g (63%) of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylpyrimidine.

1H-NMR (CDC13, ): 7,50 (d, 1H, aromatic N6), 7,27 (d, 1H, aromatic H3), to 7.15 (DD, 1H, aromatic H4), 4,13 (2N, ), to 3.58 (s, 2H, CH2of benzyl), 3,55 is-3.45 (m, 4H, piperazine protons), 2,50-to 2.42 (m, 4H, piperazine protons), of 1.26 (t, 3H, ).

A solution containing 13 g of 1-(2,5-dichlorobenzyl)-4-ethoxycarbonylphenyl and under reflux. Then added 30 ml of water and 30 ml of ethyl acetate at room temperature, brought the pH to 11 by addition of 35% sodium hydroxide. The organic phase was dried over anhydrous sodium sulfate and was evaporated to dryness in vacuum. The crude material was purified flash chromatography (chloroform : methanol 7:3) to obtain the 4,46 g (50%) 1-(2,5-dichlorobenzyl)piperazine.

1H-NMR (CDC13, ): 7,50 (d, 1H, aromatic N6), 7,26 (d, 1H, aromatic H3), 7,14 (DD, 1H, aromatic H4), 3,44 (s, 2H, CH2of benzyl), 3,00-to 2.85 (m, 4H, piperazine protons), 2,55-2,48 (m, 4H, piperazine protons), 1,76 (s, 1H, NH).

1-[N-(2-Nitrophenyl)-2-amino-ethyl] -4-(2,5-dichlorobenzyl)piperazine was obtained and was purified according to the method described in the first stage of Example 5, but using 1-(2,5-dichlorobenzyl)piperazine obtained as described above, instead of 1-(4-indolyl)piperazine, and using 4-dimethylaminopyridine instead of triethylamine and conducting the reaction at 120oWith over 8 hours Yield 35%.

1H-NMR (CDC13, ): 8,45 (SHS, 1H, NH), 8,10 (d, 1H, aniline H3), was 7.45 (d, 1H, N6 dichloraniline ring), 7,38 (DD, 1H, aniline H5), 7,25 (d, 1H, H3 dichloraniline ring), 7,10 (DD, 1H, H4 dichloraniline ring), 6,77 (d, 1H, N6-aniline), 6,55 (DD, 1H, aniline H4) and 3.59 (s, 2H, CH2of benzyl), 3,35 (dt the ke, described in the second stage of Example 1 , except that 1-[N-(2-nitrophenyl)-2-amino-ethyl)-4-(2,5-dichlorobenzyl)piperazine obtained as described above was used instead of 1-[N-(2-nitrophenyl)-2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiling under reflux was carried out for 12 hours the Crude material was purified flash chromatography (ethyl acetate : petroleum ether 4:6). Yield 22%.

1H-NMR (CDC13, ): 8,03 (DD, 1H, H3 nitroaniline rings), of 7.75-7,40 (m, 4H, h6 dichloraniline rings and N4,5,6 nitroaniline rings), of 7.25 (d, 1H, H3 dichloraniline ring), 7,10 (DD, 1H, H4 dichloraniline ring), 4,05-3,90 (m, 1H ), 3,65-to 3.50 (m, 1H ), 3,52 (s, 2H, CH2of benzyl), 2,70-of 2.20 (m, 10H), piperazine protons), from 2.00 to 0.70 (m, 11N, the protons of the cyclohexyl).

Example 7.

1-[N-(2-Cyclohexylcarbonyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-(2-Carbamoylethyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that 2-aminobenzamide used instead of 2-triphtalocyaninine. The crude material was purified flash chromatography (ethyl acetate) and then was led from ethanol. Yield 36%. The melting point 134-136oC.

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-carbamoylethyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl)-4-(2-methoxyphenyl)piperazine and boiled under reflux for 6 h in the presence of 2 molar equivalents of cyclohexylcarbodiimide. The crude material was purified flash chromatography (dichloromethane : methanol (95:5). Yield 55%.

1H-NMR (DMCO-d6, ): 12,10-11,80 (W, 1H, NH), 8,08 (DD, 1H, H3 of phenylcarbene), 7,88-to 7.68 (m, 2H, H5,6 vinylcarbazole), 7,47 (dt, 1H, H4 of phenylcarbene), 7,00-to 6.80 (m, 4H, CH metoksifenilny ring), 4,50-to 4.33 (m, 2H, in ), 3.75 (s, 3H, och3), 3,15-to 2.85 (m, 5H, SNA(O) and piperazine protons), 2,80 of 2.68 (m, 2H, ), 2,68-of 2.54 (m, 4H, piperazine protons), 2,28-of 2.08 (m, 1H, SNA(O)), 1,97-of 1.05 (m, 20N, the protons of the cyclohexyl).

Example 8.

1-[N-(2-Ethoxycarbonylphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A mixture of 0.93 g of methylanthranilate, 2 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)after cooling to room temperature the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (dichloromethane : methanol 98:2) to obtain the 0,41 g (18%) 1-[N-(2-ethoxycarbonylphenyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine.

1H-NMR (CDC13, ): of 7.90 (DD, 1H, aniline H3), of 7.90-7,70 (W, 1H, NH), 7,35 (TD, 1H, H5 aniline), 7,06-to 6.80 (m, 4H, CH metoksifenilny ring) 6,70 (DD, 1H, N6 aniline), to 6.58 (dt, 1H, aniline H4), a 3.87 and 3.85 (2s, 6N, SOON3and co3), 3,43-3,30 (m, 2H, ), 3,22 was 3.05 (m, 4H, piperazine protons), 2,83-to 2.67 (m, 6N, and piperazine protons).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-ethoxycarbonylphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl)-4-(2-methoxyphenyl)piperazine, and the mixture was heated for 9 h under reflux. The crude material was purified flash chromatography (dichloromethane: methanol 95:5). Yield 38%.

1H-NMR (CDC13, ): 8,03 (DD, 1H, H3 ethoxycarbonylphenyl ring), EUR 7.57 (dt, 1H, H4 ethoxycarbonylphenyl ring), was 7.45 (dt, 1H, H5 ethoxycarbonylphenyl ring), 7,37 (DD, 1H, N6 ethoxycarbonylphenyl, 1H ), 3,10-of 2.93 (m, 4H, piperazine protons), of 2,75 2,50 (m, 4H, piperazine protons), of 2.56 (t, 2H, ), 2,00 of-1.83 (m, 1H, SNA(O)), 1,80-to 0.80 (m, 10H, cyclohexyl protons).

Example 9.

1-[N-(2-Dimethylcarbamoyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-(2-Dimethylcarbamoyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that N,N-dimethyl-2-aminobenzamide used instead of 2-triphtalocyaninine. The crude material was purified flash chromatography (ethyl acetate : methanol 97:3). Yield 36%.

1H-NMR (CDC13, ): to 7.25 (dt, 1H, H5 aniline), to 7.09 (DD, 1H, aniline H3), 7,06-to 6.80 (m, 4H, CH metoksifenilny rings), of 6.68 (DD, 1H, N6 aniline), 6,66 (dt, 1H, aniline H4), 5,50-5,10 (W, 1H, NH), 3,86 (s, 3H, och3), 3,23 (t, 2H, , 3,18-is 3.08 (m, 4H, piperazine protons), 3,05 (s, 6N, N(CH3)2), 2,78-2,62 (m, 6N, and piperazine protons).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-dimethylcarbamoyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine, and the mixture boiling the ethanol 93:7). Yield 36%.

1H-NMR (CDC13, ): 7,50-7,30 (m, 4H, CH benzamide ring), 7,06-to 6.80 (m, 4H, CH metoksifenilny ring), is 4.85 (s, 3H, och3), 4,60-and 4.40 (m, 1H ), 3,67 is 3.40 (m, 1H ), 3,35-2,95 (m, 4H, piperazine protons), 3,10 and 2,90 (2C, 6N, N(CH3)2), 2,85 at 2.45 (m, 6N, piperazine protons ), 2,10-1,90 (m, 1H, SNA(O)), 1,90-to 0.80 (m, 10H, cyclohexyl protons).

Example 10.

1-[N-(2-Methoxyphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-(2-Methoxyphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that 2-methoxyaniline used instead of 2-triphtalocyaninine and boiling was carried out at 100oC for 4 h, the Yield is 50%.

1H-NMR (CDC13, ): 7,05-6,85 (m, 5H, CH metoksifenilny ring and CH aniline), 6,85-6,60 (m, 3H, CH aniline), a 3.87 and 3.85 (2s, 6N, 2 och3) at 3.25 (t, 2H, 3,18 was 3.05 (m, 4H, piperazine protons), 2,80-to 2.65 (m, 6N, and piperazine protons).

Specified in the title compound was obtained according to the method described in the second step of Example 1, except that 1-[N-(2-methoxyphenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-nitrophenyl)-2-amino-ethyl]-4-(2-methoxyphenyl)PIP is matography (CH2CL2-Meon of 9.5:0.5 to). Yield 59%.

1H-NMR (CDC13, ): 7,38 (DD, 1H, N6 methoxyphenylalanine), 7,26 (DD, 1H, H4 methoxyphenylalanine), 7,10-6,85 (m, 6N, H3, H5 methoxyphenylalanine and protons methoxyphenyl), 4,35-4,12 (m, 1H, ), the 3.89 (s, 3H, och3), 3,86 (s, 3H, och3), 3,55-to 3.33 (m, 1H, ), 3,20 are 2.98 (m, 4H, piperazine protons), 2,80-of 2.50 (m, 6N, piperazine protons ), 2,05 (TT, 1H, CHC(O)), 1,30-0,85 (m, 10H, cyclohexyl protons).

Example 11.

1-[N-(2-Ethylcarbamate)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-(2-Ethylcarbamate)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that 2-ethylcarbodiimide used instead of 2-triphtalocyaninine and the mixture is boiled under reflux for 5 hours the Crude material was purified flash chromatography (dichloromethane: methanol 9,7:0,3). Yield 12%.

1H-NMR (CDC13, ): 7,50 (t, 1H, ), 7,38-of 7.23 (m, 2H, H4, h6 aniline), 7,07-6,83 (m, 4H, CH metoksifenilny ring) 6,70 (DD, 1H, aniline H3), 6,60 (DD, 1H, aniline H5), 6,13-5,90 (W, 1H, 3,86 (s, 3H, och3, 3,53 is 3.40 (m, 2H, ), 3,33 (K, 2N, , 3,18-to 3.02 (m, 4H, piperazine protons), and 2.83 2.63 in (m, 6N, piperazine protons) of 1.23 (t, 3H, ).

Specified in the title compound was obtained l]-4-(2-methoxyphenyl)piperazine, obtained as described above was used instead of 1-[N-(2-nitrophenyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine and that this mixture is boiled under reflux for 12 h using toluene as solvent instead of 1,2-dichloroethane. The crude material was purified flash chromatography (dichloromethane: methanol to 9.5: 0.5 to). Yield 43%.

1H-NMR (CDC13, ): of 9.30-9,12 (W, 1H ), 7,80 (DD, 1H, N6 aniline), was 7.45 (DD, 1H, aniline H4), 7,35 (DD, 1H, aniline H5), 7,20 (DD, 1H, NC aniline), 7,05 to 6.75 (m, 4H, CH metoksifenilny ring), 4,47 (dt, 1H ), 3,82 (s, 3H, och3), to 3.73-to 3.50 (m, 1H ), 3,32-3,10 (m, 1H ), 3,03 was 2.25 (m, 5H, protons of piperazine), 2,65-of 2.16 (m, 7H, protons of piperazine) and SNA(O)), 1.70 to to 0.80 (m, 10H, cyclohexyl protons), of 1.18 (t, 3H, ).

Example 12.

1-[N-(2-Triptoreline)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A solution of 2-triptorelin (3 ml), triethylamine (3.5 ml) and dichloromethane (30 ml) was stirred at room temperature under nitrogen atmosphere. Was added dropwise to 3.34 ml cyclohexylcarbodiimide. After stirring for 2.5 h at room temperature the mixture was poured into water and podslushivaet 1 N. sodium hydroxide. The organic phase was dried over anhydrous sodium sulfate and the crude material S="ptx2">

1H-NMR (CDC13, ): to 8.20 (DD, 1H, CH triptoreline ring), 7,60-7,40 (m, 3H, CH and NH triptoreline ring), 7,12 (DDD, 1H, CH triptoreline rings), of 2.30 (TT, 1H, SNA(O)), 2,10-of 1.20 (m, 10H protons of the cyclohexyl).

A mixture of 0.2 g of 1-cyclohexylcarbonyl-2-cryptomelane, obtained as described above, and 0.37 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine, 0.5 ml of 50% (m/m) sodium hydroxide, 0.16 g TEVAS and 2 ml of toluene was stirred at 80oWith over 3.5 hours and Then added additional 0.2 g 1-cyclohexylcarbonyl-2-cryptomelane and after 6 h stirring at 80oTo this mixture was poured into water and was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (ethyl acetate: petroleum ether 3: 7) to give 0.12 g (17%) specified in the connection header.

1H-NMR (CDC13, ): to 7.77 (DD, 1H, CH triptoreline ring), 7,70 was 7.45 (m, 3H, CH triptoreline ring), 7,10-to 6.80 (m, 4H, CH metoksifenilny ring), 4,70-4,50 (m, 1H ), 3,85 (s, 3H, och3), 3,20-2,90 (m, 5H, protons of piperazine), 2,85 at 2.45 (m, 7H, SNA(O), and piperazine protons), 1,90-0,75 (m, 10H, cyclohexyl protons).

Example 13.

1-[N-(2-AMINOPHENYL arbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine, obtained as described in Example 1, 2 ml of hydrazine hydrate and 1 g of Raney Nickel in 70 ml of methanol was stirred at 50oC for 1.5 h, the Insoluble material was separated by filtration and the solution was evaporated to dryness. The residue was led from ethanol to obtain 0,69 g (71%) specified in the connection header. The melting point on 138.5-140oC.

1H-NMR (CDCl3, ): to 7.15 (DD, 1H, CH aminoaniline ring), 7,10-to 6.80 (m, 5H, CH aminoaniline ring and CH metoksifenilny ring), 6,80-of 6.65 (m, 2H, CH aminoaniline ring), 4,96 (s, 2H, NH2), 4,96 with 4.65 (m, 1H ), 3,86 (s, 3H, och3), 3,20-2,80 (m, 7H, protons of piperazine), 2,45-to 2.65 (m, 4H, piperazine protons), 2,10 (TT, 1H, CH(Oh)), 1,90-to 0.80 (m, 10H, cyclohexyl protons).

Example 14.

1-[N-(2-Acetamidophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A solution of 0.04 ml acetylchloride in 0.5 ml dichloromethane was added at room temperature to stir the solution is 0.22 g of 1-[N-(2-AMINOPHENYL)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described in Example 13, and 0.08 ml of triethylamine in 5 ml dichloromethane. After 2 h stirring at the same temperature, the solvent evaporated and the residue was purified flash chromatography (di is DC13, ): 9,90 (s, 1H, NH), a 7.85 (DD, 1H, CH acetylaminophenol ring), 7,40 (TD, 1H, CH acetylaminophenol ring), 7.23 percent-7,10 (m, 2H, CH acetylaminophenol ring), 7,05-to 6.80 (m, 4H, CH metoksifenilny ring), 5,00-4,80 (m, 1H ), 3,83 (s, 3H, och3), 3,20 was 2.25 (m, 11N, and piperazine protons), of 2.15 (s, 3H, PINES3), 2,05-of 1.85 (m, 1H, SNA(Oh)), a 1.75-to 0.80 (m, 10H, cyclohexyl protons).

Example 15.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine N1oxide

Suspension 0,89 g 83% of monoperoxyphthalate magnesium, 0.6 N2About 10 ml of water was added dropwise into a solution of 1.4 g of 1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine obtained as described in Example 1, in 10 ml of chloroform and 45 ml of methanol and 5oC. After maturation over night at room temperature the solvents evaporated. The residue was placed in 50 ml of water, was podslushivaet 20% sodium carbonate and was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (chloroform : 2 n ammonia solution in methanol, gradient 100:7-100:20) to obtain 0.5 g of the crude material. Crystallization from acetone gave 0.35 g (24%) indicated in the title compounds is 0 (DDD, 1H, H5 nitroaniline ring) to 7.50 (DDD, 1H, H4 nitroaniline ring), 7,41 (DD, 1H, N6 nitroaniline ring), 7,07-6,76 (m, 4H, CH metoksifenilny ring), 4,40-4,12 (m, 2H, ), 3,85 (s, 3H, och3), 3,70-to 3.35 (m, 6N, and piperazine protons), 3,35-of 3.07 (m, 4H, piperazine protons), 2,05 and 1.80 (m, 1H, SNA(Oh)), a 1.75-0.75 in (m, 10H, cyclohexyl protons).

Example 16.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine N4oxide

Specified in the title compound was isolated during the purification of the compound obtained in Example 15. The output of 0.23 g (16%) as a glassy solid.

1H-NMR (CDC13, ): 8,75 (DD, 1H, N6 metoksifenilny rings), with 8.05 (DD, 1H, H3 nitroaniline ring), 7,71 (DDD, 1H, H5 nitroaniline ring), EUR 7.57 (DDD, 1H, H4 nitroaniline ring), 7,47 (DD, 1H, N6 nitroaniline ring), 7,37 (DDD, 1H, H4 (H5) metoksifenilny ring), 7,10 (DDD, 1H, H5 (H4) metoksifenilny ring), 6,98 (DD, 1H, H3 metoksifenilny ring), 4,72-to 4.41 (m, 2H, piperazine protons), a 4.03 (s, 3H, och3), 3,83 (t, 2H, ), 3,36-to 3.09 (m, 2H, piperazine protons), 2,98-2,77 (m, 2H, ), 2.77-to 2,30 (m, 4H, piperazine protons), 2,05-0,83 (m, 11N, the protons of the cyclohexyl).

Example 17.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxide is the example 15, but using equimolar amounts of monoperoxyphthalate magnesium and 1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine. Exit 43% after crystallization from acetonitrile. The melting point 153-157oC.

1H-NMR (CDC13, ): 8,70 (DD, 1H, N6 metoksifenilny rings), with 8.05 (DD, 1H, H3 nitroaniline rings), of 7.70 (DDD, 1H, H5 nitroaniline ring), 7,58 (DDD, 1H, H4 nitroaniline ring), 7,49-to 7.32 (m, 2H, N6 nitroaniline rings and H4 metoksifenilny ring), 7,13 (DDD, 1H, H5 metoksifenilny rings), of 7.00 (DD, 1H, NC metoksifenilny rings), of 5.92-5,67 (m, 2H, piperazine protons), 4,70 is 4.45 (m, 2H, piperazine protons), 4,45-of 4.05 (m, 2H, ), of 4.00 (s, 2H, ), 3,30-is 3.08 (m, 2H, piperazine protons), 3,05-to 2.85 (m, 2H, piperazine protons), 2,05-of 1.78 (m, 1H, SNA(O)), 1,78 to 0.70 (m, 10H, cyclohexyl protons).

Example 18.

1-[N-(2-Nitrophenyl)-N-(3-fullcarbon)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Suspension of 0.77 g of monohydrochloride 1-[N-(2-nitrophenyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine obtained as described in the first stage of Example 1, in 50 ml of toluene was stirred while boiling under reflux with removal of approximately 20 ml of distillate. After cooling down to 60-70oWith added 0.9 ml of 97% Diisopropylamine the Ali boiling under reflux for 5 h, was cooled to room temperature, washed successively with water, 1 N. sodium hydroxide and water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (ethyl acetate : petroleum ether, gradient 1:1-7:3) to obtain the 0,67 g (75%) specified in the connection header.

1H-NMR (CDC13, ): with 8.05 (DD, 1H, H3 nitroaniline ring), 7,73-7,58 (m, 2H, H5 and h6 nitroaniline ring), 7,58 was 7.45 (m, 1H, H4 nitroaniline ring), 7,15 (SHS, 1H, H2 of furan ring), 7,02-6,77 (m, 5H, H5 furan ring and CH metoksifenilny ring), 6,13 (SHS, 1H, H4 of furan ring), 4,30-4,08 (m, 1H, 3,90-3,70 (m, 1H ), a 3.83 (s, 3H, och3), 3,05 is 2.80 (m, 4H, piperazine protons), 2,80-2,62 (m, 2H, ), 2,62 at 2.45 (m, 4H, piperazine protons).

Example 19.

1-[N-(2-Nitrophenyl)-N-(2-fullcarbon)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 2-shrinkability instead of 3 shrinkability. Yield 77%.

1H-NMR (CDC13, ): with 8.05 (DD, 1H, H3 nitroaniline ring), 7,72 was 7.45 (m, 3H, CH other nitroaniline ring), 7,20 (SHS, 1H, NC furan ring), 7,05 to 6.75 (m, 4H, CH metoksifenilny rings), of 6.49 (SHS, 1H, H4 of furan ring), 6,2-to 2.65 (m, 2H, CONCH2CH2N), 2,65-2,48 (m, 4H, piperazine protons).

Example 20.

1-[N-(2-Nitrophenyl)-N-(2-thienylboronic)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 2-taylorsville instead of 3 shrinkability and boiling under reflux for 8 hours Yield 59%.

1H-NMR (CDC13, ): 8,03 (DD, 1H, H3 nitroaniline ring), 7,71-of 7.60 (m, 2H, H5 and h6 nitroaniline ring), 7,60 was 7.45 (m, 1H, H4 nitroaniline ring), 7,27 (DD, 1H, H3 (H5) thiophene rings), 7,05-6,70 (m, 6N, N4 and N5 of thiophene and SN metoksifenilny ring), 4,22-4,10 (m, 1H ), 3,92-3,71 (m, 1H, ), of 3.80 (s, 3H, OCH3), 3,10-2,80 (m, 4H, piperazine protons), 2,80-to 2.65 (m, 2H, ), 2,65 at 2.45 (m, 4H, piperazine protons).

Example 21.

1-[N-(2-Nitrophenyl)-N-(3-thienylboronic)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 3-taylorsville instead of 3 shrinkability and boiling under reflux for 7 hours Yield 88%.

1H-NMR (CDC13, ): to 7.93 (DD, 1H, H3 nitroaniline ring), 7,70-of 7.55 (m, 2H, H5 and h6 nitroaniline rings), of 7.48-7,3 1H, H4 thiophene ring), 6,91-of 6.78 (m, 4H, CH metoksifenilny ring), 4,32-4,10 (m, 1H ), 3,90-3,70 (m, 1H ), 3,81 (s, 3H, och3), 3,05-2,78 (m, 4H, piperazine protons), 2,78-to 2.65 (m, 2H, ), 2,65 at 2.45 (m, 4H, piperazine protons).

Example 22.

1-[N-(2-Nitrophenyl)-N-(4-pyridylcarbonyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 4-pyridylcarbonyl instead of 3 shrinkability and boiling under reflux for 14 hours the Crude material was purified flash chromatography (chloroform : 2,5 N. methanolic ammonia gradient 100:1.5 to 100:3). Yield 39%.

1H-NMR (CDC13, ): 8,42 (DD, 2H, H2 and h6 of pyridine ring), of 7.90 (DD, 1H, H3 nitroaniline ring), 7,62 was 7.45 (m, 2H, H5 and h6 nitroaniline ring), 7,45-7,30 (m, 1H, H4 nitroaniline ring), to 7.15 (m, 2H, H3 pyridine ring), 7,08 to 6.75 (m, 4H, CH metoksifenilny ring), 4,50-4,20 (m, 1H ), 3,90-the 3.65 (m, 1H ), of 3.80 (s, 3H, och3), 3,15-of 2.28 (m, 10H, and piperazine protons).

Example 23.

1-[N-(2-Nitrophenyl)-N-(3-pyridylcarbonyl)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 3-pyridylcarbonyl which was purified flash chromatography (chloroform : 2,5 N. methanolic ammonia 100:3). Yield 46%.

1H-NMR (CDC13, ): 8,50-8,35 (m, 2H, H2 and h6 of pyridine ring), of 7.90 (DD, 1H, H3 nitroaniline ring), 7,72 (DD, 1H, H4 pyridine ring), 7,60 is 7.50 (m, 2H, H5 and h6 nitroaniline ring), 7,43-7,28 (m, 1H, H4 nitroaniline ring), 7,30-to 7.15 (m, 1H, H5 pyridine ring), 7,03-6,76 (m, 4H, CH metoksifenilny ring), 4,35-to 4.15 (m, 1H ), 4.00 points of 3.75 (m, 1H, ), of 3.80 (s, 3H, och3), 3,10-to 2.40 (m, 10H, and piperazine protons).

Example 24.

1-[N-(2-Nitrophenyl)-N-(2-pyrazinecarboxamide)-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described in Example 18, but using 2-pyrazinecarboxamide instead of 3 shrinkability and boiling under reflux for 1 h the Crude material was purified flash chromatography (chloroform : 2,5 N. methanolic ammonia gradient 100:1-100:3). Yield 89%.

1H-NMR (CDC13, ): the remaining 9.08 (d, 1H, H3 pirazinamida rings), of 8.40 (d, 1H, N6 pirazinamida ring), 8,07 (d, 1H, H5 pirazinamida rings), of 7.97 (DD, 1H, H3 nitroaniline ring), a 7.62 to 7.50 (m, 2H, H5 and h6 nitroaniline rings), of 7.48-7,31 (m, 1H, H4 nitroaniline ring), 7,05-to 6.80 (m, 4H, CH metoksifenilny ring), or 4.31-to 4.15 (m, 1H ), 4,08-to 3.92 (m, 1H ), 3,82 (s, 3H, och3), 3,05-to 2.40 (m, 10 is oethyl] -4-(2-methoxyphenyl)piperazine

Acting as described in the first stage of Example 12, but using 1-methylcyclohexanecarboxylic [J. Org. Chem. , 47, 3242 (1982] instead of cyclohexylcarbodiimide and boiling under reflux for 50 h, obtained crude 1-methyl-N-(2-nitrophenyl)cyclohexylcarbamate. It was purified flash chromatography (petroleum ether: ethyl acetate 100:2). Output 90%.

1H-NMR (CDC13, ): is 10.75 (s, 1H, NH), cent to 8.85 (DD, 1H, N6 nitroaniline ring), by 8.22 (DD, 1H, H3 nitroaniline ring), a 7.62 (DDD, 1H, H5 nitroaniline ring), to 7.15 (DDD, 1H, H4 nitroaniline ring), 2,20-of 1.95 (m, 2H, protons of cyclohexyl), a 1.75-of 1.35 (m, 8H, cyclohexyl protons), 1,25 (s, 3H, CH3).

A mixture of 0.3 g of 1-methyl-N-(2-nitrophenyl)-cyclohexylcarbodiimide, obtained as described above, 50 ml of toluene and 0.26 g of tert-butoxide potassium was stirred while boiling under reflux, removing approximately 11 ml of distillate. Then to this mixture was added a solution of 0.32 g of 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine in 10 ml of toluene. After 16 h stirring while boiling under reflux the mixture was cooled and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude material was purified flash chromatography (n is Mr (CDC13, ): 7,98 (DD, 1H, H3 nitroaniline ring), 7,40 (DDD, 1H, H5 nitroaniline ring), 7,08-to 6.80 (m, 6N, N4 and N6 nitroaniline ring and CH metoksifenilny ring), or 4.31-4,10 (m, 2H, ), 3,85 (s, 3H, och3), 3,20 are 2.98 (m, 4H, piperazine protons), 2,88-2,62 (m, 6N, and piperazine protons), 1,90 is 1.70 (m, 2H, protons of cyclohexyl), 1,53-1,22 (m, 8H, cyclohexyl protons), of 1.18 (s, 3H, CH3).

Example 26.

1-[N-(2-Nitrophenyl)-N-(1-phenylcyclohexylamine)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine

1-Phenyl-N-(2-nitrophenyl)cyclohexylcarbamate was obtained according to the method described in the first stage of Example 25, except that 1-phenylcyclohexanecarboxylic [J. Am. Chem. Soc., 68, 2345-7 (1946)] was used instead of 1-methylcyclohexanecarboxylic, toluene was used instead of dichloromethane, DIPEA was used instead of triethylamine and the reaction mixture is boiled under reflux for 15 hours the Crude material was purified flash chromatography (petroleum ether: ethyl acetate 98:2). Yield 91%.

1H-NMR (CDC13, ): 10,32 (s, 1H, NH), 8,76 (DD, 1H, N6 nitroaniline ring) to 8.12 (DD, 1H, H3 nitroaniline rings), of 7.64-to 7.32 (m, 5H, CH of phenyl ring), 7,28 (DDD, 1H, H5 nitroaniline ring), was 7.08 (DDD, 1H, H4 nitroaniline ring), 2,54-of 2.34 (m, 2H, protons cyclo what s the connection was received, as described in the second stage of Example 25, except that 1-phenyl-N-(2-nitrophenyl)cyclohexylcarbamate used instead of 1-methyl-N-(2-nitrophenyl)cyclohexylcarbodiimide and boiling under reflux lasted 22 hours the Crude material was purified flash chromatography (petroleum ether: ethyl acetate, gradient 8:2-7:3). Yield 37%.

1H-NMR (CDC13, ): of 7.90 (DD, 1H, H3 nitroaniline ring), 7,45-7,10 (m, 7H, CH phenyl ring and N5 and N6 nitroaniline ring),? 7.04 baby mortality-is 6.78 (m, 5H, H4 nitroaniline ring and CH metoksifenilny ring), 4,30-4,12 (m, 2H, ), 3,82 (s, 3H, och3), 3,18-of 2.93 (m, 4H, piperazine protons), 2,80-of 2.50 (m, 6N, ) and piperazine protons), 2,30 is 2.10 (m, 2H, protons of cyclohexyl), 1,92 is 1.75 (m, 2H, protons of cyclohexyl), 1,74-of 1.35 (m, 6N, the protons of the cyclohexyl).

Example 27.

1-[N-[2-(2,2,2-Triptoreline)phenyl] -N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

1-[N-[2-(2,2,2-Triptoreline)phenyl] -2-amino-ethyl] -4-(2-methoxyphenyl)piperazine was obtained by the method described in the first stage of Example 2, except that 2-(2,2,2-triptoreline)aniline (EP 748800) was used instead of 2-triphtalocyaninine and the reaction mixture is boiled under reflux for 7 hours the Crude material okiwelu>, ): 7,08-to 6.80 (m, 5H, CH metoksifenilny ring and CH triftoratsetofenona ring), 6,80-to 6.57 (m, 3H, CH triftoratsetofenona ring), 5,11-4,70 (m, 1H, NH), 4,35 (K, 2H, och2CF3), 3,85 (s, 3H, och3), 3,38-3,19 (m, 2H, ), 3,19 are 2.98 (m, 4H, piperazine protons), 2,88-2,60 (m, 6N, and piperazine protons).

A mixture of 0.41 g of 1-[N-[2-(2,2,2-triptoreline)phenyl]-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine obtained as described above, to 5.4 ml of 97% DIPEA and 3.9 ml of cyclohexylcarbodiimide in 30 ml of toluene was stirred while boiling under reflux for 10 hours After cooling at room temperature the mixture was washed successively with water, 1 N. sodium hydroxide and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude material was purified flash chromatography (petroleum ether : ethyl acetate 1:1) followed by crystallization from diethyl ether to obtain 0.2 g (37%) specified in the connection header. The melting point 109,6-112oC.

1H-NMR (CDCl3, ): 7,42-7,22 (m, 2H, CH triftoratsetofenona ring), 7,15-6,77 (m, 6N, CH triftoratsetofenona ring and CH metoksifenilny rings), of 4.38 (K, 2H, och2CF3), 4,22-was 4.02 (m, 1H ), 3,82 (s, 3H, och3), to 3.58-3,39 (m, 1H ), 3,15-2,90 (m, 4H, protons pipere 28.

1-[N-(2-Cyanophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine hydrochloride

N-(2-Cyanophenyl)cyclohexylcarbamate was obtained according to the method described in the first stage of Example 12, except that 2-cyanoaniline used instead of 2-triptorelin. A yield of 75%. So pl. 135-137oC.

1H-NMR (CDC13, ): 8,40 (DD, 1H, H3 cyanoaniline ring), 7,70-to 7.50 (m, 3H, H5 and h6 cyanoaniline rings and NH), 7,12 (DDD, 1H, 4, N4 cyanoaniline rings), of 2.30 (TT, 1H, SNA(O) 2,05-1,10 (m, 10H, cyclohexyl protons).

Specified in the title compound was obtained as described in the second stage of Example 25, except that N-(2-cyanophenyl)cyclohexylcarbamate obtained as described above was used instead of 1-methyl-N-(2-nitrophenyl)cyclohexylcarbodiimide and boiling under reflux lasted 1 h the Crude material was purified flash chromatography (dichloromethane : methanol 98: 2). The residue was dissolved in acetone and the solution was added hydrogen chloride in ether. The solution was evaporated to dryness and was led from a mixture of acetone : diethyl ether to obtain specified in the connection header. Exit 7%.

1H-NMR (DMCO-d6, ): 11,28-11,07 (W, 1H, NH+), with 8.05 (DD, 1H, N6 cyanoaniline analnogo ring), 4,45-4,30 (m, 1H, 3,92 of 3.75 (m, 1H, ), of 3.80 (s, 3H, och3), 3,70 is 3.40 (m, 4H, piperazine protons), 3,40-3,00 (m, 6N, and piperazine protons), 1,98 and 1.80 (m, 1H, SNA(O)), 1,80-0,75 (m, 10H, cyclohexyl protons).

Example 29.

1-[N-(2-Nitrophenyl)-N-cyclohexylcarbonyl-1-amino-2-propyl] -4-(2-methoxyphenyl)piperazine

A mixture of 1 g of 1-(2-methoxyphenyl)piperazine, or 0.57 g of 2-chloropropionate, 1 ml of DIPEA and 5 ml of toluene was stirred while boiling under reflux for 3 h under nitrogen atmosphere. After cooling to room temperature the mixture was poured into water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvents evaporated. The residue was purified flash chromatography (dichloromethane : 2 n ammonia in methanol 95:5) to give 0.88 g(63%) 2-[4-(2-methoxyphenyl)-1-piperazinil]propionamide.

1H-NMR (CDC13, ): 7,25-7,10 (W, 1H ), 7,10-to 6.80 (m, 4H, CH metoksifenilny rings), of 5.75-the ceiling of 5.60 (W, 1H ), 3,85 (s, 3H, och3), 3,20-3,00 (m, 5H, protons of piperazine ), 2,85-2,60 (m, 4H, piperazine protons), of 1.30 (d, 3H, ).

2 ml of 2 M solution of dimethyl sulphide of DIBORANE in tetrahydrofuran was added dropwise to a solution of 0.28 g of 2-[4-(2-methoxyphenyl)-1-piperazinil]propionamide, obtained as described above, in 7 ml of tetrahydrofuran, and stirred pranala. The solvents are evaporated and the residue was placed into the water. The organic phase obtained by extraction with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (dichloromethane : 2 n ammonia solution in methanol 95:5) to give 0.07 g(24%) 2-[4-(2-methoxyphenyl)-1-piperazinil]-Propylamine.

1H-NMR (CDC13, ): 7,10-to 6.80 (m, 4H, CH metoksifenilny ring), 3,85 (s, 3H, CH3), 3,20-2,90 (m, 4H, piperazine protons), 2,85-of 2.50 (m, 7H, protons of piperazine ), 2,05-1,85 (W, 2H, NH2), of 0.95 (d, 3H, CH2).

A mixture of 0.08 g of 2-[4-(2-methoxyphenyl)-1-piperazinil]Propylamine obtained as described above, of 0.03 ml of 2-nitrofluoranthene, 0.3 ml of DIPEA and 5 ml of DMF was stirred at 140oC for 3 h in nitrogen atmosphere. The cooled mixture was diluted with water and was extracted with diethyl ether. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified flash chromatography (petroleum ether : ethyl acetate 8:2) to give 0.07 g (62%) of 1-[N-(2-nitrophenyl)-1-amino-2-propyl]-4-(2-methoxyphenyl)piperazine.

1H-NMR (CDC13, ): 8,90-8,70 (W, 1H, NH), 8,15 (DD, 1H, H3 nitroaniline ring), 7,40 (DDD, 1H, H5 nitroaniline ring), 7,15-6,70 (m, 5H, h6 nitroaniline ring and CH methoxy ), of 1.10 (d, 3H, CH3).

Specified in the title compound was obtained according to the method described in the second step of Example 2, except that 1-[N-(2-nitrophenyl)-1-amino-2-propyl] -4-(2-methoxyphenyl)piperazine obtained as described above was used instead of 1-[N-(2-trifloromethyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine, toluene was used instead of 1,2-dichloroethane and the mixture is boiled under reflux for 13 hours the Crude material was purified flash chromatography (petroleum ether : ethyl acetate 1:1). Yield 61%.

1H-NMR (CDC13, ): with 8.05 (DD, 1H, H3 nitroaniline ring), 7,85 was 7.45 (m, 3H, N4, N5 and N6 nitroaniline ring), 7,10 to 6.75 (m, 4H, CH metoksifenilny ring), 3,85 (s, 3H, CH3), 3,90 of 3.75 (m, 1H ), 3,65-of 2.30 (m, 10H, piperazine protons ), 2,10 and 1.80 (m, 1H, SNA(O)), 1,80-0,80 (m, 13H, the protons of the cyclohexyl and CH3).

Example 30.

Actions induced displacement rhythmic emptying bladder contractions have shot rats

A. Methods.

Used female rats, Sprague-Dawley weighing 225-275 g (Cri: CDo BR, Charles River Italia). Animals were kept with free access to feed and water and were maintained on a compulsory 12-hour peremejayutsya cycle light - dark at 22-24oo(C) saline until then, until you appear reflex emptying of the bladder contractions (usually of 0.8-1.5 ml). For intravenous (IV) injection of bioactive compounds polyethylene pipe PE 50, filled with physiological saline was inserted into the jugular vein.

Using cystometrogram, was determined by the number of beats recorded for 15 min before (baseline values, background) and after processing, as well as the average amplitude of these contractions (average height of the peaks in mm of mercury hundred the and which led to complete cessation of contractions of the bladder, the bioactivity conveniently be assessed by measuring the duration of inactivity of the bladder (i.e., the length of time during which there will be no reduction). The number of animals that found a reduction in the number of contractions of >30% of that observed in the base period, was also registered.

For comparison, the activity of test compounds against the emptying inhibition of contractions of the bladder, equally effective doses, which led to the time of the disappearance of abbreviations 10 min (ED10min), was calculated using least squares linear regression analysis. In the same way expected the extrapolated dose, which induced a decrease in the number of reductions greater than 30%, in 50% of treated rats (ED50frequency) by the method of bliss (Bliss, C. I., Quart. J. Pharm. Pharmacol. , 11, 192-216, 1938). After the termination of suppressing the injection of the medicinal product height contractile peaks were compared with peaks recorded earlier, after controlling intravenous media. The activity of test compounds (the value of the ED50; extrapolated dose inducing a 30% decrease in the amplitude of contractions in 50% of treated rats) on the th, by the method of bliss (Bliss, C. I., Quart. J. Pharm. Pharmacol., 11, 192-216, 1938).

C. The Results.

Rapid stretching of the bladder in shot urethane rats caused a series of rhythmic emptying contractions of the bladder, the characteristics of which were described and is well known in this area (Maggi et al., Brain Res., 380:83, 1986; Maggi, et al., J. Phannacol. Exp. Ther. , 230: 500, 1984). The frequency of these contractions is associated with sensory afferent shoulder reflex urination and integrity of the center of urination, while their amplitude is a property of efferent shoulder of this reflex. In this model system compounds that act primarily on the Central nervous system (such as morphine), call blocking emptying reduction, whereas drugs that act at the level of the muscles of the sphincter, such as oxybutynin, reduce the amplitude of contractions of the bladder.

The results obtained after administration of the known compounds and compounds of the present invention, is shown in Table 1.

The compound a, the compound described in the prior art, is more active than flavoxate, oxybutynin, emptying inhibition of contractions. This compound, in contrast Exibir.

However, unexpectedly, compounds with substituents (e.g., NO2in position 2 the aniline ring in the formula I, such as compound of Example 1 are significantly higher activity than the unsubstituted compound And, in particular, for values ED10 min. Like the connection And the connection of Example 1 does not affect the contractility of the bladder. Comparative connections, and with the nitro-group in position 3 or 4 of the phenyl ring, respectively, found no pharmacological activity.

Example 31.

Steps on sistematicheskie parameters that are in the minds of rats

A. Methods.

Used male rats Sprague-Dawley weighing 250-350 g (Cri: CDo BR, Charles River Italia). Animals were kept with free access to feed and water and were maintained on a compulsory 12-hour peremejayutsya cycle light - dark at 22-24oC for at least one week, except for the time of the experiment. To quantify Uro dynamic parameters of conscious rats, cystometrograms studies were performed using methods described previously (Guarneri et al., Pharmacol. Res., 24: 175, 1991). Male rats were anestesiologi with Nembutal (30 mg/kg) and chloralhydrate (125 mg/kg) in b/W siteline 10 mm The bladder was carefully released from the anchoring tissue, emptied and then Coulibaly through an incision in the dome polyethylene cannula (Portex PP30), which is permanently sewn with silk thread. The cannula taken out through a subcutaneous tunnel in retrolateral zone, where it connected with a plastic adapter to avoid the risk of removal by the animal. For intravenous (IV) administration of test compounds tube from polyethylene (PE 50, filled with physiological saline was inserted into the jugular vein and drew in retrolateral zone. Rats used exclusively within one day after implantation. On the day of experiment, rats were placed in a cell Bollman; after a period of stabilization for 20 min free tip of the bladder catheter was connected via a T-shaped tube with a pressure sensor (Bentley T 800/Marb P 82) and peristaltic pump (Gilson minipuls 2) for continuous infusion at a constant rate of 0.1 ml/min, saline into the bladder. The signal intraluminal pressure during infusion was continuously recorded on a polygraph (Battaglia Rangoni TO 380 steering ADCI/T).

Evaluated two urodynamic parameters: capacity of the bladder (BVC) and the pressure of urination (Mr). BVC (ml) opredelyayuschaya). Mr (in mm Hg) was determined as the maximum pressure inside the bladder induced contraction of sphincter during voiding. Base value (background) BVC and MP were calculated as averages of the first two registered cystometrogram. At this point in the analysis infusion was interrupted and was administered the test compound. Fifteen minutes after intravenous recorded two additional cystometrogram for each animal was calculated averages of these two cystometrograms parameters. Statistical significance was evaluated using t-student test for paired data.

C. The Results.

Various doses of the test compounds shown in Table 2. Connection And behaved like flavoxate, increasing BVC. No connection was not impaired contractility of the bladder, so as not observed persistent changes in MP. In contrast, oxybutynin and significantly dependent on the dose was reduced Mr without affecting the BVC. The compound of Example 1 was more active than compound a and flavoxate; significant increase BVC was observed after the/in the 0.3 mg/kg compound of Example 2, in comparison with the necessity of 1.0 mg/knake this effect was not dependent on dose and was clearly below, than the effect induced by oxybutynin.

Example 32.

Binding of radioactive receptor and 5-HT1Aand a variety of other binding sites neurotransmitters

A. Methods.

Recombinant 5-HT1Areceptors man

The genomic clone G-21, encoding 5-HT1A-serotonergic receptor human, consistently had transfusional in a line of human cells (HeLa). HeLa cells were grown as monolayers in a modified method of Dulbecco environment Needle (DMEM), supplemented with 10% fetal calf serum and gentamicin (100 mg/ml), 5% CO2at 37oC. the Cells were separated from the bulb to grow at 95% confluence scraper for cells and literally in chilled on ice 5 mm Tris and 5 mm EDTA buffer (pH 7.4). The homogenates were centrifuged at 40,000 x g for 20 min and precipitation resuspendable in a small volume of chilled on ice 5 mm Tris and 5 mm EDTA buffer (pH 7.4) and immediately frozen and kept at -70oWith to use. On the day of the experiment the cell membrane resuspendable in the buffer to bind: 50 mm Tris-Hcl (pH 7.4), 2.5 mm MgCl2, 10 μm pargyline (Fargin et al., Nature 335, 358-360, 1988). Membranes were incubated in a final volume of 1 ml for 30 min at 30oWith from 0.2-1 nm [+ was determined in the presence of 10 μm 5-HT. The incubation was stopped by adding chilled on ice Tris-model HC1 buffer and rapid filtration through treated with 0.2% polyethylenimine filters Whatraan GF/B or Schleicher & Schuell GF52.

Native 5-HT2A-serotonergic receptors and2-adrenergic receptors (from animal tissues)

Research associate at native2-adrenergic receptors (L. Diop et al. , J. Neurochem., 41, 710-715, 1983) and 5-HT2A-serotonergic receptors (Craig A. and Kenneth J., Life Sci., 38, 117-127, 1986) was performed in the membranes of the cerebral cortex of the rat. Male rats Sprague-Dawley (200-300 g, Harlan SD/Nossan, Italy) were killed by cervical displacement and the cerebral cortex were cut and immediately frozen in liquid nitrogen and kept at -70oWith to use. Tissue is homogenized (2 x 20) in 50 volumes of cold 50 mm Tris-Hcl buffer, pH 7.4, using a homogenizer transmitter station (speed 7). The homogenates were centrifuged at 49000xg for 10 min, resuspendable in 50 volumes of the same buffer, incubated at 37oC for 15 min and centrifuged and resuspendable two more times. The final precipitates suspended in 100 volumes of 50 mm Tris-model HC1 buffer, pH 7.4, containing 10 μm pargyline and 0.1% ascorbic acid (2-adrenergic receptiona volume of 1 ml for 30 min at 25oWith from 0.5 to 1.5 nm [H3]rauwolscine (2-adrenergic receptors) or for 20 min at 37oWith from 0.7-1.3 nm [3N]ketanserin (5-HT2Areceptors), in the absence or presence of competing drugs. Nonspecific binding was determined in the presence of 10 μm fentolamina (2-adrenergic receptors) or 2 μm ketane-serine (5-HT2A-serotonergic receptors). The incubation was stopped by adding chilled on ice in 50 mm Tris-HCl buffer and rapid filtration through preprocessed 0.2% polyethylenimine filters Whatman GF/B or Schleicher & Schuell GF52.

C. The Results.

Inhibition of specific binding of radio-tested drugs were analyzed to estimate the IC50using fitting nonlinear curves Allfit (De Lean et al., Am. J. Physiol. , 235, E97-E102, 1978). The value of the IC50turned in the affinity constant (Ki) by the equation of Cheng & Prusoff (Cheng Y. C., Prusoff W. H. Biochim., Pharmacol., 22, 3099-3108, 1973).

The results, shown in Table 3A show that the compound a and the compound of Example 1 both have very high affinity to 5-HT1Areceptors, but their binding profiles are different is compared with the 5-HT2Areceptor and (2-adrenoceptors. All other tested compounds of this invention (table 3B) had a high affinity to 5-HT1A-receptor.

Measuring antagonistic activity against pre - and postsynaptic 5-HT1Areceptor

A. Methods.

Antagonistic activity against hypothermia induced by 8-OH-DPAT in mice (presynaptic antagonism)

Antagonistic action of antagonists of 5-HT1Areceptors of this invention in relation to hypothermia induced by 8-OH-DPAT, was estimated by the method of Moser (Moser, Eur. J. Pharmacol., 193:165, 1991) with minor modifications as described below. Male mice CD-1 (28-38 g) obtained from Charles River (Italy), were kept in a room with controlled climate (temperature 222oC; humidity 5515%) and were maintained on a 12-hour cycle of light / dark with free access to feed and water. On the day of experiment, mice were placed individually in transparent plastic boxes under the same environmental conditions. Body temperature was measured by introducing a temperature sensor (Termist TM-S LSI) into the rectum to a depth of 2 cm Rectal temperature was measured immediately before intravenous injection test Ivanovo temperature change was calculated relative to the level of preprocessing and the average value was calculated for each group processing. The linear regression equation was used to estimate values ID50defined as the dose of antagonist required to block 50% of the hypothermic action induced by 0.5 mg/kg 8-OH-DPAT, introduced subcutaneously.

Inhibition trample paws induced by 8-OH-DPAT in rats (postsynaptic antagonism)

The inhibitory activity of antagonists of 5-HT1Areceptors in relation to trample paws induced in rats by subcutaneous injection of 8-OH-DPAT, was evaluated by way of Trickle-bank (Tricklebank et al., Eur. J. Pharmacol., 117:15, 1985) with minor modifications as described below.

Male rats Sprague-Dawley (150-175 g) obtained from Charles River (Italy), were kept in a room with controlled climate and were maintained on a 12-hour cycle of light / dark with free access to feed and water. On the day of experiment, rats were placed individually in transparent plastic boxes. Rats were treated with reserpine, 1 mg/kg s/C for 18-24 h before the test to depletion of intracellular reserves of norepinephrine. To evaluate the antagonistic activity of the compounds was administered/16 min before 8-OH-DPAT (1 mg/kg s/C). Monitoring a duration of 30 s was started after 3 min after treatment with agonist and repeated every 3 min on about eskay stimulation of 5-HT1Areceptors, and its intensity was assessed as a score using the classification scale of intensity, in which: 0 - absent, 1 - doubtful 2 - and 3 present - intensive. Behavioral scores for each treated rats accumulated over the course of time (5 periods of observations) and were expressed as mean values for 8-10 rats. The linear regression equation was used to estimate values ID50defined as the dose of antagonist required to block 50% of the intensity of marking time paws induced by 1 mg/kg 8-OH-DPAT, introduced subcutaneously.

C. The Results.

The results are shown in Table 4. These results show that the compound of Example 1 exhibits significant presynaptic and postsynaptic antagonistic activity against 5-HT1A-receptor. The connection And, in contrast, was at least 10 times less active than the compound of Example 1 in both models.

Scheme for the preparation of 3.

An alternative method of preparing compounds of formula I (Scheme 3), where R2represents an electron-withdrawing group (i.e., NO2CN, I) is the acylation conventional method used in the ed, can be alkylated with compounds V, where X is a leaving group. Alkylation of compound X can be done by pre-education Aza-anion compounds X, using a base (for example, tert-piperonyl potassium, NaNH2, Na, NaH, utility or other lithium base, NaOH/KOH by catalysis of the transfer phases) in a solvent such as toluene, dimethylsulfoxide, DMF, acetonitrile, acetone, diethyl ether, dioxane, tetrahydrofuran, at temperatures from -25oC to the boiling point of the solvent. Illustrated below alkylation to produce compounds I can be carried out by adding to the reaction mixture of compounds V in the same reaction conditions as above.

As alternative methods for obtaining compounds IX, the same reaction of alkylation of compound X can be carried out using compounds VII.

The compounds of formula I (R - alkylsulphonyl, R2-AlkCO) can be obtained from corresponding compounds X (R2-alkyls) by protecting ketogroup (such as 1,3-dioxopyrimidine) using standard methods, followed by alkylation of the nitrogen aminogroup, as described above. the W methods some examples listed in vicepresidency table 5.

Example 46. 1-[N-Cyclohexylcarbonyl-N-(2-methanesulfonylaminoethyl)-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine

The solution is 0.22 g of compound of example 27 and 0.08 ml of triethylamine (tea) in 5 ml of CH2CL2mixed at room temperature in an atmosphere of anhydrous nitrogen was added dropwise a solution of 0.04 ml methanesulfonanilide in 0.5 ml of CH2Cl2. The solution was stirred for 6 h at room temperature; it is then evaporated to dryness in vacuum and the residue was purified flash chromatography (CH2Cl2-MeCN 9:1) to obtain 0.10 g (39%) specified in the connection header.

1H-NMR (D13, ): of 9.55 (s, 1H, NH), 7,60 (DD, 1H, CH ring methanesulfonylaminoethyl), 7,30 was 7.45 (m, 1H, CH ring methanesulfonylaminoethyl), 7,10-of 7.23 (m, 2H, CH ring methanesulfonylaminoethyl), 6,80-7,05 (m, 4H, CH group ring methoxyphenyl), 4,90-5,10 (m, 1H, ), 3,83 (s, 3H, och3), 2,35-of 3.60 (m, 11H, protons, piperazine ), 3,05(c, 3H, SO2CH3), 0,70-of 2.20 (m, 11H, cyclohexyl protons).

Example 54. 1-[N-(2-Trifloromethyl)-2-amino-ethyl]-4-(2-methoxy-4-nitrophenyl)piperazine

Specified in the title compound was synthesized by the interaction of the compounds 50V and 1-(2-methoxy-4-nitrophenyl)Pieniny of example 50, when heated at 120oWith over 13 hours the Residue was purified flash chromatography (petroleum ether : EtOAc 70:30). Yield 57%.

1H-NMR (D13, ): 7,88 (DD, 1H, H5 ring methoxyphenyl), 7,72 (d, 1H, H3, ring methoxyphenyl), 7,09-7,22 (m, 2H, H3 and H5 ring trifloromethyl), of 6.90 (d, 1H, N6 ring methoxyphenyl), 6,60-to 6.80 (m, 2H, H4 and h6 ring trifloromethyl), 4,90 (user. s, 1H, NH), of 3.95 (s, 3H, och3), 3,10-of 3.45 (m, 6N, piperazine protons), 2,55-2,90 (m, 6N, piperazine protons).

Example 56. 1-[N-Cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(4-amino-2-methoxyphenyl)piperazine

Specified in the title compound was obtained in accordance with the procedure of example 27 but replacing the compound of example 2 compound of example 55 and boiling under reflux for 3 hours, the Residue was purified flash chromatography (EtOAc). Yield 58%.

1H-NMR (D13, ): 7,25-rate of 7.54 (m, 4H, group SN rings trifloromethyl), to 6.75 (d, 1H, N6, ring AMINOPHENYL), 6,18-6,30 (m, 2H, H3 and H5 ring AMINOPHENYL), 4,20-and 4.40 (m, 1H, ), of 3.78 (s, 3H, CH3O) 3,50 (user.s, 2H, NH2), 3,15-to 3.38 (m, 1H ), 2,80 is 3.15 (m, 4H, piperazine protons), 2.40 a is 2.75 (m, 6N, protons, piperazine ), 1.85 to 2.05 is (m, 1H, SNCO), 0,80-of 1.75 (m, 10H, cyclohexyl protons).

Example 57. 1-[N-Cyclohexylcarbodiimide received in accordance with the method of example 28, but replacing the compound of example 27 compound of example 56 and with stirring for 20 hours the Residue was purified flash chromatography (l3- 2 n solution of NH3in methanol 100:3) to obtain the specified title compound as a glassy solid hot pink color. Yield 77%.

1H-NMR (D13, ): 7,25-7,52 (m, 5H, group SN rings trifloromethyl and CH ring methoxyphenyl), 7,18 (s, 1H, NHCO), PC 6.82 (s, 2H, group SN rings methoxyphenyl), 4,22 was 4.42 (m, 1H ), 3,85 (s, 3H, CH3O), 3,17 is 3.40 (m, 1H ), 2,85-3,10 (m, 4H, piperazine protons), 2,40-3,10(m, 4H, piperazine protons, ), of 2.15 (s, 3H, CH3WITH), 1.85 to 2.05 is (m, 1H, SNCO), 0.75 to about 1.75 (m, 10H, cyclohexyl protons).

Example 60. 1-[N-Cyclohexylcarbonyl-N-(2-nitrophenyl)-2-amino-ethyl]-4-[4-(N-acetyl-N-cyclohexylcarbonyl)amino-2-methoxyphenyl]piperazine

Obtain 1-[N-(2-nitrophenyl)-2-amino-ethyl] -(4-amino-2-methoxyphenyl)piperazine (Compound 60A)

Specified in the title compound was obtained according to the method of example 12, except that instead of 1-(4-indolyl)piperazine used 1-(4-amino-2-methoxyphenyl)piperazine instead of triethylamine used DIPEA. The mixture was heated at 90oWith over 16 h and purified flash chromatography (EtOAc - 3 N. the solution N in Mauser.with, 1H, NH), 8,18 (d, 1H, H3 rings nitrophenyl), was 7.45 (DD, 1H, H5 ring nitrophenyl), for 6.81-to 6.95 (m, 2H, H2 rings nitrophenyl and N6 ring methoxyphenyl), 6,60 (DD, 1H, H4 ring nitrophenyl), 6,20 of 6.31 (m, 2H, H3 rings methoxyphenyl, H5), of 3.80(s, 3H, CH3O), 3,29-to 3.52 (m, 2H, ), 2,50-4,00 (m, 2H, NH2), 2,90-3,20 (m, 4H, piperazine protons), 2,58-2,90 (m, 6N, piperazine protons, ).

Obtain 1-[N-(2-nitrophenyl)-2-amino-ethyl] -4-(4-acetylamino-2-methoxyphenyl)piperazine (Compound 60)

Specified in the title compound was synthesized according to the method of example 28, but replacing the compound of example 27 compound of example 60A, replacement of CH2Cl2on SNS3and stirring for 3 hours After evaporation of the solvent used conventional method of processing the connection is 60V. A yield of 99%.

1H-NMR (D13, ): 8,40 (user.s, 1H, NHCO), 8,18 (d, 1H, H3 rings nitrophenyl), 7,40-7,52 (m, 2H, H5 and h6 ring nitrophenyl (or H3 rings methoxyphenyl), 7,20 (user.s, 1H ), 6,70-6,97 (m, 3H, N6 and N3 ring methoxyphenyl (or N6 ring nitrophenyl) and H4 ring nitrophenyl), only 6.64 (DD, 1H, H5, ring methoxyphenyl), 3,85 (s, 3H, och3), 3,34-to 3.58 (m, 2H, ), 2,95-3,20 (m, 4H, piperazine protons), 2,62-2,95 (m, 6N, piperazine protons ), of 2.15 (s, 3H, CH3WITH).

Obtain 1-[N-R> Specified in the title compound was synthesized following the procedure described to obtain the compound in example 42, except that the compound of example 41 was replaced by a connection 60V and boiling under reflux was continued for 2 hours, the Crude substance was purified flash chromatography (EtOAc : petroleum ether 9:1). The output is 27%.

1H-NMR (D13, ): with 8.05 (DD, 1H, H3 rings nitrophenyl), 7,42-7,73 (m, 3H, H4, H5 and h6 ring nitrophenyl), 6,91 (d, 1H, N6, ring methoxyphenyl), of 6.68 (DD, 1H, H5 ring methoxyphenyl), 6,55 (d, 1H, H3 rings methoxyphenyl), 3,55-4,18 (m, 5H, CH3WITH and ), 2,37-is 3.21 (m, 10H, piperazine protons and CONCH2CH2N) to 2.35 (s, 3H, CH3WITH), 0,72-2,05 (m, 22N, the protons of the cyclohexyl).

Example 63. 1-[N-(2-Nitrophenyl)-N-(2-pyrimidinamine)-2-amino-ethyl)]-4-(2-methoxyphenyl)piperazine

Getting 2-pyrimidinecarbonitrile (Connection A)

Stir the mixture 0,837 g of the hydrochloride of 2-pyrimidinecarboxylic acid (obtained as described in S. Gronowitz et al., Ark.Chemi, 1964, 22, 66-82), 30 ml SNS3and 2 ml of thionyl chloride are boiled under reflux for 12 hours After cooling to room temperature, the suspension was filtered and the filtrate evaporated in vacuo to dryness to obtain 0,306 g (67%) specified in sustained fashion cleanup.

Obtain 1-[N-(2-nitrophenyl)-N-(2-pyrimidinamine)-2-amino-ethyl)]-4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described to obtain the compound in example 32, except that instead of 3 shrinkability used connection 61A and boiling under reflux was continued for 11 hours the Crude substance was purified flash chromatography (SNS3- 2 n solution of NH3in methanol 100:3). Yield 65%.

1H-NMR (DMSO-d3, ): 9,00 and at 8.60 (2D, 2H, H4 and h6 pyrimidine), 8,10 and 7,98 (DD, 1H, H3 rings nitrophenyl), of 7.90-7,78 and 7,70-7,52 (2m, 2H, H5 and h6 ring nitrophenyl), 7,52-the 7.43 (m, 1H, H4 ring nitrophenyl), 7,32 (m, 1H, pyrimidine H5), 7,00-of 6.65 (m, 4H, group SN rings methoxyphenyl), 4,45-4,22 and 4.12-3,80 (2m, 1H ), 3,72 and of 3.69 (2s, 3H, CH3O), 2,15-2,95 (m, 11N, ), piperazine protons).

Example 71. 1-[N-(2-Trifloromethyl)-2-amino-ethyl] -4-(2-trifloromethyl)piperazine

Specified in the title compound was obtained following the procedure described for example 54, but using 1-(2-trifloromethyl)piperazine instead of 1-(4-nitro-2-methoxyphenyl)piperazine. The reaction mixture was heated for 8 h at 120oC. the Residue obtained by traditional processing and extraction Et2VCE connection. Yield 41%.

1H-NMR (D13, ): 7,09-7,30 (m, 4H, group SN ring triphtalocyaninine), 6,90-to 7.09 (m, 2H, group SN rings trifloromethyl), 6,58-to 6.80 (m, 2H, group SN rings trifloromethyl), to 4.92 (s, 1H, NH), 2,98-to 3.38 (m, 6N, piperazine protons), 2,45-to 2.85 (m, 6N, piperazine protons).

Example 73. 1-[N-(2-Nitrophenyl)-N-(5-triazolylmethyl)-2-amino-ethyl)]-4-(2-methoxyphenyl)piperazine

Specified in the title compound was obtained following the procedure described for the compound in example 32, except that instead of 3 shrinkability used 5-thiazolecarboxamide (obtained as described in ER). The crude compound was purified flash chromatography (SNS3- 2 n solution of NH3in methanol 100:1). Yield 68%.

1H-NMR (DMSO-d3, ): 9,06 (s, 1H, H2 of thiazole), 8,17(DD, 1H, H3 rings nitrophenyl), 7,81-of 7.96 (m, 2H, H4 and h6 ring nitrophenyl), a 7.62-7,81 (m, H5 ring nitrophenyl), was 7.45 (s, 1H, H4 of thiazole), 6,70-6,98 (m, 4H, group SN rings methoxyphenyl), 3,80-4,10 (m, 2H, ), 3,71 (s, 3H, CH3O), 2,45-2,90 (m, 6N, piperazine protons), 2,20-2,40 (m, 4H, piperazine protons).

Example 81. 1-[N-(2-Acetylphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine

Obtaining N-(2-acetylphenyl)cyclohexanecarboxylate (With the tion, instead of 2-triptorelin used 2-acetylation. Output 90%.

Obtaining N-[2-(2-methyl-1,3-dioxolane-2-yl)phenyl]cyclohexanecarboxylic (Connection W)

A solution of 8 ml of ethylene glycol, of 0.23 g of compound A and 0.03 g of p-toluenesulfonic acid. H2About 20 ml of toluene was boiled under reflux for 6 h, removing the H2O using traps Dean-stark. The solution was washed H2O (10 ml) and 5% NaHCO3(2 x 10 ml). The dried (Na2SO4) organic phase was evaporated to dryness and the residue was purified flash chromatography (petroleum ether : EtOAc 95: 5) to give 0.11 g (42%) specified in the connection header.

1H-NMR (D13, ): a 9.25 (s, 1H, NH), of 8.25 (DD, 1H, H6 of phenyl ring), was 7.45 (DD, 1H, H3 of phenyl ring), 7,28 (m, 1H, H4 of phenyl ring), 7,05 (t, 1H, H5 phenyl ring), 3,95-4,12 and 3.75-3,90 (2m, 4H, och2CH2About in), 2.25 (TT, 1H, SNCO), by 1.68 (s, 3H, CH3), 1,20-2,10 (m, 10H, cyclohexyl protons).

Obtain 1-[N-cyclohexylcarbonyl-N-[2-(2-methyl-1,3-dioxolane-2-yl)phenyl]-2-amino-ethyl]-4-(2-methoxyphenyl)piperazine (Compound 81s with).

Specified in the title compound was obtained following the procedure described for the compound of example 39, but instead of connecting 39A used connection V and boiling with reverse cold methanol 100:2) to obtain specified in the connection header. Yield 40%.

1H-NMR (D13, ): to 7.67-7,73 (m, 1H, h6 of phenyl ring), 7,25-7,35 (m, 3H, H3, H4 and H5 phenyl ring), 6,80-7,05 (m, 4H, protons of ring methoxyphenyl), 4,40-4,63 (m, 1H ), 3.95 to 4,12 and 3.75-3,90 (2m, 4H, och2CH2O), 3,85 (s, 3H, och3), 2,95 is 3.23 (m, 5H, protons of piperazine), 2,55-2,90 (m, 6N, piperazine protons), of 1.65 (s, 3H, CH3), 0,75-1,90 (m, 11N, the protons of the cyclohexyl).

Obtain 1-[N-(2-acetylphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)piperazine

A solution of 0.10 g of compound 81s with and 0.09 g PTSAH2O in 4 ml of Me2CO was stirred at 20-25oC for 15 h Then the solution was poured into 10 ml of N2O, podslushivaet 5% Panso3and was extracted with CH2C12(3 x 7 ml). The dried (Na2SO4) the organic layer was varibale to dryness and purified flash chromatography (SNS3- 2 n solution of NH3in methanol 100:2) to give 0.05 g (54%) specified in the connection header.

1H-NMR (D13, ): of 7.75 (DD, 1H, h6 of phenyl ring), 7,35-of 7.60 (m, 3H, H4, H4, H5 phenyl ring), 6,80-7,05 (m, 4H, group SN rings methoxyphenyl), 4,27 is 4.45 (m, 1H, 3,85 (s, 3H, och), 2,95-3,20 (m, 5H, protons of piperazine), 2,47-to 2.85 (m, 6N, piperazine protons), of 2.50 (s, 3H, CH3), 1,80-2,05 (m, 1H, SNCO), 0,75 and 1.80 (m, 10H, cyclohexyl protons).

Example 84. 1-[is shown in the title compound was obtained as a side product during the synthesis of the compound of example 51. Output 10%.

1H-NMR (D13, ): 8,15 (DD, 1H, H7 of indolyl), 7,18-of 7.55 (m, 6N, N2 and N6 of indolyl, group SN rings trifloromethyl), to 6.75 (DD, 1H, H5 of indolyl), of 6.65 (DD, 1H, H3 of indolyl), 4,12-of 4.25 (m, 1H ), 2.95 and-3,50 (m, 6N, piperazine protons), 2.40 a-2,85 (m, 6N, piperazine protons), 0,70-2,10 (m, N, SNCO, the protons of the cyclohexyl).

Example 85. 1-[N-Cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(8-chinolin)piperazine

Obtaining N-(2-trifloromethyl)cyclohexanecarboxylate (Compound 85A)

This compound was obtained following the procedure described for compound 26A of example 26, except that instead of 2-triptorelin used 2-cryptomaterial. Output 100%.

1H-NMR (D13, ): 8,44 (DD, 1H, h6 of phenyl ring), 7,47 (user.s, 1H, CONH), 7,21-7,30 (m, 2H, H4 and H5 phenyl ring), 7,08-7,14 (m, 1H, H3 of phenyl ring), 2,21 is 2.43 (m, 1H, SNCO), 1,20-of 2.08 (m, 10H, cyclohexyl protons).

Obtaining N-(2,2-dimethoxymethyl)-N-(2-trifloromethyl)cyclohexanecarboxylate (85B)

A solution of compound 85A (0.15 g) in toluene (20 ml) was boiled under reflux to distillation 5 ml of toluene; then added t-BuOK (0.09 g) and the mixture is boiled under reflux, removing by evaporating 2 ml solvent; then added in kapl the fere N2within 12-15 hours After cooling to room temperature, the solvent evaporated in vacuo to dryness and the crude product was purified flash chromatography (petroleum ether : EtOAc 9:1) to obtain the 0,106 g (54%) indicated in the title compound in the form of butter.

1H-NMR (D13, ): 7,31-of 7.48 (m, 4H, group CH of phenyl ring), br4.61-4,60 (m, 1H, 4,16-4,24 (m, 1H ), 3,39 (s, 3H, och3), of 3.32 (s, 3H, och3), 3,13-3,24 (m, 1H ), 1,92-of 2.09 (m, 1H, SNCO), 0,85-to 1.79 (m, 10H, cyclohexyl protons).

Obtaining N-(2-oxoethyl)-N-(2-trifloromethyl)cyclohexanecarboxylate (85C)

Suspension connection 85V (0,106 g), hydroquinone (0.003 g) in 2 N. of PC1 (1,14 ml) was heated at 80oC for 30-40 min After cooling to room temperature was added Panso3(pH 7) and the resulting mixture was extracted with CH2Cl2(3 x 10 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated to dryness under reduced pressure obtaining of 0.081 g (88%) indicated in the title compound in the form of butter.

1H-NMR (D13, ): 9,62 (s, 1H, Cho), 7.29 trend-EUR 7.57 (m, 4H, group CH of phenyl rings), of 4.67 (d, 1H, 3,86 (d, 1H, 2,02-to 1.98 (m, 1H, SNCO), 0,85 of-1.83 (m, 10H, cyclohexyl protons).

Obtaining 1-(8-chinolin)piperazine (85D)

A mixture of 8-amine which does boiling under reflux for 5 hours After cooling to room temperature the mixture was treated with 2 N. NaOH (10 ml) and was extracted with CH2Cl2(3 x 20 ml). Purification was performed using flash chromatography (CH2Cl2- 2 n solution of NH3in methanol, 97:3) to obtain the 0,48 g (22%) specified in the connection header.

1H-NMR (D13, ): 8,80(DD, 1H, H2 chinoline), 8,17 (DD, 1H, H4 chinoline), 7,32-7,53 (m, 3H, h6, H5, H3 chinoline), 7,12(m, 1H, H7 chinoline), 3,38-3,51 (m, 4H, piperazine protons), 3,21-of 3.32 (m, 4H, piperazine protons), 2,21 (user.s, 1H, NH).

Obtain 1-[N-cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(8-chinolin)piperazine

To a solution of compound 85C (of 0.081 g), compounds 85D (0.06 g) and acetic acid (0.06 ml) in 1,2-DCE (10 ml), stirred in an atmosphere of N2added N(SLA)3N (0,078 g). The resulting mixture was stirred for 2 h at 20-25oWith, podslushivaet 1 N. NaOH (pH 8) and was extracted with CH2Cl2(3 x 10 ml). The organic layer was dried over Na2SO4, was filtered and was evaporated at reduced pressure. The crude product was purified flash chromatography (toluene : acetone 75: 25) to give 0.09 g (73%) specified in the connection header. So pl. 141,5-143oC.

1H-NMR (D13, ): 8,86 (DD, 1H, H2 chinoline), 8,14 (l is 1 (m, 5H, protons of piperazine and 2,53-to 2.94 (m, 6N, piperazine protons and 1,89-2,07 (m, 1H, SNCO), 0,81-to 1.79 (m, 10H, cyclohexyl protons).

Example 86. 1-[N-Cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(4-amino-2-cyanophenyl)piperazine

Obtain 1-(2-cyano-4-nitrophenyl)piperazine (Compound 86A)

A mixture of 2-chloro-5-nitrobenzonitrile (1 g) and piperazine (2,12 g) in monopetalum ether of ethylene glycol (5 ml) was heated at 60oC for 30 minutes After cooling to room temperature was added N2O (50 ml) and the solution was extracted using CH2Cl2(3 x 25 ml). The combined organic layers were washed H2O, dried over Na2SO4and evaporated to dryness to obtain 1.27 g (99%) of the desired compound.

1H-NMR (D13, ): 8,46 (d, 1H, H3 phenyl), of 8.27 (DD, 1H, H5 phenyl), of 6.68 (d, 1H, h6 of phenyl, 3,48 of 3.56 (m, 4H, piperazine protons), 3,03-3,14 (m, 4H, piperazine protons), 1,75 (user.s, 1H, NH).

Obtain 1-[N-cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(2-cyano-4-nitrophenyl)piperazine (Compound V)

Specified in the title compound was obtained by the method described in example 85, substituting 1-(8-chinolin)piperazine compound 86A.

The crude product was purified flash chromatographia ring cyanophenyl), 7,29-7,49 (m, 4H, group SN rings trifloromethyl), of 6.96 (d, 1H, N6 ring cyanophenyl), 4,22-to 4.41 (m, 1H, 3,41-of 3.60 (m, 4H, piperazine protons), 3,21-3,39 (m, 1H, 2,70-and 2.83 (m, 2H, 2,47-2,69 (m, 4H, piperazine protons), 1,88-2,07 (m, 1H, SNCO), or 0.83-to 1.79(m, 10H, cyclohexyl protons).

Obtain 1-[N-cyclohexylcarbonyl-N-(2-trifloromethyl)-2-amino-ethyl]-4-(4-amino-2-cyanophenyl)piperazine

Specified in the title compound was obtained as described in example 27, using the connection example 86A 86 instead of the compound of example 1. The crude product was purified flash chromatography (EtOAc : MeOH 95:5, then toluene : acetone 75:25). Yield 43%.

1H-NMR (D13, ): of 7.48-of 7.69 (m, 4H, group SN rings trifloromethyl), 6,86-6,98(m, 1H, N6 ring cyanophenyl), 6,76-6,84 (m, 2H, H3, H5 ring cyanophenyl), to 5.17 (s, 2H, NH2), 4,01-4,20 (m, 1H, 3,09 of 3.28 (m, 1H, 2,72-of 2.93 (m, 4H, piperazine protons), 2,31 at 2.59 (m, 6N, and piperazine protons), 1,76-of 1.97 (m, 1H, SNCO), 0,72-of 1.73 (m, 10H, cyclohexyl protons).

1. Derivatives of 1-(N-phenyliminomethyl)piperazine of General formula I:

< / BR>
where R denotes cycloalkylcarbonyl, substituted alkyl or phenyl cycloalkylcarbonyl group or monocyclic heteroarylboronic group having 5-6 ring atoms selected from the group comprising furyl the/BR>R1is a hydrogen atom or a lower alkyl group;

R2is a halogen atom or alkoxy group, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulfonyl, alkoxycarbonyl, carbarnoyl, allylcarbamate, dialkylamino, arylcarbamoyl, trifluoromethyl or polyporaceae;

In denotes phenyl, bicyclic heteroaryl group selected from the group comprising indolyl and finalyl or benzyl group, each of which may be unsubstituted or substituted alkoxy, halogen, nitro, amino, acylamino, diarylamino, acertravelmate or cyano, provided that if In - alkoxy-substituted phenyl, this alkoxygroup must be in position 2 of the phenyl ring,

or its enantiomer, N-oxide, hydrate or pharmaceutically acceptable salt.

2. Connection on p. 1, where In - group, 2-methoxyphenyl, 2,5-dichlorobenzyl or 4-indolyl.

3. Connection under item 1 or 2, where R2the iodine atom or a methoxy group, phenoxy, nitro, cyano, acetyl, amino, acetamido, methoxycarbonyl, carbarnoyl, ethylcarbitol, dimethylcarbamoyl, cyclohexylcarbonyl, trifluoromethyl, triptoreline or 2,2,2-triptoreline.

4. The compound according to any preceding paragraph, where R is teleradiology, 3-pyridylcarbonyl or 2-pyrazinecarboxamide.

5. The compound according to any preceding paragraph, where R1is a hydrogen atom or a methyl group.

6. Connection on p. 1, selected from

1-(N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-trifloromethyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-2-methoxyphenyl)-piperazine,

1-[N-(2-phenoxyphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-itfeel)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(4-indolyl) piperazine,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2,5-dichlorobenzyl)-piperazine,

1-[N-(2-cyclohexanecarbonitrile)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-ethoxycarbonylphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-dimethylcarbamoyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4(2-methoxyphenyl)-piperazine,

1-[N-(2-methoxyphenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-ethylcarbamate)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-Pieper is 2-AMINOPHENYL)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-acetamidophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl]-4-{2-methoxyphenyl)-piperazine-N1-oxide,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine-N4-oxide,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine-N1N4-dioxide,

1-[N-(2-nitrophenyl)-N-(3-fullcarbon)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-{ 2-nitrophenyl)-N-(2-fullcarbon)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(2-thienylboronic)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(3-thienylboronic)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(4-pyridylcarbonyl)-2-amino-ethyl)-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(3-pyridylcarbonyl)-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(2-pyrazinecarboxamide)-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(1-methylcyclohexylamine)-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-(1-phenylcyclohexylamine)-2-amino-ethyl]-4-(2-methoxyphenyl)-piperazine,

1-[N-[2-(2,2,2-cryptonetx arbonyl-2-amino-ethyl] -4-(2-methoxyphenyl)-piperazine,

1-[N-(2-nitrophenyl)-N-cyclohexylcarbonyl-1-amino-2-propyl] -4-(2-methoxyphenyl)-piperazine,

or its enantiomer, N-oxide, hydrate or pharmaceutically acceptable salt.

7. Pharmaceutical composition for treating neuromuscular dysfunction of the lower urinary tract of a mammal, characterized in that it contains a compound according to any one of the preceding paragraphs in a mixture with a pharmaceutically acceptable diluent or carrier.

 

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The invention relates to new substituted derivatives of piperidine derivatives, to processes for their preparation, to pharmaceutical compositions and to their use in medical therapy, particularly in treatment of psychotic disorders

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to trehzameshchenny phenyl derivative of the General formula (1) in which Y represents a group or SIG1where R1represents a C1-C6alkyl group, optionally substituted by up to three halogen atoms; R2represents a C1-C6alkyl or C3-C8cycloalkyl provided that Y and-OR2are not both methoxypropane; R3represents a hydrogen atom or a hydroxy-group; R4and R5that may be the same or different, represent a group -(CH2)nAr, where n = 0 or 1 and Ar is a phenyl or heteroaryl group containing one or two 5 - and/or 6-membered ring containing up to three heteroatoms selected from oxygen, sulfur and nitrogen, where Ar is optionally substituted with halogen, C1-C6the alkyl, C1-C6hydroxyalkyl,1-C6alkoxy, C1-C6alkoxy-C1-C6the alkyl, C1-C6halogenation, amino,

di-(C1-C6)alkylamino-C1-C6by alkyl, hydroxyl, formyl, carboxyla,1-C6alkoxycarbonyl,1-C6alkanoyloxy, thiol, carboxamido,1-C6alkanolamine,

The invention relates to new piperidine derivative of the formula I, where R1means sensational, benzofuranyl, naphthyl which may be substituted with halogen, C1-C6-alkyl, C1-C6-alkoxygroup, substituted thienyl or substituted furanyl, which is substituted by halogen, C1-C6-alkyl, C3-C6-cycloalkyl or1-C6-alkenyl, R2means halogen and R3means1-C6-alkyl or C3-C6-cycloalkenyl, or their pharmaceutically acceptable salt, or solvate

The invention relates to new derivatives benzoylpyridine General formula (I), where R1means alkyl with 1-8 carbon atoms, a represents a group represented by the formula of the invention, means (-CH2-)aor (-CO-)band means an integer of 0 to 8, preferably 1, 2, 3 or 4, b means of 0,1 or 2, preferably 1, R2means unsubstituted or substituted alkyl with 1-8 carbon atoms, unsubstituted phenyl, NR3R4or preferably the five-membered heterocycle represented in the claims, in which U, V, W, X and Z can mean CH, NH, O or S, R3and R4denote alkyl with 1-8 carbon atoms

The invention relates to new Bermatingen compounds, the United propylenebis communication, General formula I where Ar represents a radical of formula (a) or (b), R1is-OR6or-COR7, R2represents a polyether radical, comprising 1 to 6 carbon atoms and 1 to 3 atoms of oxygen or sulfur, and if in the latter case, R4represents a linear or branched C1-C20alkyl, he is in ortho - or meta-position relative to X-Ar connection, R3represents lower alkyl, or R2or R3taken together form a 6-membered ring, optionally substituted by at least one of the stands and/or optional split the atom of oxygen or sulfur, R4represents H, linear or branched C1-C20alkyl or aryl, R5represents H or-OR8, R6represents H, R7represents H, -OR10or-N(r)r (r) r are H, lower alkyl or taken together with the nitrogen atom form a ring of morpholino, R8represents H or lower alkyl, R10represents H, linear or branched C1-C20alkyl, X represents a divalent radical, which is from right to left or Vice versa has the formula (d), R11Fri carboxylic acid and the optical and geometrical isomers of the above compounds of formula (I)

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new derivatives of chloropyridinyl formula I where Het is a group of formula a, b, C, d or e, R1is hydrogen, unsubstituted or substituted C1- C6alkyl, and the substituents selected from the group comprising halogen, phenyl, cyano, C1- C4alkoxy, C1- C4alkylthio,1- C4alkylsulphonyl; C2- C4alkenyl, unsubstituted or substituted C1- C4alkoxygroup; phenyl or unsubstituted or substituted 1 or 21- C4alkoxygroup, n = 1 or 2, and their acid additive salts

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

The invention relates to new benzofuranyl derivatives and to the method of obtaining these derivatives

The invention relates to a derivative of urea of General formula I, in which R1denotes hydrogen or lower alkyl, R2is hydrogen or halogen and R3is hydrogen or lower alkoxy, and their physiologically compatible acid additive salts

The invention relates to a method for the preparation of 3-acylated indoles of formula I

< / BR>
where R1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl, optionally substituted by one or more hydroxy-, WITH1-C4-alkyl, C1-C4-alkoxy, fluorine, fluorine(C1-C4)-alkyl and fluorine(C1-C4)-alkoxy; X is hydrogen or one or more substituents independently selected from CN, G, NO2WITH1-C6-alkyl, C1-C6-alkoxy, C3-C7-cycloalkyl, aryl, which is optionally substituted by one or more cyano-, G, NO2WITH1-C4-alkyl, C1-C4-alkoxy, fluorine(C1-C4)alkyl and fluoro(C1-C4)alkoxy; or R - N-carboxymethyl-2-pyrrolidinyl, and X Is 5-Br

The invention relates to billnum compounds or substituted pyridinium formula (I), where X denotes N or CR8where R8denotes hydrogen, halogen, phenyl, alkyl, alkoxy, alkoxycarbonyl, carboxy, formyl or-NR4R5where R4and R5denote hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, naphthyl; R1aand R1Brepresent trifluoromethyl, alkyl, alkenyl, quinil, cycloalkyl, alkanoyl; R2denotes alkyl, alkenyl, quinil, cycloalkyl; R3denotes hydroxy, TRIFLUOROACETYL, alkanoyl, alkenyl; AG denotes an aromatic or heteroaromatic ring, for example phenyl, naphthyl, pyridyl, furanyl, thiophenyl

The invention relates to novel azole compounds having antifungal activity, their preparation and application
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