Derivatives of 3-(5-tetracarbonyl)aminopiperidine, methods for their preparation and pharmaceutical composition based on them

 

(57) Abstract:

Derivatives of 3-(5-tetracarbonyl)aminopiperidine formula I, where R1- C1-4alkoxy; R2- the residue of formula (a); R3- H or halogen; R4, R5- H, halogen, C1-4alkyl, C1-4alkoxy, CF3; R6- H, C1-4alkyl, (CH2)mcyclopropyl, -S(O)nWITH1-4alkyl, phenyl, NR7R8CH2C(O)CF3or CF3; R7, R8- H, C1-4alkyl or acyl; x = 0 or 1; n = 0, 1, or 2; m = 0 or 1, or its pharmaceutically acceptable salt, or solvate are strong and specific antagonists of tachykinins, including substance P and other neurokinin. 5 C. and 17 C. p. F.-ly, 1 Il.

The invention relates to derivatives of piperidine derivatives, process for their preparation, containing their pharmaceutical compositions and their use in medicine.

More specifically, the invention relates to new compounds which are strong and specific antagonists of tachykinins, including substance P and other neurokinin.

Known [application PCT WO-A-9109844 and WO-A-9301170] derivatives of 3-aminopiperidine, which has antagonistic activity against substance P.

According to the present Jerusalem. represents C1-4alkoxygroup;

R2represents a

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R3denotes a hydrogen atom or halogen;

R4and R5independently from each other represent a hydrogen atom or halogen or the group C1-4alkyl, C1-4alkoxy or trifluoromethyl;

R6denotes a hydrogen atom, a C1>-4alkyl, (CH2)mcyclopropyl, -S(O)nC1-4alkyl, phenyl, NR7R8CH2C(O)CF3or trifluoromethyl;

R7and R8independently from each other represent a hydrogen atom or a group C1-4alkyl or acyl;

x represents 0 or 1;

n represents 0, 1 or 2;

m represents 0 or 1,

and pharmaceutically acceptable salt and solvate of such compounds.

Suitable pharmaceutically acceptable salts of the compounds of General formula (I) are salts obtained by addition of acid, namely salts formed with pharmaceutically acceptable organic or inorganic acids, such as hydrochloride, hydrobromide, sulphates, alkyl - or arylsulfonate (such as methanesulfonate or p-toluensulfonate), phosphates, acetates, citrates, succinate, tartratami, fumarate and maleate. Most PR is efticiency acceptable but can be used to obtain salts, which are intermediate compounds in the formation of compounds of formula (I) and their pharmaceutically acceptable acid additive salts.

The solvate may be, for example, hydrates.

In this text the phrase "joint invention" means both the compounds of formula (I) and their pharmaceutically acceptable salts obtained by addition of acid, and pharmaceutically acceptable solvate.

The specialist should be clear that the compounds of formula (I) have at least two centers of chirality, marked with asterisks in the formula (I), and thus exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof, including racemic mixtures.

For example, the compounds of formula (I) may be CIS-isomers, as shown in figures (a) and (b), or TRANS-isomers, as shown in figures (C) and (d), or mixtures thereof.

All isomers of the compounds of formula (I) are presented in figures (a) through (d) and their mixtures, including racemic, are included in the scope of the invention.

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The compounds of formula (I) are preferably in the form of CIS-isomers, that is, as shown n the th formula (I) C1-4alkoxygroup can be alkoxygroup with normal or branched chain, such as methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or 2-methylprop-2-oxy. Group C1-4the alkyl can be an alkyl group with a normal or branched chain, such as methyl, ethyl, propyl, prop-2-yl, butyl, but-2-yl, 2-methylprop-1-yl or 2-methylprop-2-yl.

In the General formula (I), the halogen atom may be a fluorine atom, chlorine, bromine or iodine, for example fluorine, chlorine or bromine.

In the General formula (I) as R1ideal group is methoxy, ethoxy or prop-2-oxy.

In the General formula (I) as R2suitable group

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If in the General formula (I) R3represents a halogen atom, this may be chlorine or, more preferably, fluorine.

If in the General formula (I) R4or R5is a group of C1-4alkyl, suitable is a methyl group, if R4or R5represents a C1-4alkoxygroup, then appropriate is the methoxy group. Suitable values for R5are hydrogen, fluorine, chlorine or bromine. R4and R5both can be hydrogen or both can be fluorine, or one of the groups R4and R6is a group NR7R8this group may represent NH2, NH(C1-4alkyl), for example NH, NH, that is NHC(O)methyl, or N(C1-4alkyl)2for example N(methyl)2N(ethyl)2.

If in the General formula (I) R6is a group of C1-4alkyl, it may be methyl, ethyl or propyl.

If in the General formula (I) R6is a group S(O)nC1-4alkyl, it may be-S(OH)nmethyl, for example-S-methyl or-SO2methyl.

If in the General formula (I) R2is defined above group (A), R6may be a hydrogen atom or a group C1-4alkyl, for example methyl, ethyl or propyl, (CH2)mcyclopropyl, where m is zero, S(O)nC1-4alkyl, for example S(O)nmethyl, such as S-methyl or SO2is methyl, phenyl, NR7R8for example NH2, NH(C1-4alkyl), for example NH, NH, that is NHC(O)methyl, or N(C1-4alkyl)2for example N(methyl)2or N(ethyl)2CH2C(O)CF3or trifluoromethyl.

If in the General formula (I) R2is defined above, (B), R6suitable hydrogen. If R2is defined above, (C), t is equal to 1.

If in the General formula (I) R2is defined above group (A), then x can be 0 or 1. If R2is defined above, (B), then x can be 0 or 1. If in the General formula (I) R2is defined above, (C), then x can be 0.

R1preferred is a methoxy group.

R2preferably is defined above group (A).

R3preferably is a hydrogen atom.

R4and R5preferably are hydrogen atoms.

R6preferably is a hydrogen atom, a C1-4alkyl, for example methyl, or trifluoromethyl.

x is preferably zero.

A preferred class of compounds of formula (I) are compounds in which

R1represents a C1-4alkoxygroup,

R2represents a

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where R6is a hydrogen atom, a C1-4alkyl, cyclopropyl or trifluoromethyl,

x is zero, and

R3, R4and R5each represents a hydrogen atom.

Also preferred class of compounds of formula (I), where

R1represents a C1-4alkoxycarbonyl, S(O)nC1-4alkyl (where n is zero or trifluoromethyl,

x is zero, and

R3, R4and R5each represents a hydrogen atom.

Another preferred class of compounds of formula (I) is the where

R1represents a methoxy group,

R2to pose the above group (A),

x is equal to zero,

R3, R4and R5represent hydrogen atoms, and

R6represents a hydrogen atom or a methyl group, or trifluoromethyl.

Specific compounds according to the invention include:

2-methoxy-[5-(5-propertyreal-1-yl)benzyl] -(CIS-phenylpiperidine-Z-yl)amine,

[5-(5-elitetrader-1-yl)-2-methoxybenzyl]-(CIS-phenylpiperidine-Z-yl)amine,

(2-methoxy-5-tetrazol-1-yl)benzyl]-(CIS-phenylpiperidine-Z-yl)amine,

[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -(CIS-phenylpiperidine-3-yl)amine,

[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl] -(CIS-phenylpiperidine-3-yl)amine,

[5-(5-cyclopropylmethyl-1-yl)-2-methoxybenzyl] -(CIS-phenylpiperidine-3-yl)amine,

2-methoxy-[5-(5-methylsulfonylmethyl-1-yl)benzyl] -(CIS-phenylpiperidine-3-yl)amine,

their 2S, 3S enantiomers and pharmaceutically acceptable salts and co-yl-benzyl)-(2-p-tripeptides-3-yl)amine,

CIS-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl] -(2-p-tripeptides-3-yl)amine,

CIS-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -( 2-p-tripeptides-3-yl)amine,

CIS-[2-(3-bromophenyl)piperidine-3-yl] -(2-methoxy-5-tetrazol-1-yl)benzyl] amine,

CIS-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -[2-(4-methoxyphenyl)piperidine-3-yl]amine,

CIS-[2-(3-bromo-4-were)piperidine-3-yl] -(2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine,

CIS-[2-(3-chlorophenyl)piperidine-3-yl] -(2-methoxy-5-tetrazol-1-yl)benzyl] amine,

CIS-[2-(3-forfinal)piperidine-3-yl] -[2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)benzyl]amine,

CIS-[2-(3-fluoro-4-were)piperidine-3-yl] -[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine,

CIS-[2-(3-forfinal)piperidine-3-yl] -[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine,

CIS-[2-(4-forfinal)piperidine-3-yl] -[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine,

CIS-[2-(3,4-differenl)piperidine-3-yl] -[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine,

CIS-[2-(3,4-differenl)piperidine-3-yl] -[2-methoxy-5-tetrazol-1-yl-benzyl]amine,

CIS-[2-(3,4-differenl)piperidine-3-yl] -[2-methoxy-5-(5-cryptomaterial-1-yl-benzyl]amine,

CIS-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -[2-(4-triptoreline)piperidine-3-yl]amine,

CIS-[2-methoxy what ethoxy-5-(5-phenyltetrazol-1-yl)benzyl] -(2S-phenylpiperidine-3S-yl)amine,

[2-methoxy-5-(5-methylamino-4,5-dihydrotetrazolo-1-yl)benzyl]-(2S-phenylpiperidine-3S-yl)amine,

N-(1-(4-methoxy-3-[(2S-phenylpiperidine-3S-yl-amino)methyl] phenyl)-1H-tetrazol-5-yl)acetamide", she

[5-(5-dimethylaminoethanol-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine,

[5-(5-diethylaminomethyl-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine,

1,1,1-Cryptor-3-(1-(4-methoxy-3-[(2S-phenylpiperidine-3S-yl-amino)methyl] phenyl)-1H-tetrazol-5-yl)propan-2-it,

[5-(5-methanesulfonamido-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine,

[3-chloro-2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -(2S-phenylpiperidine-3S-yl)amine,

[2S-(4-forfinal)piperidine-3S-yl] -[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]amine,

(2S, 3S)-[2-(4-forfinal)piperidine-3S-yl] -(2-methoxy-5-tetrazol-1-yl)benzyl]amine,

[5-(5-aminotetrazole-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine,

(2 ethoxy-5-tetrazol-1-yl-benzyl]-([2S, 3S]-2-phenylpiperidine-3S-yl)amine,

(2 isopropoxy-5-tetrazol-1-yl-benzyl] -([2S, 3S]-2-phenylpiperidine-3S-yl)amine

and their pharmaceutically acceptable salt and solvate.

Preferred compounds according to the invention are:

(2-methoxy-5-tetrazol-1-yl-benzyl]-(2S-phenylpiperidine-3S-yl)amine and

[2-methoxy-5-(5-trifloromethyl is loride and solvate.

Should be taken into account the fact that chemical compounds can be named in different ways according to different items. For example, dihydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S, 3S]-2-phenylpiperidine-3-yl)amine can be called also "[dihydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S, 3S]-2-phenylpiperidine-3-yl)amine [2S]-phenylpiperidine-[3S] -yl)amine] or dihydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-(2S-phenylpiperidine-3S-yl)amine". "(2-Methoxy-5-tetrazol-1-yl-benzyl)-(CIS-2-phenylpiperidine-3-yl)amine can also be called "CIS-(2-methoxy-5-tetrazol-1-yl-benzyl)-(2-phenyl-piperidine-3-yl) - amine". The compounds can be named "...3-piperidylamine" or "...piperidine-3-yl-amines". All names are equally valid. Moreover, denote R, S can appear in square brackets, for example [2S], and without them.

Compounds according to the invention are antagonists of tachykinins, including substance P and other neurokinin, both in vitro and in vivo, and can therefore be used in the treatment of conditions mediated by tachykinins, including substance P and other neurokinin.

Compounds according to the invention have a binding affinity of NK1receptors, which was determined by their sporatically. Were prepared U-373MG membrane (25-35 μg per tube) and incubated with [3H]-SP (0.6-0.8 nm) at 20oC for 40 minutes Was determined and the nonspecific binding binding, which in the presence of 1 μm(+) SR,994.

It was shown that the compounds according to the invention have antiemetic activity, as indicated, for example, their ability to inhibit radiation-induced emesis in ferrets. In this model, vomiting, retching to vomit and vomiting started after about 20 min after total body irradiation (2 gray = 200 Rad). The test compound was administered (for example intraperitoneally, orally, intravenously, or subcutaneously) immediately after irradiation, and determined their effect on vomiting, compared with a suitable control.

Antiemetic activity can also be demonstrated using other causing vomiting tools such as cisplatin and Ipecacuanha. In alternative cases, the compounds according to the invention can be administered before irradiation or before processing, causing vomiting, for example 1.5, 3 or 6 h before irradiation.

It is shown that the compounds according to the invention inhibit radiation-induced vomiting in a dose of 0.03-3 mg/kg subcutaneously in the above TEC is Rosa bioavailability when introduced through the mouth and favorable duration of action.

Compounds according to the invention is applicable as analgesics, in particular, in the treatment of traumatic pain such as postoperative pain; pain from traumatic entereza, such as brachial plexus; chronic pain such as arthritic pain, appearing, for example, in osteoarthritis, rheumatoid arthritis or psoriatic arthritis; neuropathic pain such as neuralgia after shingles, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, neuropathy induced by chemotherapy, neuralgia, AIDS-related, occipital neuralgia, neuralgia syndrome geniculate ganglion, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headaches, such as migraine, acute or chronic headache with pressure, TMJ pain, pain in the maxillary sinus, "histamine" headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; pain when pinched nerve; pain sports injuries; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; skeletal-muscle the ith spondylitis; gout; burns; pain in scars; itching and thalamic pain such as talamasca pain after a stroke.

Compounds according to the invention are also suitable as anti-inflammatory agents, in particular they can be used in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract, such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and lesions caused by non-steroidal anti-inflammatory drugs; inflammatory skin diseases such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urinary incontinence.

Compounds according to the invention is also suitable for the treatment of allergic diseases such as allergic skin diseases such as urticaria, and allergic respiratory diseases such as rhinitis.

Compounds according to the invention can also be used in the treatment of disorders of the Central nervous system, in particular psychoses, such as schizophrenia, mania or acquired dementia; cognitive disorders such as Alzheimer's disease; painful feelings, trouble is kinson; dependence on drugs or substances, addictive; the compounds according to the invention can also act as muscle relaxants and antispasmodic tools.

Compounds according to the invention is also suitable for the treatment of vomiting, that is, nausea, urge to vomit, and the eruption of vomiting. Vomiting involves acute emesis, delayed emesis or late vomiting and premature vomiting. Compounds according to the invention are suitable for the treatment of vomiting, regardless of its origin. For example vomiting can be caused by drugs, such as funds cancer chemotherapy including alkylating agents such as cyclophosphamide, carmustine, lomustine and hlorambuzila; cytotoxic antibiotics, such as dactinomycin, doxorubicin, mitomycin-C and bleomycin; antimetabolites, for example citarabinom, methotrexate and 5-fluorouracil; Vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as zaplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation, for example by irradiation of the thorax or abdomen, such as conduct in the treatment of cancer; poisons; toxins such as toxins caused by metabolic narushenyi or viral infection of the gastrointestinal tract; pregnancy; disorders of the vestibular apparatus, such as kineton, dizziness and Meniere's disease; post-operative sickness; obstruction of the gastrointestinal tract; reduced motility of the gastrointestinal tract; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intracranial pressure; low intracranial pressure (e.g. altitude sickness ); opioid analgesics, such as morphine; a disease of the gastro-food reflux; heartburn; overeating or excessive drinking; sour stomach, acid stomach, heartburn/regurgitation, such heartburn as episodic heartburn, nocturnal heartburn and heartburn, caused by eating, and dyspepsia.

Compounds according to the invention can also be used in the treatment of gastrointestinal diseases such as syndrome of stimulation of the intestine; skin diseases such as psoriasis, itching and sunburn; vasospastic diseases such as angina, vascular headache and sickness rino, cerebral ischemia such as cerebral vasospasm following cerebral hemorrhage; fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis; bolesna as fibrosis; and cough.

Thus according to the invention proposed the compounds of formula (I) or their pharmaceutically acceptable salt or solvate for use in therapy, in particular in human medicine.

Also according to the invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt or MES in the preparation of a drug that is used in the treatment of conditions mediated by tachykinins, including substance P and other neurokinin.

Further, or alternatively, a method for treating mammals, including humans, in particular the treatment of conditions mediated by tachykinins, including substance P and other neurokinin, which apply an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

It is necessary to consider that the reference to the treatment involves both prevention and alleviation of established symptoms. The compounds of formula (I) can be used as chemical raw product, but it is preferable that the active ingredient was present in the form of a pharmaceutical preparation.

Accordingly, a pharmaceutical composition containing at least one connection Akai composition preferably is in the form adapted for use in medicine, particularly human medicine, and can be prepared in a known manner using one or more pharmaceutically acceptable carriers or excipients.

That is, the compound of formula (I) can be prepared for oral, transbukkalno, parenteral, local (including ocular and nasal), deposited or rectal or in a form suitable for application by inhalation or insufflation (either through the mouth or through the nose).

For oral administration the pharmaceutical composition can be prepared in the form of, for example, tablets or capsules obtained in the traditional way with excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose or acidic calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrant (for example, potato starch or starch glycolate sodium); wetting agents (e.g. sodium lauryl sulphate ). Tablets can be coated membrane according to known methods. Liquid is Pensi or they can be a dry product, to be diluted with water or other acceptable media before use. Such liquid preparations can be prepared by traditional methods with pharmaceutically acceptable additives such as suspendresume agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or gum Arabic); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents.

Preparations for oral administration can be prepared in such a way that the release of active agent from the drug was controlled.

For transbukkalno application of the compositions can be prepared in the form of tablets or lozenges traditional way.

Compounds according to the invention can be prepared for parenteral administration by injection or continuous infusion. Preparations for injection may be in unit dose form, for example in the ampoule is astory or emulsions in oily or aqueous carriers, and may contain agents that are required to obtain the drug, for example suspendida, stabilizing and/or dispersing agents. Alternatively the active ingredient may be in powder form, which before use is subject to connection to a suitable carrier, such as sterile, free from pyrogen water.

Compounds according to the invention can be prepared for topical application in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye drops, nasal drops or ear). Ointments and creams may, for example, be prepared in an aqueous or oily base with the addition of the corresponding thickening or gelling agents. Ointment for application to the eye can be manufactured in a sterile manner using sterile components.

Lotions can be prepared in water or oil based and usually also contain one or more emulsifying agents, stabilizing, dispersing, suspendida, condensing agents or dyes. Drops can be prepared in an aqueous or nonaqueous basis, and also contain one or more dispersing, stabilizing, solvent or suspendida aeny deposited in the form of drugs. Such long acting drugs can be entered using implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So, for example, the compounds according to the invention can be prepared with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ionoobmennoi resin, or in the form of poorly soluble derivative, for example in the form of a slightly soluble salt.

For insertion into the nose of the compounds according to the invention can be prepared in the form of solutions, introduced through a suitable metering device, or a device for injection of a single dose, or alternatively as a powder mix with a suitable carrier input with suitable for these purposes.

These compositions may contain from 0.1% or more, for example about 0.1-99%, of active ingredient, depending on method of application. The proposed dose of the compounds according to the invention is from 0.05 to 400 mg/kg of body weight per day, for example from 0.05 to 5 mg/kg / day. It should be noted that you may need to make regular changes to the dosage depending on the age and condition of the patient, and determining the exact dosage is located in cómpeta is tion.

The compounds of formula (I) optionally may be used in combination with one or more therapeutic agents, and such a drug can be prepared in the traditional way for the introduction of any traditional way. The appropriate dosage can be readily determined by a specialist. For example, the compounds of formula (I) can be administered in combination with systemic anti-inflammatory corticosteroid, as methylprednisolone or dexamethasone, or 5HT3-antagonist, as ondansetron, granisetron or metoclopramide. Antagonists of tachykinins, including substance P and other neurokinin, for example the compound of formula (I) may be introduced in combination with sympathomimetics such as ephedrine, pseudoephedrine and oxometabolite. Compounds, which are specific antagonists of NK1receptors, such as the compound of formula (I) can be administered in combination with compounds which are specific antagonists of NK2-receptors.

The compounds of formula (I), their salts and solvate can be obtained according to the General method described below. In the following description, the groups R1, R2, R3, R4and R5and x are the same? as defined previously for samoset be derived as follows: the compound of formula (II)

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subjected to interaction with the compound of the formula (III)

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obtaining the intermediate imine, which, if required, can be allocated, then restore Imin using a suitable metal reducing agent such as a metal hydride, such as boron hydride, the hydride Alan or metal hydride complexes such sociallyengaged or sodium borohydride, or ORGANOMETALLIC complexes, such as bromethalin, 9-borabicyclo (9-BBN), triethylsilane, triacetoxyborohydride sodium, lambrogini sodium, etc. In an alternative case can be used catalytic hydrogencyanide, for example, using a platinum catalyst in a suitable solvent, for example ethanol.

The condensation reaction is conveniently performed in a suitable solvent, such as alcohol (e.g. methanol), aromatic hydrocarbon (e.g. benzene, toluene or xylene) or a chlorinated hydrocarbon (e.g. dichloromethane or dichloroethane), at a temperature in the range from room temperature to the temperature of reflux distilled reaction mixture. Preferably the reaction is carried out in the presence of catalytic quantities approach ageratifolia agent, such as a molecular sieve, or the reaction may take place under conditions of Dean-stark.

The stage of restoration is convenient to carry out in a suitable solvent, such as acetonitrile, dimethylformamide, benzene, chlorinated hydrocarbons, such as dichloromethane or dichloroethane, an ether such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and alcohols, such as ethanol, at a temperature of from 0oWith up to the temperature of reflux distilled reaction mixture.

Method (A) can be done in one stage, without isolating the intermediate imine, provided that the condensation reaction takes place in the presence of lamborginid sodium or triacetoxyborohydride sodium. In this case, further recovery is not required.

If in the process (A) R2is defined above, (C), R6preferably a is a group C1-4alkyl.

The compound of formula (II) can be obtained by recovering the compounds of formula (IV)

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in appropriate reducing conditions, such as catalytic hydrogencyanide, for example, using a platinum catalyst such as platinum oxide (IV) in a suitable solvent, that is (IV) can be obtained by reacting 2-chloro-C-nitropyridine with the compound of the formula (V)

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in the presence of a catalyst of palladium (0), such as tetrakis-(triphenylphosphine)palladium (0). The reaction is conveniently carried out in the presence of a solvent, such as ether, for example dimethoxyethane, at elevated temperature and preferably in the presence of a base such as sodium carbonate.

The compound of formula (V) can be obtained by transformation of the corresponding bromine compounds in Grenada, and then interact with triisopropylsilane.

Alternatively the compound of formula (II) can be obtained by recovering the compounds of formula (VI)

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in appropriate reducing conditions, for example, using complex metalhydride, such as borohydride sodium, in the presence of chloride, zirconium (IV) in a suitable solvent, such as tetrahydrofuran.

The compound of formula (VI) can be obtained by reacting the compounds of formula (VII)

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with hydroxylamine hydrochloride in the presence of pyridine.

The compounds of formula (VII) can be obtained by reacting compounds of the formula (VIII)

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with ozone in the presence of tert-butoxide potassium in a suitable solvent such as a mixture of dichloro is rmula (IX)

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with methyl-4-nitrobacteria and ammonium acetate in a suitable solvent, such as alcohol, for example ethanol, at elevated temperature.

The compounds of formula (III) can be obtained by reacting compounds of the formula (X)

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with C1-4alkylating agent, such as C1-4alkylated, in the presence of a base such as potassium carbonate.

The compounds of formula (X) can be obtained by reacting compounds of the formula (XI)

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with hexamethylenetetramine in the presence of triperoxonane acid at elevated temperature.

The compounds of formula (XI), where R2to pose the above group (a) and x is zero, can be obtained by reacting the appropriate n-hydroxylysine or its protected derivative with compounds of the formula (XII)

R6-C(OR9)3, (XII)

(where R9represents a methyl or ethyl), such as triethylorthoformate, acetic acid, and subsequent interaction with sodium azide at elevated temperature and, if necessary, remove the protection.

The compounds of formula (XI), where R2to pose the above group (A) and x is zero, can also be polucha in acetic acid at elevated temperature and, if necessary, remove the protection.

The compounds of formula (XIII) can be obtained by reacting the compounds of formula (XIV)

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or a protected derivative with triethylphosphine on the substrate from the resin in carbon tetrachloride at an elevated temperature.

The compounds of formula (XIV) can be obtained by reacting the corresponding n-hydroxyanisole or its protected derivative with a suitable acid chloride or anhydride, that is, R6-COCl or R6-COOCO-R6for example triperoxonane anhydride or chloride cyclopropanecarbonyl.

The compounds of formula (XI), where R2to pose the above group (A) and x is zero, or their protected derivatives in the alternative case can be obtained by reacting compounds of the formula (XIV) or a protected derivative with an acid anhydride, such as triperoxonane anhydride or triftormetilfullerenov anhydride or sodium azide in acetonitrile.

The compounds of formula (III), where R2to pose the above group (A), x is zero and R6represents NH2in an alternative case can be obtained by reacting compounds of perature, in the preferred case, in a solvent such as dimethylformamide, followed by removal of the protection if necessary.

The compounds of formula (XV) can be obtained by reacting compounds of the formula (III), where R2to pose the above group (A), x is zero and R6is hydrogen, or their protected derivatives with n-butyllithium in a suitable solvent, such as tetrahydrofuran.

The compounds of formula (III) or their protected derivatives, in which R6represents one group, can be converted into other compounds of formula (III) or their protected derivatives, in which R6represents another group, using suitable methods, such as alkylation, acylation or oxidation.

The compounds of formula (III) alternative can be obtained by oxidation of compounds of formula (XVI)

< / BR>
a suitable oxidizing agent such as manganese dioxide, in a suitable solvent, such as ether, for example tetrahydrofuran, at an elevated temperature.

The compounds of formula (XVI) can be obtained by the reduction of compounds of formula (XVII)

< / BR>
suitable regenerating agent, tonitetheater, or alcohol, for example ethanol, or mixtures thereof.

The compounds of formula (XII), where R2to pose the above group (A) and x is zero, can be obtained from the corresponding methyl ester of 2-alkoxy-5-aminobenzoic acid by reacting with compounds of the formula (XII) as defined above, such as triethylorthoformate, and sodium azide in glacial acetic acid and dimethylformamide at elevated temperature.

Suitable methyl esters of 2-alkoxy-5-aminobenzoic acid either known or can be obtained according to known for obtaining the known connection methods [Bergman et al. in the Can. J. Chem. (1973), 51, 162-170].

The compounds of formula (III), where R2to pose the above group (A) or (B), and x is 1, can be obtained by reacting the compounds of formula (XVIII)

< / BR>
(where hal denotes a halogen atom, that is, bromine or chlorine) with tetrazole in the presence of a base such as triethylamine or potassium carbonate, in a suitable solvent such as dichloromethane or dimethylformamide.

The compounds of formula (XVIII), where x is 1, can be obtained by reacting the compounds of formula (XIX)

< / BR>
or protected proizvoditeli, such as ether, followed by removal of the protection if necessary.

The compounds of formula (XIX) can be obtained by recovering the corresponding aldehyde after protection of the aldehyde group in ortho-position with respect to R1.

The compounds of formula (XI), where R2to pose the above group (B), and x is equal to zero, can be obtained by reacting the appropriate 1-fluoro-4-nitrobenzene with IH-tetrazole in a suitable solvent at elevated temperature, followed by reduction of the nitro group by catalytic gidrogenizirovanii and then converting the received aminophenol in alcohol function using nitrous acid.

The compounds of formula (III), where R2represents a higher group (C) can be obtained by reacting the compounds of formula (XX)

< / BR>
with the compound of the formula (XXI)

< / BR>
in the presence of a catalyst of palladium (0), such as tetrakis-(triphenylphosphine)palladium (0), in a suitable solvent such as an ether (for example, dimethoxyethane), at elevated temperature.

The compounds of formula (XX) can be obtained in a manner analogous to the method of obtaining the above-described compounds is by the above group (S), x is zero and R6is hydrogen, can be obtained by reacting compounds of the formula (XXII)

< / BR>
or their protected derivatives with azide anti elevated temperature with a subsequent removal of the protection if necessary.

The compounds of formula (XXII) can be obtained from the appropriate p-hydroxybenzonitrile and hexamethylenetetramine as described above to obtain compounds of the formula (X) compounds of formula (XI).

According to the following General method (B) compounds of formula (I), where R2to pose the above group (A), x is zero and R6is the group-NH2can be obtained by reacting compounds of the formula (XXIII)

< / BR>
with ammonium chloride and sodium azide under conditions described above for preparing compounds of the formula (III) from compounds of formula (XV).

The compounds of formula (XXII) can be obtained by reacting compounds of the formula (XV) with compounds of the formula (II) under the conditions described above for process (A).

According to the following General method (C) compounds of formula (I) can be obtained by the reduction of compounds of formula (XXIV)

< / BR>
using a suitable reducing and trageriemen, at room temperature.

The compounds of formula (XXIV) can be obtained by reacting compounds of the formula (III) with compounds of formula (XXV)

< / BR>
under the conditions described above for process (A).

The compounds of formula (XXV) are either known or can be obtained according to known methods for known compounds [Application for the European patent EP-A-0436334].

Suitable protective groups for hydroxyl include a benzyl group, which may be inserted and removed according to conventional methods. For example, removing the protection can be carried out by catalytic hydrogenative.

Aldehyde functions can be protected as acetals, which

can be inserted and removed according to conventional methods. For example, removing the protection can be carried out by acid hydrolysis.

Compounds of formula (III), (IV), (X), (XI), (XIII), (XIV), (XV), (XVI), (XVII), (XXIII) and (XXIV) are new and, therefore, form another characteristic of the invention.

Compounds of formulae (XXIII) and (XXIV) besides the fact that they are used as intermediates in obtaining the compounds of formula (I) have activity antagonists magicianhalo obtaining the compounds of formula (I) as a salt, for example, pharmaceutically acceptable salt, this may be achieved by reacting the compounds of formula (I) in free base form with the required amount of the appropriate acid in a suitable solvent, such as alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g. diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts can also be obtained from other salts, including other pharmaceutically acceptable salts of compounds of formula (I) using conventional methods.

The compounds of formula (I) can easily be isolated in Association with solvent molecules by crystallization from a suitable solvent or evaporation of a suitable solvent to obtain the corresponding solvate.

If you want to obtain a specific enantiomer of the compounds of General formula (I), it can be obtained, for example, by dividing the corresponding mixture of enantiomers of compounds of formula (I) using conventional methods.

Namely, in one case, for the formation of a salt with an enantiomeric mixture of compounds of formula (I) can be used with a suitable optically active acid. what crystallization on diastereoisomeric salt, of which can be obtained compound of General formula (I) by conversion of the salt to the desired free base.

In another case, the enantiomer of the compounds of General formula (I) can be synthesized from the appropriate optically active intermediate compounds using the methods described above.

In particular, the best method of obtaining optically active intermediate compounds of formula (II) from their enantiomeric mixture is fractionated crystallization using (2R,3S)-bis-(4-methylbenzoate)succinic acid. That is, CIS (S,S)- form intermediate compound (II) can be obtained from their enantiomeric mixtures (e.g. racemic mixtures) by fractionated crystallization with (2R, 3S)-bis-(4-methylbenzoate)succinic acid in a suitable solvent such as aqueous alcohol, e.g. aqueous ethanol, followed by separation of the salts and converting it into the corresponding optically active free base by conventional methods, for example using aqueous ammonia. This method is new and forms another characteristic of the invention.

Salts formed between the intermediate compound (II), including 2-phenylpiperidine is retene.

Specific enantiomers of compounds of formula (I) can also be obtained by chromatography of the corresponding enantiomeric mixture on a chiral column, for example by chiral preparative VGH.

Specific diastereoisomeric compounds of General formula (I) can be obtained by conventional methods, for example by synthesis from a suitable asymmetric source materials using the methods described above, or by transformation of a mixture of isomers of compounds of General formula (I) in a suitable diastereoisomer derivatives, such as salts, which can then be separated by conventional methods, for example by chromatography or fractional crystallization.

In the alternative case, diastereoisomer can be separated without the need to obtain the following derivatives.

Standard separation methods described ["Sterechemistry of Carbon Compounds", E. L. Eliel (McGraw Hill, 1962) and "Tables of Resolving Agents", S. H. Wilen].

Various General methods described above can be used for introduction of the desired groups at any stage of the step by step process of obtaining the required connections, and it should be clear that these General methods can be differently combined in this mn is tions and examples which do not limit the invention. All temperatures are given inoC. Thin-layer column chromatography (FCC) was carried out on silica (Merck 9385). Used reduction: ether - diethyl ether.

Intermediate compound 1. 4-Tetrazol-1-yl-phenol.

To a stirred solution of p-aminophenol (0.1 mol) in glacial acetic acid (140 ml) at 70-75oC in nitrogen atmosphere add triethylorthoformate (0.1 mol). The mixture is stirred at this temperature for 4 h, then portions add sodium azide (0.32 mol) and the reaction continued for 18 h, then the mixture is cooled to room temperature and poured into ice water (400 ml), extracted with diethyl ether (3x400 ml) and ethyl acetate (CH ml), dried (MgSO4), filtered and concentrated to obtain a dark brown residue, which is grinded into powder with a mixture of ethanol/ diethyl ether ( 1: 1 o/o ) and filtered to obtain the connection specified in the header, with 30% output.

TLC (ether): Rf of 0.65.

Obtained similarly:

Intermediate compound 2. 4-(5-Methyltetrazol-1-yl)phenol.

From p-aminophenol (0.05 mol), triethylorthoformate (0.05 mol) and sodium azide (0.16 mol) of the compound obtained specified in zagolovok connection 3. 4-( 5-Elitetrader-1-yl )phenol.

From p-aminophenol (0.05 mol), triethylorthoformate (0.05 mol) and sodium azide (0.16 mol) of the compound obtained specified in the header, in the form of a dark brown solid with a 9% yield.

TLC (ether): Rf 0,72.

Intermediate compound 4. 4-(5-Propertyreal-1-yl)phenol.

From p-aminophenol (6 g), triethylorthoformate (8,1 g) and sodium azide (10 g) obtained the connection specified in the header, in the form of a dark brown liquid (0.55 g).

TCX (ether/dichloromethane, 1:9): Rf 0,27.

The intermediate compound 5. 2-Hydroxy-5-tetrazol-1-yl-benzaldehyde.

A solution of 4-tetrazol-1-yl-phenol (0.01 mol) in triperoxonane acid (20 ml) and hexamethylenetetramine (0.04 mol) was kept at a temperature of 70oC for 18 h, then cooled to room temperature and neutralized 2N sulfuric acid solution (50 ml). The mixture was extracted with ethyl acetate (CH ml), dried (MgSO4), filtered and concentrated to obtain residue, which was purified by FCC (dichloromethane/methanol, 9:1) to obtain the compound indicated in the title, with 30% output.

TCX (dichloromethane/methanol, 9:1): Rf of 0.6.

Obtained similarly:

The intermediate connection the network connection, specified in the header, in the form of a light yellow solid (yield 70%).

TCX ( dichloromethane/methanol, 9:1): Rf of 0.9.

Intermediate compound 7. 5-(5-Elitetrader-1-yl)-2-hydroxybenzaldehyde.

From 4-(5-elitetrader-1-yl)phenol (4,73 mmol) obtained the connection specified in the header, in the form of a white solid (yield 50%).

TCX (dichloromethane/methanol, 9:1): Rf of 0.9.

Intermediate compound 8. 2-Hydroxy-5-(5-propertyreal-1-yl)benzaldehyde.

From 4-(5-propertyreal-1-yl)phenol (0.55 g) obtained the connection specified in the header (0.3 g) as a pale yellow liquid.

TCX (ether/dichloromethane, 1:9): Rf 0,41.

Intermediate compound 9. 5-(5-Cyclopropylmethyl-1-yl)-2-hydroxybenzaldehyde.

From 4-(5-cyclopropylmethyl-1-yl)phenol (1.5 g) obtained the connection specified in the header, (810 mg) as a white solid. So pl. 96oC.

Intermediate compound 10. 2-Hydroxy-5-(5-methylsulfonylmethyl-1-yl)benzaldehyde.

From 4-(5-sulfenylation-1-yl)phenol (at 10.64 g) obtained the connection specified in the header, in the form of a white solid (5.0 g).

TCX (dichloromethane): Rf 0.35 in.

Intermediate compound 11. 2-Hydroxyzine in the header, in the form of a white solid (1.75 g).

TCX (5% ethyl acetate/dichloromethane): Rf of 0.6.

Intermediate compound 12. 3-fluoro-2-hydroxy-5-(5-methyltetrazol-1-yl)benzaldehyde.

From 2-fluoro-4-(5-methyltetrazol-1-yl)phenol (2.8 g) obtained the connection specified in the header, in the form of a white solid (2.2 g).

TCX (cyclohexane/ethyl acetate 1:1): Rf of 0.7.

The intermediate connection 13. 2-Hydroxy-5-(5-cryptomaterial-1-yl)benzaldehyde.

From 4-(5-cryptomaterial-1-yl)phenol (45 mmol) of the compound obtained specified in the header, in the form of a solid light yellow substance (8.8 g).

TCX (hexane/ether, 2:1): Rf 0,36.

The intermediate connection 14. 2-Methoxy-5-tetrazol-1-yl-benzaldehyde.

To a solution of 2-hydroxy-5-tetrazol-1-yl-benzaldehyde (2,63 mmol) in dimethylformamide (5 ml) is added potassium carbonate (3.95 mmol) and itmean (3.95 mmol) and stirred the mixture in a nitrogen atmosphere for 2 hours the Mixture was poured into water (100 ml) and the resulting white solid was filtered to obtain the connection specified in the header (yield 67%).

TCX (ether): Rf 0.45 in.

Obtained similarly:

Intermediate compound 15. 2-Methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde.

TCX (dichloromethane/methanol, 9:1): Rf 0.5 in.

The intermediate connection 16. 5-(5-Elitetrader-1-yl)-2-methoxybenzaldehyde.

From 5-(5-elitetrader-1-yl)-2-hydroxybenzaldehyde (2.48 mmol) of the compound obtained specified in the header, in the form of a white solid (yield 68%).

TCX (ether): Rf of 0.4.

Intermediate compound 17. 2-Methoxy-5-(5-propertyreal-1-yl)benzaldehyde.

From 2-hydroxy-5-(5-propertystate-1-yl)benzaldehyde (300 mg) obtained the connection specified in the header, in the form of a white solid (265 mg).

TCX (ether): Rf 0,27.

The intermediate connection 18. 5-(5-Cyclopropylmethyl-1-yl)-2-methoxybenzaldehyde.

From 5-(5-cyclopropylmethyl-1-yl)-2-hydroxybenzaldehyde (800 mg) obtained the connection specified in the header, in the form of a white solid (800 mg). So pl. 142oC.

Intermediate compound 19. 2-Methoxy-5-(5-methylsulfonylmethyl-1-yl)benzaldehyde.

From 2-hydroxy-5-(5-methylsulfonylmethyl-1-yl)benzaldehyde (5.0 g) obtained the connection specified in the header, in the form of a yellow solid substance (2.1 g).

TCX (ethyl acetate): Rf of 0.8.

The intermediate connection 20. 2-Methoxy-5-(5-connection, specified in the header, in the form of a yellow solid substance (0,575 g).

TCX (5% ethyl acetate/dichloromethane): Rf of 0.55.

The intermediate connection 21. 2-Methoxy-5-(5-methylamino-4,5-dihydrotetrazolo-1-yl)benzaldehyde.

From 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazol-5-yl-amine (0.5 g) obtained the connection specified in the header, in the form of a solid (0.15 g).

TCX (5% methanol/dichloromethane): Rf of 0.6.

The intermediate connection 22. 3-fluoro-2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde.

From 3-fluoro-2-hydroxy-5-(5-methyltetrazol-1-yl)benzaldehyde (2.2 g) obtained the connection specified in the header, in the form of a solid creamy substance (1.5 g).

TCX (ethyl acetate/cyclohexane, 1:1): Rf of 0.4.

The intermediate connection 23. 2-Methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde.

From 2-hydroxy-5-(5-cryptomaterial-1-yl)benzaldehyde (1.56 mmol) of the compound obtained specified in the header, in the form of a yellow solid substance (0,48 g).

TCX (ether/hexane, 2:1): Rf of 0.3.

The intermediate connection 24. 2 Ethoxy-5-tetrazol-1-yl-benzaldehyde.

From ethyliodide and 2-hydroxy-5-tetrazol-1-yl-benzaldehyde (2.6 mmol) of the compound obtained specified in the header, in the form of 25. 2 Isopropoxy-5-tetrazol-1-yl-benzaldehyde.

From isopropylidene and 2-hydroxy-5-tetrazol-1-yl-benzaldehyde (2.6 mmol) of the compound obtained specified in the header, in the form of a yellow solid substance (0.40 g).

max(KBr): 1681 cm-1.

The intermediate connection 26. [2S]-Phenylpiperidine-[3S]-yl-amine[2R,3R]-bis-(4-methylbenzoate)succinate (1:1).

[2R,3R]-bis-(4-methylbenzoate)succinic acid (143 g) for 5 min added in several portions to a stirred solution of 2-phenylpiperidine-3-yl-amine (66 g) in ethanol (to 5.21) and water (783 ml) at 60oC. Then the solution is kept under stirring for 0.5 h at a temperature of 60-70oC. Then the solution is left to cool overnight at room temperature. The solid material is collected and dried under vacuum at 70o(80 g). One sample (10 g) is recrystallized from ethanol (510 ml) and water (90 ml) to give an almost colorless crystalline solid substance (7.6 g). So pl. 169-171oC.

Received: With 62.6; H 6,2; N 4,5%. For C11H16N2C20H18O8]2D0= 34,3o.

Obtained similarly:

The intermediate connection 27. 2S-(4-Forfinal)piperidine-3S-yl-amine-2R, 3R-bis-(4-methylbenzoic the si)succinic acid (2.0 g) obtained connection, specified in the header, in the form of a solid crystalline white matter (803,5 g).

(CD3OD) includes 1,5-2,2 (m, 5H), and 1.4 (s, 6H), 2,85 was 3.05 (m, 1H), 3,5-3,6 (m, 1H), 4,27 (d, 1H, J=2 Hz), 5,86 (s, 2H), 7,0 (t, 2H, J=8.7 Hz), and 7.3 (d, 4H, J=8.5 Hz), was 7.45 (dd, 2H, J=8.7 and 5 Hz).

Chiral VGH on CHIRALCEL-OD-H column, elution with hexane containing 2% isopropyl alcohol, showed only one enantiomer (tR=35,83 min).

TCX (cyclohexane/ethyl acetate, 9:1): Rf 0,36.

The intermediate connection 28. [2S]-Phenylpiperidine-[3S]-yl-amine.

Salt of [2S, 3S]-bis-(4-methylbenzoate)succinic acid [2S] -phenylpiperidine-[3S] -yl-amine (1:1) (6,9 g) was collected in a concentrated 0,880 aqueous ammonia (100 ml) and a few minutes which. The basic solution was extracted with chloroform (CH ml), dried (Na2SO4) and concentrated in vacuum to obtain [2S]-phenylpiperidine-[3S]-yl-amine (1.85 g) as a colourless oil. []2D0(HCl salt)=+55,48o(C=0,006 g/ml).

1NMR (HCl salt, DO2), : 2,05 (m, 2H), 2,30 (m, 2H), 3,36 (m, 1H), 3,74 (m, 1H), 4.16 the (d, 1H, J=4 Hz), 4,99 (d, 1H, J=4 Hz), was 7.45 (m, 2H), to 7.59 (m, 3H).

A small sample of the free base (50 mg) was treated as his trifluoracetyl similar to chiral VIH analysis. The sample was dissolved in acetone, what was koncentrirebuli in vacuum and the residue was dissolved in dichloromethane (5 ml). The organic layer was washed with diluted sulfuric acid (2 ml), then the organic layer was concentrated and dissolved in hexane/isopropyl alcohol (98:2) for application to the column VGH.

Chiral VIH (column Chiracel-OD-H lot. on 09-02 - 20709, eluent hexane/isopropanol, 98:2, flow rate 1 ml/min, UV detection on 230 nm temperature 40oC): delay time 12,93 minutes

The intermediate connection 29. N-(4-Benzyloxyphenyl)-2,2,2-triptorelin.

To a mixture of the hydrochloride of 4-benzyloxyaniline (to 0.19 mol) in dichloromethane (750 ml) at 0oC in an atmosphere of nitrogen was added dropwise triperoxonane anhydride (27,6 ml) and then triethylamine (60 ml). After 24 h the mixture was poured into tert-butyl methyl ether (1.5 l) and washed with 2N hydrochloric acid (1 liter). The organic phase was dried (MgSO4) and evaporated under vacuum to obtain the connection specified in the header, in the form of a white solid (52,3 g).

TCX ( cyclohexane/ethyl acetate, 9:1): Rf 0,36.

The intermediate connection 30. TRANS-6-(3-Bromophenyl)-5-nitropyrimidin-2-it.

A mixture of 3-bromobenzaldehyde (82,20 g), methyl-4-nitrobutane (65,3 g) and ammonium acetate (68,5 g) in ethanol (400 m is scrap (400 ml) to obtain compound, specified in the header, in the form of a white solid (97,46 g).

NMR (CDCl3), : 2,30 (1H, m), to 2.55 (3H, m), 4,70 (1H, m), 5.25-inch (1H, m), 6,7 (1H, s), 7,2-7,6 (4H, m).

Obtained similarly:

The intermediate connection 31. TRANS-6-(4-Methoxyphenyl)-5-nitropyrimidin-2-it.

From p-anisaldehyde (5 g) and methyl - 4-nitrobutane (5,4 g) obtained the connection specified in the header, in the form of a white powder (7,37 g).

TCX (ethyl acetate): Rf 0.35 in.

The intermediate connection 32. TRANS-6-(3-Bromo-4-were)-5-nitropyrimidin-2-it.

From 3-bromo-4-methylbenzaldehyde (30 g) and methyl-4-nitrobutane (22,17 g) obtained the connection specified in the header, in the form of a brown powder (24.5 g).

TCX (ethyl acetate): Rf of 0.4.

The intermediate connection 33. 6-(3-Chlorophenyl)-5-nitropyrimidin-2-it.

3-chlorobenzaldehyde (5 g) and methyl-4-nitrobutane (5,23 g) obtained the connection specified in the header, in the form of a white powder (6,84 g).

TCX (ethyl acetate): Rf of 0.55.

The intermediate connection 34. 6-(3-Bromophenyl)piperidine-2,5-dione.

tert-Piperonyl potassium (of 38.7 g) was added to a stirred solution of TRANS-6-(3-bromophenyl)-5-nitropyrimidin-2-it (96,3 g) in dichloromethane (500 ml) and methanol (500 ml). The mixture was cooled to -70oC the private buffer (500 ml), a pH of 6.5. To the mixture was added sodium thiosulfate (120 g) and water (500 ml) and after the mixture has warmed to room temperature, stirred her during the night. The mixture was tested for peroxides, and then was extracted with dichloromethane (600 ml x 3). The combined organic extracts were washed with water (500 ml), then saturated brine (500 ml), dried (MgSO4) and evaporated in vacuo. After trituration with ether and hexane received the connection specified in the header, in the form of a white solid (70,0).

TCX (ethyl acetate): Rf of 0.43.

Obtained similarly:

The intermediate connection 35. 6-(4-Methoxyphenyl)piperidine-2,5-dione.

From TRANS-6-(4-Methoxyphenyl)-5-nitropyrimidin-2-it (7,37 g) obtained the connection specified in the header, in the form of a yellow powder (5.53 g).

TCX (ethyl acetate): Rf of 0.3.

The intermediate connection 36. 6-(3-Bromo-4-were)piperidine-2,5-dione.

From TRANS-6-(3-Bromo-4-were)-5-nitropyrimidin-2-it (24.5 g) obtained the connection specified in the header, in the form of a brown oil (19.9 g).

TCX (ethyl acetate): Rf 0.45 in.

The intermediate connection 37. 6-(3-Chlorophenyl)piperidine-2,5-dione.

From 6-(3-chlorophenyl)-5-nitropyrimidin-2-she (6.8 g) obtained the connection specified by the connection 38. 5-Oxime 6-(3-bromophenyl)piperidine-2,5-dione.

A mixture of 6-(3-bromophenyl)piperidine-2,5-dione (38,2 g) and hydroxylamine hydrochloride (19,8 g) in pyridine (300 g) was stirred at room temperature under nitrogen atmosphere. After 4 h the mixture was evaporated in vacuum. The crude mixture was separated in chloroform (200 ml) with water (200 ml), then was podslushivaet the addition of an 8% aqueous sodium bicarbonate solution (300 ml). The mixture was extracted with chloroform (300 ml x 2). The combined organic extracts were washed with saturated brine and evaporated in vacuum. After trituration with ether got the connection specified in the header, in the form of a pale yellow solid (34,9 g).

TCX (ethyl acetate): Rf of 0.44, 0.28 in (mixture of E/Z).

Obtained similarly:

The intermediate connection 39. 5-Oxime 6-(4-methoxyphenyl)piperidine-2,5-dione.

From 6-(4-methoxyphenyl)piperidine-2,5-dione (5,27 g) and hydroxylamine (3,34 g) obtained the connection specified in the header, in the form of a light brown powder (to 4.38 g).

TCX (ethyl acetate): Rf 0.34 in, 0,21.

The intermediate connection 40. 5-Oxime 6-(3-bromo-4-were)piperidine-2,5-dione.

From 6-(3-bromo-4-were)piperidine-2,5-dione (19.7 g) and hydroxylamine hydrochloride (9,77 g) the compound obtained, decree of the internal connection 41. 5-Oxime 6-(3-chlorophenyl)piperidine-2,5-dione.

From 6-(3-chlorophenyl)piperidine-2,5-dione (5,27 g) and hydroxylamine (3,27 g) obtained the connection specified in the header, in the form of a yellow powder (of 4.57 g).

TCX (ethyl acetate): Rf of 0.55, 0,33 (mixture of E/Z).

The intermediate connection 42. CIS-2-(3-Bromophenyl)piperidine-3-yl-amine.

Dry tetrahydrofuran (100 ml) is added to the flask containing the chloride of zirconium (IV) (6,17 g), cooled to 0oC, in nitrogen atmosphere. Add borohydride sodium (4.0 g) and after the mixture is heated to room temperature, stirred for 15 minutes added dropwise a suspension of 5-oxime 6-(3-bromophenyl)piperidine-2,5-dione (x g) in dry tetrahydrofuran (50 ml) and stirred the mixture at room temperature for 18 hours Carefully add concentrated hydrochloric acid (10 ml) in methanol (60 ml) and heat the mixture with delegacia for 3 hours the Mixture is evaporated in vacuum and separate the remainder 0.88 water (200 ml) ammonia (40 ml) with chloroform (100 ml). Extracted the aqueous phase with chloroform (100 ml x 3). The combined organic extracts dried (Na2SO4) and evaporated to education oils. It is dissolved in ethanol (50 ml) and acidified by adding ethereal hydrogen chloride. Restthe substance is treated with 2N sodium hydroxide solution and extracted with dichloromethane (200 ml x 3 ). The combined organic extracts dried (Na2SO4) and evaporated in vacuo to obtain the connection specified in the header, in the form of a yellow-brown oil (1.10 g).

TCX (dichloromethane/ethanol/ammonia, 91:8:1): Rf 0,51.

Obtained similarly:

The intermediate connection 43. The dihydrochloride, CIS-2-(4-methoxyphenyl)piperidine-3-yl-amine.

From 5-oxime 6-(4-methoxyphenyl)piperidine-2,5-dione (4,18 g) obtained the connection specified in the header, in the form of a white powder (2,07 g).

TCX (dichloromethane/ethanol/ammonia, 150:8:1): Rf of 0.1.

The intermediate connection 44. CIS-2-( 3-Bromo-4-were)piperidine-Z-yl-amine.

From 6-(3-bromo-4-were)piperidine-2,5-dione (6.2 g) obtained the connection specified in the header, in the form of a yellow oil ( 2 g ).

TCX (dichloromethane/ethanol/ammonia, 150:8:1): Rf of 0.3.

The intermediate connection 45. The dihydrochloride, CIS-2-(3-chlorophenyl)piperidine-3-yl-amine.

From 5-oxime 6-(3-chlorophenyl)piperidine-2,5-dione (4,55 g) obtained the connection specified in the header, in the form of a white solid (361 mg).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf 0,49.

The intermediate connection 46. 2-(3-Fluoro-4-were)-3-nitropyridine.

A solution of 2-chloro-3-neath,547 g) in an atmosphere of nitrogen and stir the resulting solution at room temperature in a period of 0.75 hours The solution is treated with 3-fluoro-4-methylphenylacetic acid (6,179 g) in ethanol (24 ml, degassed), and then aqueous solution of sodium carbonate (2M, 47 ml) to give a bright yellow suspension, which is heated with delegacia within 5 hours After cooling to room temperature the reaction mixture was diluted with ethyl acetate (100 ml). The resulting mixture is filtered and the filtrate washed with water (2 x 100 ml) and saturated aqueous sodium bicarbonate (150 ml). The organic layer was separated and further extracted with an aqueous solution with ethyl acetate. The combined organic phases are washed with brine (100 ml), dried (MgSO4) and evaporated to obtain red-black oil (12,106 g). FCC (cyclohexane/ethyl acetate 4:1) gives compound indicated in the title, in the form of a yellow solid substance (of 5.55 g).

Microanalysis for C12H9FN2O2.

Calculated: 62,07; H 3,91; N 12,07; F, 8,18%.

Received: C 61,58; H To 3.92; N 11,80; F 8,2%.

Obtained similarly:

The intermediate connection 47. 2-(3-Forfinal)-3-nitropyridine.

From 2-chloro-3-nitropyridine (6,371 g) and 3-ftorhinolonovy acid (8,30 g) obtained the connection specified in the header, in the form of a yellow crystalline solid (3,39 g).

From 2-chloro-3-nitropyridine (4,60 g) and 4-ftorhinolonovy acid (5,99 g) obtained the connection specified in the header, in the form of a yellow solid (5,07 g).

(d6-DMSO): to 7.35 (t, 2H, J=8.5 Hz), a 7.62 (dd, 2H, J=8.5 and 5.5 Hz), 7,71 (dd, 1H, J=8.0 and 5.0 Hz), 8,48 (d, 1H, J=8.0 Hz), to 8.94 (d, 1H, J=5.0 Hz).

The intermediate connection 49. 2-(3,4-Differenl)-3-nitropyridine.

From 2-chloro-3-nitropyridine (2.24 g) and 3,4-diftorhinolonom acid (2,90 g) obtained the connection specified in the header (2,84 g).

(d6-DMSO): 7,46-of 7.55 (m, 1H), 7,62-7,89 (m, 3H), 8,64 (dd, 1H, J=7.5 and 1 Hz), 9,06 (d, 1H, J=4.5 Hz).

The intermediate connection 50. CIS-2-(3-Fluoro-4-were)-3-piperidine.

A solution of 2-(3-fluoro-4-were)-3-nitropyridine (5,514 g) in ethanol (200 ml) was carefully added under nitrogen atmosphere to platinum oxide (1,592 g) in ethanol (10 ml). The mixture is then treated with concentrated hydrochloric acid (16 ml) and stirred at room temperature under atmospheric pressure of hydrogen for 16 hours, the Reaction mixture was diluted with water (150 ml) and filtered, the filtrate is evaporated to obtain a light-yellow solid, which is then suspended in chloroform (200 ml) with water (200 ml) with good stirring. Concentrated in the aqueous phase is extracted with chloroform (2 x 150 ml). The combined organic portions are washed with brine, dried (MgSO4) and the solvent evaporated to obtain a transparent yellowish-brown oil (4,316 g). FCC (dichloromethane/ methanol/ concentrated ammonia, 95:4:1) to obtain the compound indicated in the title, in the form of a waxy solid (2,584 g).

(d6-DMSO): 1,3-1,8 (m, 4H), 2,2 (s, 3H), 2,55 of 2.68 (m, 1H), 2,58 (d, 1H, J=2 Hz), 3,01 (dm, 1H, J=12 Hz), 2,7-3,8 (broad s, 2H), 3,68 (s, 1H), of 6.96-was 7.08 (m, 2H), 7,19 (t, 1H, J=8 Hz).

Obtained similarly:

The intermediate connection 51. CIS-2-(3-Forfinal)-3-piperidine.

From 2-(3-forfinal)-3-nitropyridine (3,292 g) obtained the connection specified in the header (0,584 g). Mass spectrometry for C11H15FN2: 389 (2M + H+), 195 (MH+).

The intermediate connection 52. CIS-2-(4-Forfinal)-3-piperidine.

From 2-(4-forfinal)-3-nitropyridine (4,88 g) obtained the connection specified in the header, in the form of a colorless oil (is 3.08 g). Mass spectrometry for C11H15FN2: m/z 195 (MH+).

The intermediate connection 53. CIS-2-( 3,4-Differenl)-3-piperidine.

From 2-(3,4-differenl)-3-nitropyridine (2.83 g) obtained the connection specified in the header, in the form of a light yellow oil (1,69 g). IU 54. 3,4-Diftorhinolonom acid.

Shavings of magnesium (1,32 g) was stirred in nitrogen atmosphere for 10 min, then was added anhydrous tetrahydrofuran (30 ml) followed by 1-bromo-3,4-differental (7.0 g) for 5 minutes and the Mixture was left at reflux distilled for 30 min, and then allowed it to cool to room temperature. The solution triisopropylsilane (13,65 g) in dry tetrahydrofuran (80 ml) under nitrogen atmosphere was cooled to -78oC (dry acetone) was added a previously prepared solution of Grenada for 10 minutes and the Mixture was stirred for 2 h, and then she was allowed to warm to room temperature within 45 minutes the Reaction was neutralized with hydrochloric acid (4M, 80 ml) and during the night was stirred at room temperature. The solution was extracted with ethyl acetate (3 x 100 ml) and the combined organic solutions were extracted water hydroxyl sodium (1 M, 4 x 100 ml). The combined aqueous basic solution was acidified to pH 3 ( 4M hydrochloric acid ), were extracted with ethyl acetate (3 x 150 ml) and the combined organic fractions were washed with acidified brine (200 ml) and dried (MgSO4). When the solvent is received the connection specified in the header, in the form of a white solid (2.7 g).

(d6-DMSO+is phenyl)piperidine-2-it.

Ammonium acetate (21,21 g), 4-triftormetilfosfinov (19,61 ml) and methyl-4-nitrobutyl (17.5 ml) in ethanol (150 ml) is stirred and heated under reflux distilled within 3.5 hours After cooling to room temperature, forming solid organic substance which is filtered, washed with ethanol ( 2 x 100 ml) and dried in vacuum to obtain compound indicated in heading (30,56 g). Mass spectrometry for C12H11F3N2O3m/z: 5,77 (2M+H+), 3006 (M+NH4), 289 (MH+).

The intermediate connection 56. 6-(4-Triptoreline)piperidine-2,5-dione.

tert-Piperonyl potassium (8,665 g) is gradually added to a stirred suspension of TRANS-5-nitro-6-(trifluoromethyl)phenylpiperidine-2-it (20,18 g) in a mixture of dichloromethane (100 ml) and methanol (100 ml) at room temperature under nitrogen atmosphere. Produced an orange solution, which is cooled to -70oC and pass through the ozone for 4 h, and then for 20 min in nitrogen. Add phosphate buffer (pH 6, 200 ml) and sodium thiosulfate (pentahydrate, 25,1 g) and allow the mixture to warm to room temperature. After extraction with ethyl acetate (4 x 200 ml) get a solid yellow substance (15,82 g) which is purified by FCC (ethyl acetate, then methanol/dichloromethane, 1:15) to receive Hz), at 7.55 and to 7.77 (2d, 4H, J=8 Hz for both), 8,29-at 8.36 (broad s, 1H).

The intermediate connection 57. 5 Oxime 6-(4-triptoreline)piperidine-2,5-dione.

Pyridine (47 ml) and hydroxylamine hydrochloride (8,18 g) is added to a stirred solution of 6-(4-triptoreline)piperidine-2,5-dione (5,04 g) in a nitrogen atmosphere. The mixture is heated with delegacia for 21 h, cooled to room temperature, poured into aqueous hydrochloric acid (2M, 100 ml) and extracted with ethyl acetate (100 ml). The organic extract was washed with aqueous hydrochloric acid (3 x 100 ml) and the combined aqueous solution is extracted with ethyl acetate (2 x 50 ml). The combined organic solutions dried (MgSO4) and evaporated in vacuo to obtain the crude product (of 5.84 g), which azeotropic toluene (33 x 50 ml). FCC (dichloromethane/methanol 12:1) gives compound indicated in heading (3,26 g) as an inseparable mixture of geometric isomers (2:1).

(d6-DMSO) for the main isomer: by 2.0-2.4 (m, 4H), of 5.15 (d, 1H, J=3.5 Hz), 7,49 and 7.75 (2d, 4H, J=8 Hz for both), 8,39 (d, 1H, J=3.5 Hz), 11,08 (s, 1H).

1H-NMR signals for the minor isomer include 5,77 (d, 1H, J=2.5 Hz), to 7.59 and 7,72 (2d, 4H, J=8 Hz for both), 8,10 (d, 1H, J=2.5 Hz), 11,14 (s, 1H).

The intermediate connection 58. CIS-5-Amino-6-(4-trifloromethyl is (15 ml) and ethanol (60 ml) and added to Raney Nickel [50% suspension in water, of 5.05 g, washed with water (2 x 25 ml) and ethanol (25 ml)] in nitrogen atmosphere. The mixture hydrogenizing when the hydrogen pressure of 50 psi for 40 h at room temperature and then filtered. The filtrate is evaporated in vacuum to obtain crude product (2,43 g). FCC (10% methanol/dichloromethane, and then the same solvent system containing 0.5% concentrated ammonia) to give the compound indicated in heading (1,262 g).

Mass spectrometry for C12H13F3N2O, m/z: 259 (MH+).

The intermediate connection 59. Hydrochloride [4-methoxy-3-(2S-phenylpiperidine-3S-yl-aminomethyl)phenyl]cyanamide.

To a suspension of (3-formyl-4-methoxyphenyl)of cyanamide (0,238 g) in dichloromethane (10 ml) add 2S-phenylpiperidine-3S-yl-amine (0,225 g), triacetoxyborohydride sodium (0.5 g) and acetic acid (0,14 ml), and the mixture is stirred at room temperature under nitrogen atmosphere for 18 h the Resulting solution is treated with 8% aqueous sodium bicarbonate solution (20 ml) and extracted with dichloromethane (3 x 30 ml). The combined organic layers dried (Na2SO4) and evaporated in vacuo. The resulting residue is purified column chromatography, elwira a mixture of dichloromethane/ ethanol/ ammonia (100:10:5). Oily p is the teaching of the precipitated solids. The solvents were removed and the residue dried in vacuum to obtain compound indicated in the title, in the form of a white solid (0,175 g), so pl. 255-258oC (decomposition).

Obtained similarly:

The intermediate connection 60. CIS-5-(2-Methoxy-5-tetrazol-1-yl)benzylamino-6-(4-triptoreline) piperidine-2-it.

From CIS-5-amino-6-(4-triptoreline)piperidine-2-she (404 g) and 2-methoxy-5-tetrazol-1-yl-benzaldehyde (411 g) obtained the connection specified in the header (273 mg).

(d6-DMSO): 1,59-to 1.86 (m, 3H), 2,16-2,31 (m, 1H), 2,35 is 2.46 (m, 1H), 2,95-to 3.09 (m, 1H), 3,53-3,82 (m, 2H), 3,66 (s, 3H), 4,78 (s, 1H), 7,12 (d, 1H, J=9.5 Hz), 7,47, (d, 2H, J=8 Hz), of 7.64-7,76 (m, 4H), to 7.84 (s, 1H), to 9.93 (s, 1H).

The intermediate connection 61. CIS-5-[2-Methoxy-5-(5-methyltetrazol-1-yl)benzylamino]-6- (4-triptoreline)piperidine-2-it.

From CIS-5-amino-6-(4-triptoreline)piperidine-2-she (207 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (155 mg) obtained the connection specified in the header (217 mg).

Mass spectrometry for C22H23F3N6O2m/z: 461 (MH+).

The intermediate connection 62. 4-(5-Phenyltetrazol-1-yl)phenol.

To a suspension of 4-benzylaminopurine ether acetic acid (10,28 g) in acetonitrile (200 ml) at 0o2SO4) and evaporated in vacuo. The residue is purified column chromatography, elwira 10% ethyl acetate in dichloromethane to obtain the compound indicated in the heading in the form of a solid (2.5 g).

TCX (5% ethyl acetate/dichloromethane): Rf 0.28 in.

The intermediate connection 63. N-[1-( 3-Formyl-4-methoxyphenyl)-1H-tetrazol-5-yl]ndimethylacetamide.

To a suspension of 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenol)-1H-tetrazol-5 Il-amine (0.5 g) in dichloromethane (5 ml), add triethylamine (0,53 ml), acetic anhydride (0,18 ml) and dimethylaminopyridine (10 mg). The mixture is stirred for 2 h in nitrogen atmosphere. Then add pyridine (1 ml) and the mixture is stirred for 18 hours Then the solvent is evaporated to dryness and dissolve the residue in tetrahydrofuran (10 ml). Then add an aqueous solution of hydrogen chloride (10 ml, 2N) and the mixture is stirred for 30 minutes the mixture is Then diluted with dichloromethane (50 ml) and add brine (20 ml). The phases are separated and the aqueous layer was extracted with dichloromethane (2 x 50 ml). The organic layers are combined dried (Na2SO4) and evaporated in vacuo, the residue is purified to result by trituration in ether to obtain compound, specified in the header, in the form of a yellow solid substance (155 mg).

TCX (5% methanol/dichloromethane): Rf of 0.3.

The intermediate connection 64. 1-(3-[1,3]Dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazol.

To a suspension of 2-methoxy-5-tetrazol-1-yl-benzaldehyde (8 g) in toluene (400 ml) was added ethylene glycol (8 ml) and p-toluensulfonate acid (50 mg). The mixture is heated at reflux distilled in the conditions of a Dean-stark in nitrogen atmosphere for 12 h, after which the water allocation is terminated. Mixture was allowed to cool, poured solution and extracted with 8% aqueous sodium bicarbonate solution (100 ml). The remaining solid is dissolved in dichloromethane (200 ml) and then extracted with a water layer. Then the aqueous layer was extracted with dichloromethane (100 ml). Then the organic layers are combined dried (Na2SO4) and evaporated in vacuo to obtain the connection specified in the header, in the form of a yellow solid (9,12 g).

TCX (5% methanol/methyl tert-butyl ether): Rf 0.5 in.

Obtained similarly:

The intermediate connection 65. 1-(3-[1,3]Dioxolane-2-yl-4-methoxyphenyl)-5-methyl-1H-tetrazol.

From 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (400 mg) and ethylene glycol (0,32 ml) of the compound obtained, ukazannnoj 66. 1-(3-[1,3]Dioxolane-2-yl-4-methoxyphenyl)-5-methylsulfanyl-1H-tetrazol.

From 2-methoxy-5-(5-methylsulfonylmethyl-1-yl)benzaldehyde (2.1 g) and ethylene glycol (9,3 ml) of the compound obtained specified in the header (2.3 g) in the form of not-quite-white solid.

TCX (ethyl acetate/cyclohexane, 1:1): Rf=0, 8.

The intermediate connection 67. (2-[1,3] Dioxolane-2-yl-4-methoxyphenyl)cyanamide.

To a solution of 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazole (a 9.09 g) in dry tetrahydrofuran (200 ml) at -78oC in nitrogen atmosphere add a solution of n-utility in hexane (30 ml of a solution of 1.6 mol DM-3). Gaseous nitrogen is excreted. After stirring in an atmosphere of nitrogen for 5 min, the mixture was allowed to warm to 0oC for 10 min and add 8% aqueous sodium bicarbonate (200 ml). After stirring for 10 min add ethyl acetate (150 ml) and separate the layers. The aqueous layer was extracted with dichloromethane (2 x 200 ml) and combine the organic layers, dried (Na2SO4) and evaporated in vacuo to obtain the connection specified in the header, in the form of an oil (8.0 g).

TCX (5% methanol/methyl tert-butyl ether): Rf of 0.7.

The intermediate connection 68. 1-(3-[1,3]Dioxolane-2-yl-4-methoxyphenyl)-1H is e (150 ml) is added ammonium chloride (22,8 g) and sodium azide (18.5 g) and heat the mixture to 80oC in nitrogen atmosphere. After 2.5 h the mixture is cooled and add brine (250 ml) and water (100 ml). The mixture is extracted with dichloromethane (3 x 250 ml 1 x 100 ml). The organic layers are combined dried (Na2SO4) and evaporated in vacuo. The resulting solid residue was washed with ether (100 ml) and dried in vacuum to obtain compound indicated in the title, in the form of a bright yellow solid (7.2 g).

The intermediate connection 69. 5-(5-Dimethylaminoethanol-1-yl )-2-methoxybenzaldehyde.

To a suspension of 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazol-5-yl-amine (500 mg) in dry tetrahydrofuran (5 ml) add a solution hexamethyldisilazide sodium (2 ml, 1.0 M solution in tetrahydrofuran) at room temperature under nitrogen atmosphere. Before you can add methyliodide (0.15 ml), the mixture is stirred for 5 minutes Before adding another solution hexamethyldisilazide sodium (2 ml, 1.0 M in tetrahydrofuran), and the mixture is stirred for 10 minutes Before adding another under the conditions (0.15 ml), the mixture is stirred for 5 minutes the Mixture is stirred for 18 h, then add aqueous solution of hydrogen chloride (10 ml, 2 M) and the mixture is stirred for another 30 minutes Add brine (20 ml) and dichloromethane (50 ml) and the layers separated. The aqueous layer was extracted with dichloromethane the camping residue purified column chromatography, elwira 10% ethyl acetate in dichloromethane to obtain the compound indicated in the heading in the form of a yellow solid (230 mg).

TCX (5% methanol/dichloromethane): Rf 0.45 in.

Obtained similarly:

The intermediate connection 70. 5-(5-Diethylaminomethyl-1-yl)-2-methoxybenzaldehyde.

From 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazol-5-yl-amine (0.5 g) and ethyliodide (0,32 ml in two portions) received the connection specified in the header, in the form of a yellow solid (0,224 g).

TCX (5% methanol/dichloromethane): Rf 0.5 in.

The intermediate connection 71. (3-Formyl-4-methoxyphenyl)cyanamide.

To a solution of 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazole ones (0.46 g) in tetrahydrofuran (10 ml) at 0oC in an atmosphere of nitrogen was added n-utility (1.7 ml, 1.6 M solution in hexane). After stirring for 5 min add a dilute solution of aqueous hydrogen chloride (5 ml) and acetone (2 ml). The mixture is stirred for 1 h, and then added dichloromethane (30 ml) and 8% aqueous sodium bicarbonate solution. The layers separated, the aqueous layer was extracted with dichloromethane (3 x 30 ml). The organic layers are combined dried (Na2SO4) and evaporated in vacuo to obtain organic solids. what I specified in the header in the form of a solid orange substance (0.31 g).

TCX (5% methanol/methyl tert-butyl ether): Rf of 0.6.

The intermediate connection 72. 2-Methoxy-5-[5-(3,3,3-Cryptor-2-oxopropyl)tetrazol-1-yl]benzaldehyde.

n-Utility in hexane (0.25 ml, 1.6 M) are added to a solution of 1-(3-[1,3] dioxolane-2-yl-4-methoxyphenyl)-1H-tetrazole (100 mg) in tetrahydrofuran (5 ml) at -78oC. After 10 min add triperoxonane anhydride (0,064 ml) and the reaction mixture was stirred in nitrogen atmosphere at room temperature for 72 hours Add 8% aqueous acidic sodium carbonate (20 ml) and the product extracted into dichloromethane (3 x 20 ml). The combined organic portion was concentrated in vacuo to obtain a yellow oil. The solution of this oil in acetone (3 ml) and 2N hydrochloric acid (3 ml) was stirred at room temperature for 2 hours, the Acetone is removed in vacuo and extracted the product with dichloromethane (3 x 20 ml). The combined organic portion is dried over sodium sulfate and concentrated in vacuo to obtain a yellow resin. Purified chromatographically as eluent using methanol/ methyl tert-butyl ether (2,5: 97,5) to obtain the compound indicated in heading (50 mg) as a pale yellow wertanalytiker-1H-tetrazol.

m-Chloroperbenzoic acid (MCPBA) (1.2 g) are added to a solution of 1-(3-[1,3]dioxolane-2-yl-4-methoxyphenyl)-5-methylsulfanyl-1H-tetrazole (800 mg) in chloroform (15 ml) at room temperature under nitrogen atmosphere. After 3 hours, add another portion of MCPBA (1.2 g ) and leave the mixture was mixed for 24 hours the Mixture was poured into aqueous sodium sulfite (200 ml) and stirred for 30 minutes the mixture is Then extracted with chloroform (3 x 60), dried (Na2SO4) and evaporated to obtain the connection specified in the header, in the form of a yellow oil (800 mg).

TCX (ethyl acetate/cyclohexane, 1:1): Rf=0.5 in.

The intermediate connection 74. 5-(5-Methanesulfonamido-1-yl)-2-methoxybenzaldehyde.

1-(3-[1,3] Dioxolane-2-yl-4-methoxyphenyl)-5-methanesulfonyl-1H-tetrazol (800 ml) in tetrahydrofuran (13 ml) and hydrochloric acid (2N, 7.5 ml) was stirred at room temperature for 1.5 hours the Solution is alkalinized with sodium bicarbonate solution (8%), saturated brine (50 ml), extracted with ether (3 x 50 ml), dried (Na2SO4) and evaporated to obtain the connection specified in the header, in the form of a solid orange substance (307 mg).

TCX (ethyl acetate/cyclohexane, 1:1): Rf=0.5 in.

The intermediate connection 75. 1-(4-Benzyloxy-3-forfinal)-5-UP>oC in nitrogen atmosphere. Add triethylorthoformate (10.3 ml). Incubated for another 45 min at the same temperature and added in portions sodium azide (7.8 g). The temperature of the support for 3 h, then the reaction mixture is cooled overnight and poured into sodium bicarbonate solution (8%, 500 ml), extracted with dichloromethane (3 x 100 ml), dried (Na2SO4) and evaporated. The residue is purified by FCC with a mixture of dichloromethane/methanol (995:5) to obtain the compound indicated in the title, in the form of a solid (4.6 g).

TCX (dichloromethane/methanol, 995:5): Rf 0.45 in.

The intermediate connection 76. 2-Fluoro-4-(5-methyltetrazol-1-yl)phenol.

A suspension of 1-(4-benzyloxy-3-forfinal)-5-methyl-1H-tetrazole (4.6 g) in ethanol (300 ml) hydrogenizing at room temperature and pressure over a pre-restored palladium-carbon (10% paste, 1.4 g) suspension until such time until absorption. The catalyst is filtered off and the filtrate is evaporated to obtain the connection specified in the header, in the form of a cream solid (3.6 g).

TCX (dichloromethane/methanol, 995:5): Rf 0.45 in.

The intermediate connection 77. (4-Benzyloxyphenyl)amide cyclopropanecarbonyl acid.

Cyclopropanemethylamine (15,33 ml) in dichloromethane (60 ml). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 2 hours the Solution was diluted with 2N hydrochloric acid (100 ml) and dichloromethane (200 ml). The organic layer was washed with 2N sodium carbonate (100 ml), water (100 ml), 10% brine (50 ml) and dried over anhydrous sodium sulfate. Concentrated in vacuo to obtain a light brown solid, which was washed with diethyl ether (3 x 50 ml) to obtain the compound indicated in heading (12 g) as a white solid. So pl. 162oC.

The intermediate connection 78. 1-(4-Benzyloxyphenyl)-5-cyclopropyl-1H-tetrazol.

Triftormetilfullerenov anhydride (9,42 ml) is added dropwise over 10 min to a solution of (4-benzyloxyphenyl)amide cyclopropanecarbonyl acid (15 g) and sodium azide (of 3.64 g) in acetonitrile (250 ml) at 0oC. the Reaction mixture was stirred at room temperature under nitrogen atmosphere for 16 hours to Add a 10% aqueous solution of acid sodium carbonate (80 ml) and separate the organic layer. The aqueous layer was extracted further with ethyl acetate (2 x 100 ml). The combined organic part was dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a brown oil. Clean chromatography is in the form of a yellow solid. So pl. 118oC.

The intermediate connection 79. 4-(5-Cyclopropylmethyl-1-yl)phenol.

A solution of 1-(4-benzyloxyphenyl)-5-cyclopropyl-1H-tetrazole (2.3 g) in ethanol (75 ml) are added to a suspension of 10% palladium-carbon catalyst (400 mg) in ethanol (10 ml) and the mixture is stirred in hydrogen atmosphere for 1 h, the Catalyst was removed by filtration and the solution concentrated in vacuo to obtain the connection specified in the header (of 1.57 g) as a pale yellow solid, So pl. 184oC.

Obtained similarly:

The intermediate connection 80. 4-Tetrazol-2-yl-phenylamine.

From 2-(4-nitrophenyl)-2H-tetrazole (7,3 g) obtained the connection specified in the header, in the form of a beige solid (5.4 g).

TCX (cyclohexane/ethyl acetate 3:1): Rf of 0.65.

The intermediate connection 81. 4-(5-Methylsulfonylmethyl-1-yl )phenol.

A solution of sodium hydroxide (to 2.06 g) in water (120 ml), and then methyliodide (3.5 ml) was added to a solution of 1-(4-hydroxyphenyl)-1H-tetrazol-5-thiol (10 g) in tetrahydrofuran (30 ml) and stirred at room temperature for 5 hours the Mixture was poured into brine (120 ml), was extracted with ethyl acetate (3 x 60 ml), dried (Na2SO4) and evaporated to obtain specified in ,42.

The intermediate connection 82. 3-Nitro-2-p-toluamide.

The stirred mixture of 2-chloro-C-nitropyridine (10.6 g), p-tolylboronic acid (19,69 g) and tetrakis(triphenylphosphine)palladium (0) (0.16 g) in 2N solution of sodium carbonate (100 ml) and dimethoxyethane (100 ml) was heated with delegacia in nitrogen atmosphere. After 64 h the mixture was cooled, filtered through a broadband filter, elwira a large number of dichloromethane. The filtrate is evaporated in vacuum to obtain the oil, which then pererestorani in ether (300 ml) and washed with 5N-sodium hydroxide solution (300 ml). The aqueous portion again was extracted with ether (300 ml x 2). The combined organic extracts were washed with water (200 ml), 1N hydrochloric acid (2 x 100 ml) and saturated brine, dried (MgSO4) and evaporated in vacuo, the resulting solid substance was washed with hexane to obtain specified in the title compound as a yellow crystalline solid (11,66 g).

TCX (hexane/ethyl acetate, 2:1): Rf=0.52 in.

The intermediate connection 83. 5-(1-Ethyl-1H-tetrazol-5-yl)-2-methoxybenzaldehyde.

From 5-bromo-1-ethyl-1H-tetrazole (620 mg) and 3-formyl-4-methoxyphenylacetic acid (0,69 g) obtained specified in the header connect the-(1-Cyclopropylmethyl-1H-tetrazol-5-yl )-2-methoxybenzaldehyde.

From a mixture of 5-bromo-1-cyclopropylmethyl-1H-tetrazole with 5-bromo-2-cyclopropyl-2H-tetrazolium (1,91 g) and 3-formyl-4-methoxyphenylacetic acid (1.86 g) was obtained is listed in the title compound (657 mg) in the form of a yellow solid substance.

NMR (CDCl3), : 0,45 (2H, m), 0,70 (2H, m), 1,3 (1H, m), of 4.05 (3H, s), 4,3 (2H, d), 7,2 (1H, d), and 8.0 (1H, m), 8,15 (1H, d), 10,55 (1H, s).

The intermediate connection 85. CIS-2-p-Colorvitality-3-yl-amine.

Stir a solution of 3-nitro-p-colorvitality (5.0 g) in ethanol (200 ml) and concentrated hydrochloric acid (15 ml) was hydrogenosomal over previously restored with platinum oxide (1.5 g) at the 23oC and 1 ATM until then, until it was ended by the absorption of hydrogen (about 31 hours). The mixture was filtered through a high-speed filter with water, then evaporated the filtrate in vacuo. Recrystallization from isopropanolate water gave a solid creamy substance. This solid was treated with 2N sodium hydroxide solution and was extracted with dichloromethane (5 x 200 ml). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to obtain specified in the title compound as an orange-brown oil which upon standing partially crystallized (2.20 g).

TCX (dichlotride)amine.

A mixture of triphenylphosphine on the substrate from the resin (3 mmol of triphenylphosphine/1 g of resin; 58,6 g) and N-(4-benzyloxyphenyl)-2,2,2-trifurcated in carbon tetrachloride (800 ml) was heated with delegacia in nitrogen atmosphere for 18 hours the Mixture was allowed to cool, then filtered, washed the resin with dichloromethane (1 l) and ether (1 l). The organic phase was concentrated in vacuum to obtain specified in the connection header in the form of a yellow solid substance (20.7 g).

TCX (cyclohexane/ethyl acetate, 9:1): Rf=0,81.

The intermediate connection 87. 1-(4-Benzyloxyphenyl)-5-trifluoromethyl-1H-tetrazol.

(4-Benzyloxyphenyl)-(1-chloro-2,2,2-triptoreline)amine (66 mmol) was added into the flask with glacial acetic acid (250 ml) under stirring at 70oC in nitrogen atmosphere. After 4 min was added sodium azide (210 ml) and continued heating for another 3 hours After cooling, the mixture was filtered, the filtrate was poured into water (750 ml) and then was extracted with dichloromethane (500 ml x 3). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. Was purified by FCC, using hexane/ethyl acetate (19:1), obtaining specified in the title compound as white solid (14.5 g).

TCX (cyclohexane/ethyl acetate 19:1): Rf=0,22.

TCX ( dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,3.

The intermediate connection 89. 2-Methoxy-5-tetrazol-2-yl-methylbenzaldehyde (a) and 2-methoxy-5-tetrazol-1-yl-methylbenzaldehyde (B).

A mixture of 5-methyl bromide-2-methoxybenzaldehyde with 5-chloromethyl-2 - methoxybenzaldehyde (0.5 g), tetrazole (306 mg) and triethylamine (608 μl) in dichloromethane (10 ml) was stirred at room temperature for 48 hours the Mixture was washed with hydrochloric acid (20 ml, 2N), then a solution of sodium carbonate (20 ml, 2N), dried (MgSO4) and solvent was removed to obtain the crude product (373 mg). It was purified column chromatography, elwira ether, obtaining specified in the title compound (103 mg), TCX (ether): Rf=0,37, and are specified in the connection header B (170 mg), TCX (ether): Rf=0,05.

The intermediate connection 90. 2-(4-Nitrophenyl)-2H-tetrazol.

A mixture of 1-fluoro-4-nitrobenzene (20 g), potassium carbonate (23,5 g) and 1H-tetrazole (12 g) in dimethylformamide (60 ml) maintained at 100oC in nitrogen atmosphere for 24 hours After cooling, the solvent evaporated and collected balance in the water, was extracted with dichloromethane (the FCC (cyclohexane/ethyl acetate, 3:1) to obtain the specified title compound as a solid (6.5 g).

TCX (cyclohexane/ethyl acetate, 3:10): Rf=0,43.

The intermediate connection 91. 4-Tetrazol-2-yl-phenol.

A suspension of 4-tetrazol-2-yl-phenylamine (5,4 g) in water (42 ml) and concentrated sulfuric acid (10 ml) was slowly added to a solution of sodium nitrite (2.3 g) in water (8.5 ml) in 5oC. the Resulting green solution was stirred at this temperature for about 30 min, treated with a mixture of water (50 ml) and concentrated sulfuric acid (67 ml) and maintained at 120oC 1 h was Added water (170 ml) was cooled reaction mixture, saturated brine (100 ml) and was extracted with dichloromethane (3 x 100 ml), dried (Na2SO4) and evaporated to obtain specified in the connection header in the form of a solid orange substance (1.6 g).

TCX (ethyl acetate/cyclohexane, 1:1): Rf=0,55.

The intermediate connection 92. 2-Hydroxy-5-tetrazol-2-yl-benzaldehyde.

Hexamethylenetetramine (5.6 g) was added to 4-tetrazol-2-yl-phenol (1.6 g) in triperoxonane acid (40 ml) and the mixture was stirred for 24 h at 60oC. After cooling, the solution was poured into sulfuric acid (2N, 100 ml), was extracted with ether (3 x 100 ml), dried (Na2SO4what about the yellow substance (930 mg).

TCX (dichloromethane), Rf=0,56.

The intermediate connection 93. 2-Methoxy-5-tetrazol-2-yl-benzaldehyde.

Sodium carbonate (1.06 g) and methyliodide (0.5 ml) was added to a solution of 2-hydroxy-5-tetrazol-2-yl-benzaldehyde (930 mg) in dimethylformamide (6 ml) at room temperature. The mixture was stirred 2 h, then evaporated to obtain a solid orange substance. It was dissolved in water (40 ml), was extracted with dichloromethane (3 x 30 ml), dried (Na2SO4) and evaporated. The residue was purified by FCC (dichloromethane) to obtain the specified title compound as yellow solid substance (423 mg).

TCX (ethyl acetate/cyclohexane, 1:1): Rf=0,44.

The intermediate connection 94. 2-Methoxy-5-(1H-tetrazol-5-yl)benzaldehyde.

Tributyltins (1.7 g) was added to 3-[1,3]dioxolane-2-yl-4-methoxybenzonitrile (500 mg), and then added two more servings tributyltinoxide (2 x 1.7 g). The mixture was stirred at 160oC 2 h After cooling, the thick oil was divided into 2N solution of sodium hydroxide (30 ml) with ether (3 x 30 ml). The aqueous phase was acidified with concentrated hydrochloric acid and was extracted with a mixture ethyl acetate (3 x 70 ml). An ethyl acetate fraction was dried (MgSO4) and concentrated to obtain specified in the header is (d); to 8.57 (1H, d); 10,53 (1H, s).

The intermediate connection 95. 2-Methoxy-5-(1-methyl-1H-tetrazol-5-yl)benzaldehyde and 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzaldehyde (B).

A mixture of potassium carbonate (400 mg) and 2-methoxy-5-(1H-tetrazol-5-yl)benzaldehyde (400 mg) in dimethylformamide (10 ml) was stirred 0.5 h, then was added itmean (of 0.18 ml) and continued stirring for 20 hours was Added water (20 ml) and was extracted with a mixture of ethyl acetate (3 x 20 ml). The organic extracts were dried (MgSO4) and concentrated in vacuum to obtain yellow solid substance (370 mg). It cleared the FCC, elwira petrol/ether (1:1 -> 0: 1) to obtain specified in the connection header B (320 mg), TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,62, and are specified in the connection header And TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,37.

The intermediate connection 96. 1-Cyclopropylmethyl-1H-tetrazole and 2-cyclopropylmethyl-2H-tetrazol.

A mixture of cyclopropanemethylamine (15 g), tetrazole (12 g), triethylamine (23,8 ml) and 4-dimethylaminopyridine (25 mg) in dichloromethane (500 ml) was left overnight at room temperature. The mixture was washed with water (250 ml) and 2N aqueous sodium carbonate (2 x 250 ml), dried (MgSO4) and concentrated in vacuum to obtain specified in the header connect the azole and 5-bromo-2-cyclopropylmethyl-2H-tetrazol.

A solution of bromine (21,5 g) in chloroform (20 ml) was added dropwise to a solution of 1-cyclopropylmethyl-1H-tetrazole and 2-cyclopropylmethyl-2H-tetrazole (8.0 g) in acetic acid (50 ml) and chloroform (100 ml) at reflux distilled in a nitrogen atmosphere. After heating for 18 h the mixture was cooled and evaporated in vacuum to obtain a red oil. It was dissolved in ethyl acetate (200 ml) and washed with an aqueous solution of sodium metabisulfite, water (100 ml), saturated brine, dried (MgSO4) and evaporated in vacuo. Triturated with ether to obtain specified in the connection header (1,91 g) in the form of a solid gray matter.

TCX (hexane/ethyl acetate, 9:1): Rf=0,87.

Evaporation after trituration gave the second portion specified in the title compound as a black oil (7.51 g).

The intermediate connection 98. Methyl ester 2-methoxy-5-(tetrazol-1-yl)benzoic acid.

Sodium azide (0.54 g) was added to a stirred solution of methyl ether 2-methoxy-5-amino-benzoic acid (1 g) and triethylorthoformate (1,38 g) in glacial acetic acid (8 ml) and dimethylformamide (2 ml). The mixture was heated up to 79-80oC. After 1 h 15 min the solution was cooled (ice-water bath) and was slowly added a solution of sodium nitrite (0,57 g is washed in water and dried in vacuum at 25oC obtaining specified in the connection header (0,83 g). So pl. 185-187oC.

The intermediate connection 99. 2-Methoxy-5-(tetrazol-1-yl)phenylmethanol.

Borohydride lithium (196 mg) was added under nitrogen atmosphere to a stirred and cooled (ice-water bath) suspension of methyl ether 2-methoxy-5-(tetrazol-1-yl)benzoic acid (1 g) in tetrahydrofuran (15 ml). After 2 min for 1 min solution was added methanol (288 mg) in tetrahydrofuran (2 ml). Removed the cooling bath and stirred mixture of 86 minutes the Solution was cooled (ice-water bath) was added a 3 M aqueous hydrochloric acid (0.5 ml -1) with the formation of a thick gel. Was added water (5 ml), and then another 3 M aqueous hydrochloric acid (5 ml). Then the solution was added sodium nitrite (325 mg) in water (1 ml). After 1 h 15 min was added water (15 ml) and the resulting solution was extracted with ethyl acetate. The organic phase is successively washed with diluted hydrochloric acid and water, and then dried (MgSO4). After evaporation has received a yellow solid, which was stirred with ethyl acetate (3 ml). After filtering the received gray-white solid, which was washed with a mixture of ethyl acetate and petroleum ether (1:1, so Kip. 60-80oC) and vissual Hz), of 5.34 (t, 1H, J = about 8 Hz), 7,20 (d, 1H, J = 10 Hz), of 7.75 (dd, 1H, J = 10 Hz, J = about 4 Hz), 7,86 (d, 1H, J = about 4 Hz), of 10.01 (s, 1H).

The intermediate connection 100. 2-Methoxy-5-(tetrazol-1-yl)benzaldehyde.

Active manganese dioxide (77 mg) was added to a stirred solution of 2-methoxy-5-(tetrazol-1-yl)phenylmethanol (40 mg) in tetrahydrofuran (1 ml). After 30 min the mixture was placed in an oil bath at 70oC. after 30 min was added active manganese dioxide (67 mg). After 1 h the mixture was cooled and filtered. The filtrate is evaporated to obtain specified in the title compound as a yellow solid (33 mg).

NMR (d6-DMSO), : 4,4 (s, 3H), 7,53 (d, 1H, J = 10 Hz), 8,12-8,23 (m, 2H), 10,12 (s, 1H), the 10.40 (s, 1H).

Example 1. The dihydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-(CIS-2-phenylpiperidine-Z - yl)amine.

To a solution of CIS-2-phenylpiperidine-3-yl-amine (1,22 mmol) and 2-methoxy-5-tetrazol-1-yl-benzaldehyde (1,22 mmol) in dichloromethane (25 ml) was added triacetoxyborohydride sodium (1.70 mmol) and 2 drops of glacial acetic acid, the mixture was stirred at room temperature under nitrogen atmosphere for 18 hours the Solvent is evaporated in vacuum and the residue was neutralized 2N sodium carbonate solution (20 ml) and was extracted with ethyl acetate (3 x 50 a thief sodium carbonate and was extracted with dichloromethane (3 x 100 ml). The organic extracts were dried (MgSO4), filtered and concentrated to obtain residue, which was purified by FCC (dichloromethane/methanol/ ammonia, 200: 8: 1) to give a white foam which was dissolved in ethanol (15 ml) and treated with 1 M solution of hydrochloric acid in ether ( 2.5 ml ). The solvent is evaporated in vacuum and the resulting white solid is triturated with isopropanol and filtered to obtain specified in the title compound (49%). So pl. 242-243oC.

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0.5 in.

Obtained similarly:

Example 2. The dihydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S,3S]-2-phenylpiperidine-3-yl)amine.

From 2-methoxy-5-(tetrazol-1-yl)benzaldehyde (0.55 g) and [2S]-phenylpiperidine-[3S]-yl-amine (0,47 g) obtained is listed in the title compound as a white solid (yield 81%). So pl. 243-244oC.

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0.5 in.

Example 3. The dihydrochloride [2-methoxy-5-(5-methyltetrazol-1-yl)benzyl ]-(CIS-2-phenylpiperidine-3-yl)amine.

From 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (1,14 mmol) obtained is listed in the title compound as a white solid (yield 60%). So pl. 247-248oC.

TCX (dichloromaleimide-3-yl)amine.

From 5-(5-elitetrader-1-yl)-2-methoxybenzaldehyde (1.07 mmol) obtained is listed in the title compound as a white solid (yield 68%). So pl. 245-246oC.

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,6.

Example 5. The dihydrochloride of 2-methoxy-[5-(5-propertyreal-1-yl)benzyl] - (CIS-2-phenylpiperidine-3-yl)amine.

From 2-methoxy-5-(5-propertyreal-1-yl)benzaldehyde (260 mg) obtained is listed in the title compound as a white solid (343 mg). So pl. 247-249oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,47.

Example 6. The dihydrochloride [2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] - ([2S,3S]-2-phenylpiperidine-3-yl)amine.

To a solution of [2S]-phenylpiperidine-[3S]-yl-amine (4.6 mmol) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (4.6 mmol) in dichloromethane (50 ml) was added triacetoxyborohydride sodium (6,9 mmol) and 5 drops of glacial acetic acid. The mixture was stirred at room temperature under nitrogen atmosphere for 18 hours the Solvent is evaporated in vacuum and the residue was neutralized 2N solution of sodium carbonate (30 ml) and was extracted with ethyl acetate (50 ml). The organic layer was treated with 2N hydrochloric acid (50 ml) and the acid portion was podslushivaet 2N solution of sodium carbonate and intertribal with obtaining balance, which was purified by FCC (dichloromethane/methanol/ ammonia, 150:8:1) to give a light yellow oil, which was dissolved in ethanol (50 ml) and treated with 1 M solution of hydrochloric acid in ether (10 ml). The solvent is evaporated in vacuum to obtain specified in the title compound as a white solid (92%). So pl. 244-246oC.

TCX (dichloromethane/ethanol/ammonia, 150:8:1): Rf=0,30.

Example 7. The dihydrochloride [2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]- ([2S,3S]-2-phenylpiperidine-3-yl)amine.

A mixture of [2S] -phenylpiperidine-[3S]-yl-amine (to 1.14 mmol), 2-methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde (1.2 mmol), triacetoxyborohydride sodium (2,37 mmol) and acetic acid (3 drops) in dichloromethane (25 ml) was stirred at 23oC in nitrogen atmosphere for 64 hours was Added a 2N solution of sodium carbonate (50 ml) and the mixture was extracted with dichloromethane (3 x 25 ml). The combined organic extracts were washed with saturated brine (50 ml), dried (MgSO4) and evaporated. Was purified by FCC (dichloromethane/ethanol/ ammonia, 400: 10: 1 -> 100:10:1) to obtain a colorless viscous oil. It was dissolved in methanol (10 ml) and was treated with 2N solution of hydrochloric acid in ether (10 ml). Evaporated in vacuo and triturated with isopropylacetate with palutena/ammonia, 200:10:1): Rf=0,39.

Optical rotation (0.003 g/ml of water): +50,35o.

Obtained similarly:

Example 8. The dihydrochloride [5-(5-cyclopropylmethyl-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine.

From 2S-phenylpiperidine-3S-yl-amine (176 mg) and 5-(5-cyclopropylmethyl-1-yl)-2-methoxybenzaldehyde (244 mg) obtained is listed in the title compound (300 mg) as a pale yellow solid. So pl. 272oC.

TCX (dichloromethane/methanol/acetic acid/water, 120:15:3:2): Rf=0,22.

Example 9. The dihydrochloride [2-methoxy-5-(5-methylsulfonylmethyl-1-yl) benzyl]-(2S-phenylpiperidine-3S-yl)amine.

From [2S] -phenylpiperidine-[3S] -yl-amine (282 mg) and 2-methoxy-5-(5-methylsulfonylmethyl-1-yl)benzaldehyde (400 mg) obtained is listed in the title compound as a whitish solid (484 mg). So pl. 245oC.

TCX ( dichloromethane/methanol/ammonia, 945:50:5): Rf=0,3.

Example 10. The dihydrochloride [2-methoxy-5-(5-phenyltetrazol-1-yl)benzyl] -(2S-phenylpiperidine-3S-yl)amine.

From 2-methoxy-5-(5-phenyltetrazol-1-yl)benzaldehyde (0.35 g) and 2S-phenylpiperidine-3S-yl-amine (0,218 g) obtained is listed in the title compound as a white solid (0,525 g). So pl. 248-250oC.

TCX (di is razol-1-yl)benzyl]-(2S-phenylpiperidine-3S-yl)amine.

From 2-methoxy-5-(5-methylamino-4,5-dihydrotetrazolo-1-yl)benzaldehyde (117 mg) and 2S-phenylpiperidine-S-yl-amine (93 mg) obtained is listed in the title compound as a white solid (200 mg). So pl. 260-263oC (decomposition).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,05.

Example 12. The dihydrochloride of N-(1-(4-methoxy-3-[(2S-phenylpiperidine-2S-yl-amino)methyl]phenyl)-1H-tetrazol-5-yl)ndimethylacetamide.

From [1-(3-formyl-4-methoxyphenyl)-1H-tetrazol-5-yl] ndimethylacetamide (141 mg) and 2S-phenylpiperidine-3S-yl-amine (100 mg) obtained is listed in the title compound as a white solid (150 mg). So pl. 228-230oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,1.

Example 13. Trihydrochloride [5-(5-dimethylaminoethanol-1-yl)-2-methoxy-benzyl]-(2S-phenylpiperidine-3S-yl)amine.

From 5-(5-dimethylaminoethanol-1-yl)-2-methoxybenzaldehyde (200 mg) and 2S-phenylpiperidine-2S-yl-amine (150 mg) obtained is listed in the title compound as a white solid (307 mg). So pl. 266-269oC (decomposition).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0.21 in.

Example 14. Trihydrochloride [5-(5-diethylaminomethyl-1-yl)-2-methoxybenzyl]-(2S-phenylpiperidine-3S-yl)amine.

From 5-(5-diethylaminomethyl-1-yl)-2-the ideal of a white powder (0.34 g). So pl. 229-231oC (decomposition).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,24.

Example 15. The dihydrochloride 1,1,1-Cryptor-3-(1-(4-methoxy-3-[(2S-phenylpiperidine-3S-yl-amino)methyl] phenyl)-1H-tetrazol-5-yl)propan-2-it.

From 2S-phenylpiperidine-3S-yl-amine (28 mg) and 2-methoxy-5-[5-(3,3,3-Cryptor-2-oxopropyl)tetrazol-2-yl] benzaldehyde (50 mg) obtained is listed in the title compound as a white solid (150 mg). So pl. 284oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,32.

Example 16. The dihydrochloride [5-(5-methanesulfonamido-1-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine.

From [2S] -phenylpiperidine-[3S] -yl-amine (125 mg) and 5-(5-methanesulfonamido-1-yl)-2-methoxybenzaldehyde (200 mg) obtained is listed in the title compound as a white solid (173 mg). So pl. 235oC.

TCX (dichloromethane/methanol/ammonia, 967:30:3): Rf=0,12.

Example 17. The dihydrochloride [3-fluoro-2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]-(2S-phenylpiperidine-3S-yl)amine.

From [2S]-phenylpiperidine-[3S]-yl-amine (313 mg) and 3-fluoro-2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (755 mg) obtained is listed in the title compound as a white solid (275 mg). So pl. 222oC.

TCX (d is(2-p-tripeptides-Z-yl)amine.

From CIS-2-p-tripeptides-3-yl-amine (0.167 g) and 2-methoxy-5-(5-tetrazol-1-yl)benzaldehyde (0,180 g) obtained is listed in the title compound as a white solid (237 mg). So pl. 152-153oC.

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,20.

Example 19. The dihydrochloride of CIS-[2-methoxy-5-(5-cryptomaterial-1-yl-benzyl]-(2-p-tripeptides-Z-yl)amine.

From CIS-2-p-tripeptides-3-yl-amine (300 mg) and 2-methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde (429 mg) obtained is listed in the title compound as a pale yellow solid (145 mg). So pl. 240oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0.35 in.

Example 20. The dihydrochloride of CIS-[2-methoxy-5-(5-methyltetrazol-1-yl-benzyl]- (2-p-tripeptides-3-yl)amine.

From CIS-2-p-tripeptides-3-yl-amine (500 mg) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (573 mg) obtained is listed in the title compound as a white solid (191 mg). So pl. 252-253oC.

TCX (dichloromethane/ethanol/ammonia, 95:4:1): Rf=0,22.

Example 21. The dihydrochloride of CIS-[2-(3-bromophenyl)piperidine-3-yl]-(2-methoxy-5-tetrazol-1-yl-benzyl)amine.

From CIS-2-(3-bromophenyl)piperidine-3-yl-amine (500 mg) and 2-methoxy-5-tetrazol-1-yl)benzaldehyde the decomposition).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0.40 in.

Example 22. The dihydrochloride of CIS-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]- [2-(4-methoxyphenyl) piperidine-3-yl]amine.

From CIS-(4-methoxyphenyl)piperidine-3-yl-amine (443 mg) (dihydrochloride, CIS-2-(4-methoxyphenyl)piperidine-3-yl-amine (677 mg) were separated in a mixture of dichloromethane (50 ml) and 0.88 ammonia (10 ml). Separated phase and the aqueous phase was extracted with dichloromethane (2 x 30 ml). The combined organic phases were washed with water (20 ml) and brine (20 ml), dried (Na2SO4) and evaporated in vacuo to obtain the free base (443 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (469 mg) to obtain the specified title compound as a white powder (115 mg). So pl. > 145oC (dark), > 190oC (decomposes).

TCX (dichloromethane/ethanol/ammonia (150:8:1): Rf=0,23.

Example 23. The dihydrochloride of CIS-[2-(3-bromo-4-were)piperidine-3-yl]-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine.

From CIS-2-(3-bromo-4-were)piperidine-3-yl-amine (1,03 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (812 mg) obtained is listed in the title compound as a white powder (725 mg). So pl. > 220oC (decomposition).

TCX (dichloromethane/ethanol/ammonia, 150:8:1): Rf=0,27.SS="ptx2">

From 2-methoxy-5-tetrazol-1-yl-benzaldehyde (300 mg) and CIS-2-(3-chlorophenyl)piperidine-3-yl-amine (423 mg) (dihydrochloride, CIS-2-(3-chlorophenyl)piperidine-3-yl-amine (360 mg) were separated in a mixture of dichloromethane (30 ml) and 0.88 ammonia (10 ml). Separated phase and the aqueous phase washed with dichloromethane (2 x 20 ml). The combined organic phases were washed with water (30 ml) and brine (30 ml), dried (Na2SO4) and evaporated in vacuo to obtain the free base (260 mg) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (469 mg) to obtain the specified title compound as a white powder (279 mg). So pl. > 218oC (dark), > 245oC (decomposes).

TCX (dichloromethane/ethanol/ammonia, 150:8:1): Rf=0,24.

Example 25. The dihydrochloride [2S-(4-forfinal)piperidine-3S-yl]-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]amine.

Of 2S-(4-forfinal)piperidine-3S-yl-amine (300 mg) and 2-methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde (418 mg) obtained is listed in the title compound as a pale yellow solid (450 mg). So pl. 274oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,57.

Example 26. The dihydrochloride of CIS-[2-(3-forfinal)piperidine-3-yl]-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]amine.

Osceno specified in the title compound as a pale yellow solid (140 mg). So pl. 239oC (decomposition).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,51.

Example 27. The dihydrochloride of CIS-[2-(3-fluoro-4-were)piperidine-3-yl]-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine.

From CIS-2-(3-fluoro-4-were)-3-piperidylamine (0,407 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (0,452 g) obtained is listed in the title compound as a cream solid (0,603 g).

(D2O): 2,0-to 2.40 (m, 3H), of 2.28 (s, 3H), 2,43-of 2.58 (m, 1H), 2,60 (s, 3H), 3.27 to is 3.40 (m, 1H), 3,60-3,74 (m, 1H, in), 3.75 (s, 3H), 4,00-4,08 (m, 1H), 4,15 (d, 1H, J=13.5 Hz), 4,48 (d, 1H, J=13.5 Hz), of 4.95 (d, 1H, J=3.5 Hz), 6,93-to 7.09 (m, 2H), 7,13 (d, 1H, J=8.5 Hz), of 7.36-7,47 (m, 2H), 7,68 (dd, 1H, J=8.5 and 2 Hz).

Microanalysis for C22H27FN6O2HClO11H2O.

Calculated: C 54,44; H 6,07; N 7,31; Cl 14,61; H2O 0,4%.

Found: 53,98; H 5,98; N 17,05; Cl 14,6; H2O 0,4%.

Example 28. The dihydrochloride of CIS-[2-(3-forfinal)piperidine-3-yl]-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine.

From CIS-2-(3-forfinal)-3-piperidylamine (0,390 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (0,46 g) of the obtained free base (0.6 g), part of which (0,376 g) is treated with hydrogen chloride to obtain specified in the title compounds as white solids (0,409 g).

(D2O): 2,05-2,4 (m, 3H), 7,30 (dt, 1H, J=8 and 2 Hz), 7,46 (d, 1H, J=2.5 Hz), 7,52-of 7.60 (m, 1H), to 7.67 (dd, 1H, J=9 and 2.5 Hz).

Microanalysis for C21H25FN6O2HClOH2O.

Calculated: 53,52; H of 5.82; N 17,83; Cl 15,05; H2O 0,4%.

Found: 53,53; H 5,72; N 17,85; Cl 14,9; H2O 0,4%.

Example 29. The dihydrochloride [2S,3S]-[2-(4-forfinal)piperidine-3-yl]-[2-methoxy-5-tetrazol-1-yl-benzyl]amine.

Of 2S-(4-forfinal)piperidine-3S-yl-amine-2R, 3R-bis-(4-methylbenzylamino)succinate (2.14 g), which was dissolved in aqueous ammonia (25 ml of concentrated ammonia in 25 ml of H2About) and was extracted with chloroform (3 x 40 ml) to give the free base in the form of a transparent liquid (0,642 g) and 2-methoxy-5-tetrazol-1-yl)benzaldehyde (710 mg) obtained is listed in the title compound as a white powdery solid (603,6 mg).

(D2O): 2,05-is 2.37 (m, 3H), 2,45 at 2.59 (m, 1H), 3,26-to 3.49 (m, 1H), 3,6-of 3.75 (m, 1H), of 3.77 (s, 3H), 3,98-4,07 (m, 1H), 4,17 and to 4.41 (2d, 2H, J=12,5 Hz for both), to 4.98 (d, 1H, J=2 Hz), 7,22 (q, 3H, J=8 Hz), 7,39 (dd, 2H, J= 7.5 and 5 Hz), 7,66 (d, 1H, J=2.5 Hz), a 7.85 (dd, 1H, J=8 and 2 Hz).

Microanalysis for C20H23FN6O2HClO3H2O.

Calculated: 52,14; H ceiling of 5.60; N 18,24; H2O 1,21%.

Found: 51,95; H 5,46; N 18,09; H2O 1.2 percent.

Example 30. The dihydrochloride of CIS-[2-(4-forfinal)piperidine-3-yl]-[2-metaliteracy-1-yl)benzaldehyde (113 mg) was obtained is listed in the title compound (34 mg).

(D2O): 2,03 to 2.35 (m, 3H), 2,42 is 2.55 (m, 1H), 2,58 (s, 3H), 3.25 to 3,39 (m, 1H), 3,60-to 3.73 (m, 1H), of 3.78 (s, 3H), 3,94-a 4.03 (m, 1H), 4,13 and 4,39 (2d, 2H, J= 13 Hz for both), to 4.98 (d, 1H, J=4 Hz), 7,18 (d, 1H, J=9 Hz), 7,27 (t, 2H, J=8.5 Hz), of 7.36-7,46 (m, 3H), of 7.65 (dd, 1H, J=8.5 and 2.5 Hz).

Microanalysis for C21H25FN6O2HClO7H2O.

Calculated: 52,33; H 5,94; N 17,44; H2O 2.6 per cent.

Found: 52,14; H 5,94; N 17,28; H2O 2.6 per cent.

Example 31. The dihydrochloride of CIS-[2-(3,4-differenl)piperidine-3-yl]-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl]amine.

From CIS-2-(3,4-differenl)-3-piperidylamine (1,49 g) and 2-methoxy-5-(5-methyltetrazol-1-yl)benzaldehyde (218 mg) obtained product reductive amination (187 mg), part of which (120 mg) is treated with concentrated hydrochloric acid (3 drops) to obtain the specified title compound (64 mg).

(D2O): 2,03-of 2.36 (m, 3H), 2,42-of 2.56 (m, 1H), 2,58 (s, 3H), 3,26 is 3.40 (m, 1H), 3,62-3,74 (m, 1H), 3,81 (s, 3H), 3,97-4,06 (m, 1H), 4,15 and 4,42 (2d, 2H, J= 13.5 Hz for both), to 4.98 (d, 1H, J=3.5 Hz), 7.18 in-7,52 (m, 5H), to 7.68 (dd, 1H, J=9.0 and 2.5 Hz).

Microanalysis for C21H24F2N6O2HCl.

Calculated: Won With 51.75; H 5,38; N To 17.25%.

Found: 51,74; H 5,17; N 17,31%.

Example 32. The dihydrochloride of CIS-[2-(3,4-differenl)piperidine-3-yl]-[2-methoxy-5-tetrazol-1-yl-benzyl]amine.

From CIS-2-(3,4-is VCE compound (529 mg).

(D2O): 2,05-of 2.38 (m, 3H), 2,42 at 2.59 (m, 1H), 3.25 to 3,39 (m, 1H), 3,62-3,95 (m, 1H), 3,81 (s, 3H), 3.95 to of 4.05 (m, 1H), 4,16 and to 4.41 (2d, 2H, J= 13 Hz for both) 4,958 (d, 1H, J=3 Hz), 7,13-7,30 (m, 3H), 7,41 (q, 1H, J=8 Hz), 7,69 (d, 1H, J=2 Hz), 7,86 (dd, 1H, J=8 and 2 Hz), 9,59 (s, 1H).

Microanalysis for C20H22F2N6O2HClO4H2O.

Calculated: 49,99; H 5,20; N 17,49; H2O 1,5%.

Found: C 49,89; H to 5.03; N 17,38; H2O1,5%.

Example 33. The dihydrochloride of CIS-[2-(3,4-differenl)piperidine-3-yl]-[2-methoxy-5-(5-cryptomaterial-1-yl)benzyl]amine.

From CIS-2-(3,4-differenl)piperidine-3S-yl-amine (93 mg) and 2-methoxy-5-(5-cryptomaterial-1-yl)benzaldehyde (120 mg) obtained is listed in the title compound as a white solid (46 mg). So pl. 266oC.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,42.

Example 34. The dihydrochloride of CIS-[2-methoxy-5-(5-methyltetrazol-1-yl)benzyl] -2- (4-tryptophanyl)piperidine-3-yl]amine.

To a stirred solution of CIS-5-[2-methoxy-5-(5-methyl-tetrazol-1-yl)benzylamino] -6-(4-triptoreline)piperidine-2-it (193,8 mg) in dry tetrahydrofuran (10 ml) was added borane (1 M in THF, 2,53 ml). The mixture was stirred at room temperature in a nitrogen atmosphere to 70 h, neutralized with saturated aqueous sodium carbonate, was extracted with et is terukuni acid (1 ml) in methanol (25 ml) and was heated on the steam bath for 30 minutes After evaporation of getting salt triperoxonane acid, which was divided in a mixture of aqueous sodium carbonate (2 M, 50 ml) and ethyl acetate (50 ml). The organic solution was isolated, washed again in water with sodium carbonate (2 M, 2 x 50 ml), dried (MgSO4) and concentrated in vacuo to obtain the crude product (199 mg), which was purified by FCC, elwira 5% methanol/dichloromethane with product recovery (115, 8mm mg). This product recovery (107,3 mg) was dissolved in a mixture of dioxane (0.7 ml) and ethyl acetate (0.3 ml) was added concentrated hydrochloric acid (0,26 ml). Formed white precipitate, which was isolated by filtration, washed with ether, dried (98,5 mg). This hydrochloride was dissolved in methanol (5 ml) and water (0.6 ml) was added acetone (20 ml). Gradually formed a solid, which was filtered, dried at 40-45oC in vacuum to obtain specified in the connection header in the form of a cream-white solid (43,9 mg).

(D2O): 2,08-to 2.42 (m, 3H), 2,46-of 2.56 (m, 1H), 2,68 (s, 3H), 3,28-of 3.43 (m, 1H), and 3.72 (s, 3H), 3,70-3,82 (m, 1H), 4,05-4,16 (m, 2H), of 4.44 (d, 1H, J= 13.5 Hz), 5,07 (d, 1H, J=3 Hz), to 7.09 (d, 1H, J=9 Hz), 7,41 (d, 1H, J=2 Hz), 7,49 (d, 2H, J=8 Hz), to 7.64 (dd, 1H, J=9 and 2 Hz), 7,81 (d, 2H, J=8).

Mass-spectrometry. For C22H25F3N6

From CIS-5-(2-methoxy-5-tetrazol-1-yl)benzylamino-6-(4-triptoreline)piperidine-2-it (273,1 mg) and borane (1 M in THF, and 3.7 ml) were obtained is indicated in the title compound (98,8 mg).

(D2O): 2,05-2,60 (m, 4H), 3.27 to 3,44 (m, 1H), 3,67-a 3.83 (m, 1H), 3,71 (s, 3H), 4,08-is 4.21 (m, 2H), of 4.44 (d, 1H, J=13 Hz), of 5.05 (d, 1H, J=3 Hz), to 7.09 (d, 1H, J=8.5 Hz), 7,45 (q, 2H, J=8 Hz), 7,66 (d, 1H, J=2 Hz), 7,78 (d, 2H, J=8 Hz), 7,83 (dd, 1H, J=8.5 and 2 Hz), 9,59 (s, 1H).

Mass-spectrometry.

For C21H23F3N6O m/z 433 (MH+).

Example 36. Trihydrochloride [5-(5-aminotetrazole-1-yl)-2-methoxybenzyl]- (2S-phenylpiperidine-3S-yl)amine.

To the free base dihydrochloride [4-methoxy-3-(2S-phenylpiperidine-3S-yl-aminomethyl)phenyl] cyanamide (0.08 g) in dimethylformamide (1 ml) was added sodium azide (0,13 g) and ammonium chloride (0.16 g), and then the mixture was heated to 100oC 18 h under nitrogen atmosphere. The mixture was allowed to cool and was added brine (10 ml). The solution was extracted with dichloromethane (3 x 10 ml), combined organic layers, dried (Na2SO4) and evaporated in vacuo. The residue was purified column chromatography, elwira a mixture of dichloromethane/ethanol/ammonia (200:8: 1). The isolated product was dissolved in dichloromethane (5 ml) and was treated with hydrogen chloride (1 ml of 1 M solution in ether) to obtain P>C.

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,1.

Example 37. The dihydrochloride (2 ethoxy-5-tetrazol-1-yl-benzyl)-([2S,3S]-2-phenylpiperidine-3-yl)amine.

To a solution of [2S]-phenylpiperidine-[3S]-ylamine (1.9 mmol) in dichloromethane (20 ml) was added acetic acid (2.7 mol). Then add triacetoxyborohydride sodium (2.7 mmol ), the mixture was stirred 2 h and the solvent was removed. The residue was separated between ethyl acetate (50 ml) and 2N sodium carbonate solution. The aqueous phase was again extracted with ethyl acetate (2 x 50 ml) and the combined organic phases were dried (Na2SO4) and was restored to the resin which was dissolved in hot ethanol (10 ml) and treated with concentrated hydrochloric acid. Collected crystals were dried to obtain specified in the title compound (0.68 g) as a white crystalline substance.

(D2O): to 1.32 (3H, t, J=9 Hz), of 2.15 (m, 2H), 2,35 (m, 1H), has 2.56 (1H, m), 3.33 and (m, 1H), 3,74 (m, 1H), 4.00 points (m, 2H), 4,20 (d, 1H, J=16 Hz), 4,47 (d, 1H, J=16 Hz), to 4.98 (d, 1H, J=4 Hz), 7,12 (d, 1H, J=9 Hz) 7,25 (m, 2H), 7,45 (3H, m), 7,63 (d, 1H, J=3 Hz), 7,82 (dd, 1H, J=3,9 Hz), 9,58 (s, 1H).

Microanalysis for C21H26N6O2HCl.

Calculated: 55,88; H 6,25; N 18,26; Cl 15.7 Per Cent.

Found: 55,51; H 6,14; N 18,41; Cl 15.7 Per Cent.

Example 38. The dihydrochloride [2-isopropoxy-5 - mmol) obtained specified in the header of the connection (of 0.44 g) as a white crystalline solid.

(D2O): of 1.30(6H, m) and 2.14 (m, 2H), by 2.55 (m, 1H), 3.33 and (m, 1H), and 3.72 (m, 1H), was 4.02 (m, 1H), 4,18 (d, 1H, J=16 Hz), and 4.40 (d, 1H, J=16 Hz), 4,63 (1H, m), is 4.93 (d, 1H, J=3 Hz), 7,19 (m, 3H), 7,39 (m, 3H), 7,60 (d, 1H, J=3 Hz), 7,82 (dd, 1H, J=3,9 Hz), 9,58 (s, 1H).

Microanalysis for C22H28N6O2HClO8H2O.

Calculated: C 55,07; H 6,64; N 17,51; Cl4,8%.

Found: C 55,13; H 6,64; N 17,47; Cl 14.8 Per Cent.

Example 39. The dihydrochloride [2-methoxy-5-tetrazol-2-yl-benzyl]-(2S-phenylpiperidine-3S-yl)amine.

From [2S] -phenylpiperidine-[3S]-yl-amine (173 mg) and 2-methoxy-5-tetrazol-2-yl-benzaldehyde (200 mg) obtained is listed in the title compound as a white solid (285 mg). So pl. 222oC.

TCX (dichloromethane/methanol/ammonia, 945:50:5): Rf=0,3.

Example 40. The dihydrochloride [2-methoxy-5-tetrazol-1-yl-methylbenzyl]-(2S-phenylpiperidine-3S-yl)amine.

From 2S-phenylpiperidine-3S-yl-amine (134 mg) and 2-methoxy-5-tetrazol-1-yl-methylbenzaldehyde (165 mg) obtained specified in the header of soedineniya in the form of a white solid (235 mg).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0,29.

[]D= +53,13o(C=0.002 g/ml, N2O).

Example 41.

The dihydrochloride [2-methoxy-5-tetrazol-2-yl-methylbenzyl] -(2S-phenylpiperidine-3S-yl)amine.

From 2S-phenylpiperidine-3S-yl-minilogo solid (122 mg).

TCX (dichloromethane/ethanol/ammonia 100:8:1): Rf=0.36 and.

(KBr): 3412, 2927, 1561, 1510, 1455, 1259, 1029 cm-1.

Example 42. The dihydrochloride [2-methoxy-5-(1-methyl-1H-tetrazol-5-yl)benzyl] -(CIS-2-phenylpiperidine-3-yl)amine.

2-phenylpiperidine-Z-yl-amine (81 mg) and 2-methoxy-5-(1-methyl-1H-tetrazol-5-yl)benzaldehyde (100 mg) obtained is listed in the title compound (50 mg).

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,06.

(, (CDCl3): 1,45 (1H, dq), to 1.59 (1H, tt), was 1.69 (2H, brs), of 1.87 (1H, tt), and 2.14 (1H, brd), 2,73-2,87 (2H, td and q) 4,0 (3H, s), at 6.84 (1H, d), 7,12-7,31 (6H, m), 7,56 (1H, dd).

Example 43. The dihydrochloride [2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzyl] -(CIS-2-phenylpiperidine-3-yl)amine.

2-phenylpiperidine-3-yl-amine (240 mg) and 2-methoxy-5-(2-methyl-2H-tetrazol-5-yl)benzaldehyde (300 mg) obtained is listed in the title compound (370 mg).

TCX (dichloromethane/ethanol/ammonia, 200:8:1): Rf=0,10.

(, (CDCl3):of 1.41 (1H, dq), to 1.61 (1H, tt), was 1.69 (2H, brs), at 1.91 (1H, tt), of 2.16 (1H, brd), 2,8 (1H, td), 2,84 (1H, q), or 3.28 (1H, ddd), 3,44, of 3.75 (2H, AB), 3,47 (3H, s), 3,88 (1H, d), 4,39 (3H, s), of 6.75 (1H, d), 7,16-7,33 (5H, m), 7,81 (1H, d), 7,94 (1H, dd ).

Example 44. The dihydrochloride [5-(1-ethyl-1H-tetrazol-5-yl)-2-methoxybenzyl] -(2S-phenylpiperidine-3S-yl)amine.

From 2S-phenylpiperidine-3S-yl-amine (326 mg) and 5-(1-ethyl-1H-tetrazol-5-yl)-2-methoxybenzaldehyde (430 m is n/ethanol/ammonia, 100:8:1): Rf=0,43.

Example 45. The dihydrochloride [5-(1-cyclopropylmethyl-1H-tetrazol-5-yl)-2-methoxybenzyl]-(2S-phenylpiperidine-3S-yl)amine.

From 2S-phenylpiperidine-3S-yl-amine (204 mg) and 5-(1-cyclopropylmethyl-1H - tetrazol-5-yl)-2-methoxybenzaldehyde (300 mg) obtained is listed in the title compound (320 mg) as a yellow solid substance.

TCX (dichloromethane/ethanol/ammonia, 94:5:1): Rf=0.34 in.

Pharmaceutical examples.

Example A.

Sterile drug mg/ml:

The compound of example 2 (dihydrochloride) - 0.3 mg

Sodium chloride USP - 6.0 mg

Sodium acetate USP - 2.6 mg

Acetic acid, 1.1 mg

Water for injection USP to 1 ml

The components are dissolved in parts of water for injection and bring the solution to final volume, providing the content of the compound from example 2 in the form of free base in the amount of 0.25 mg/ml

The solution can be packaged for injection in ampoules, vials or syringes. Ampoules, vials or syringes can be filled aseptically and/or sterilized, for example by autoclaving at 121oC.

Similarly can be prepared with other sterile preparations containing b mg of the compound of example 2 (dihydrochloride) and esprimere.

Tablets can be prepared by conventional means, for example by direct compaction or wet granulation.

Tablets can be coated from a suitable shell material, such as Opadry White type YS-1-7027, using traditional technologies. Alternatively, the tablets may be coated with sugar.

Example B.

Tablets obtained by direct pressing, mg/tablet:

The compound of example 2 (dihydrochloride) - 0.6 mg

Magnesium stearate - 0.75 mg

Avicel PH102 - to 150.00 mg

The compound of example 2 (dihydrochloride) is passed through a 30-cell sieve and mixed with Avicel PH102 and magnesium stearate. The resulting mixture is pressed into tablets using a suitable machine for forming tablets with 9/32" diameter punch, thus providing 0.5 mg/tablet compound of example 2 in the form of free base.

Tablets of varying strength, containing 2,4, 6.0 or 12.0 mg/tablet compound of example 2 in the form of a dihydrochloride can be prepared in a similar manner, ensuring the content of the compound from example 2 in free base form of 2, 5 and 10 mg/tablet.

Example Century.

Wet granulation.

Can be espinouse solution (purified water or 10% PVP K29/32 in water ). After drying, the granules were sieved through, for example, 20-cell sieve and mixed with magnesium stearate. Pellets pressed into tablets as described in example B.

Tablet other forces, such as described in example B, can be obtained similarly.

Example,

Suppository.

The compound of example 2 (dihydrochloride) - 10.0 mg

Witepsol W32, tallow - up 2000,0 mg

In high-speed blender mix the crushed medicine in part molten Witepsol W32 at about 36oC for about 15 minutes Make gomogenizirovannogo suspension for the remainder of the molten Witepsol W32 and stirred at about 36oC to achieve an acceptable state of dispersion. Fill form 2000 mg drug, providing the content of the compound of example 2 (dihydrochloride) in an amount of 10 mg/suppository.

Example D.

Capsule mg/capsule:

The compound of example 2 (dihydrochloride) to 12.0 mg

The glycol - 92,89 mg

Propylene glycol and 200 mg

Mix together the polyethylene glycol and propylene glycol, using the necessary heat. Prevent to a homogeneous state. Add chopped compound of example 2 (dihydrochloride) to the mixture. Preceramic 200 mg drug, providing the content of the compound from example 2 in the form of a base in an amount of 10 mg/capsule. Capsules greater force, for example of 0.5, 2.0 and 5.0 mg/capsule compound of example 2 free base form, can be prepared similarly.

Example E.

Syrup for oral administration, mg/ml:

The compound of example 2 (dihydrochloride) - 6.0 mg

Sucrose 200 mg

Methylparaben - 1.2 mg

Propylparaben - 0.15 mg

Flavor - 1.5 mg

Citric acid 0.1 mg

Purified water to 1 ml

Dissolve the parabens in portions of water, heated to approximately 90oC. Add a solution of parabens to the remaining portion of water with stirring. Add and dissolve the other components. Bring the drug to the target volume and to prevent homogeneity. Fill with a drug container such as a disposable Cup or bottle for a large number of doses, providing the content of the compound from example 2 in the form of the free base in an amount of 5 mg/ml

Example g

Transdermal system.

The compound of example 2 (dihydrochloride) - 5% of compounds of formula (I)

Silicone fluid - 90%

Colloidal silica - 5%

Kremniyorganika the Material distributed doses on layered polymer, containing polyester releasing layer adjacent to the skin sticky layer of silicone or acrylic polymer, a control membrane made of polyolefin (e.g. polyethylene or polyvinyl acetate or polyurethane and impervious surface membrane of laminated polyester material. This layered polymer is then heat sealed.

Example 3.

Lyophilized product.

The compound of example 2 (dihydrochloride) - 6.0 mg

Mannitol - 50.0 mg

Acetate buffer - 8.2 mg

Water for injections to 1 ml

The components are dissolved in a portion of water for injection. The drug is brought to final volume and mix to homogeneity. Filter the product through the sterile filter and fill them sterile glass vials. Lyophilizer and sealed vials. Before using, bring to readiness addition of solvent.

Example I.

Hard gelatin capsules.

The compound of example 2 (dihydrochloride) - 12,00 mg

Lactose - 80,00 mg

Magnesium stearate - 0.75 mg

Avicel pH 102 - to 150.00 mg

The compound of example 2 (dihydrochloride) was passed through a 30-cell sieve and mixed with the lactose, Avicel pH 102 and magnesium stearate. The resulting content of the compound from example 2 in the form of a base in an amount of 10 mg/capsule.

Capsules other forces can be prepared similarly and provide the content of the compound from example 2 in the amount of 0.5, 2 and 5 mg/capsule.

Biological tests.

As mentioned above, in the above test, it was shown that the compounds according to the invention inhibit emesis induced by radiation in ferrets. More specifically, the compound of example 2, hydrochloride (2-methoxy-5-tetrazol-1-yl-benzyl)-([2S, 3S]-2-phenylpiperidine-Z-yl)amine, inhibits vomiting induced by radiation in ferrets, with the introduction of connections for 1.5 h before irradiation at a dose of 0.1 mg/ml subcutaneously. The compound from example 7, hydrochloride (2-methoxy-5-(5-cryptomaterial-1-yl)benzyl)-([2S,3S]-2-phenylpiperidine-Z-yl)amine, inhibits vomiting induced by radiation in ferrets, with the introduction of connections for 1.5 h before irradiation at a dose of 0.03 mg/ml subcutaneously.

In tests in vivo with the introduction of compounds according to the invention were not observed adverse or toxic effects.

Appendix 1 shows the graphical data that illustrate the application of the present invention in the treatment of pain. The accompanying graph demonstrates that the claimed connection GR205171 (examples 7 and 10), injected at a dose of 10 mg/kg three times a day, largely the Torno rats in the test Model of chronic inflammatory hyperalgesia".

1. Derivatives of 3-(5-tetracarbonyl)aminopiperidine formula I

< / BR>
where R1stands WITH1-4alkoxygroup;

R2represents a

< / BR>
R3denotes a hydrogen atom or halogen;

R4and R5independently from each other represent a hydrogen atom or halogen, or a group1-4alkyl, C1-4alkoxy or trifluoromethyl;

R6denotes a hydrogen atom, a group WITH1-4alkyl, (CH2)mcyclopropyl, -S(O)nWITH1-4alkyl, phenyl, NR7R8CH2C(O)CF3or trifluoromethyl;

R7and R8independently from each other represent a hydrogen atom or a group1-4alkyl or acyl;

x represents 0 or 1;

n represents 0, 1 or 2;

m represents 0 or 1,

or their pharmaceutically acceptable salt, or solvate.

2. Connection on p. 1, in which R1represents a C1-4alkoxygroup; R2does

< / BR>
where R6represents a hydrogen atom, a group WITH1-4alkyl, cyclopropyl or trifluoromethyl;

x is equal to zero;

R3, R4and R5each is a hydrogen atom.

3. Connection under item 1 or 2, oznachaet

< / BR>
5. The compound according to any one of paragraphs.1 to 4, in which R3represents hydrogen.

6. The compound according to any one of paragraphs.1 to 5, in which R4and R5each represents a hydrogen atom.

7. The compound according to any one of paragraphs.1 to 6, in which R6represents hydrogen, a group WITH1-4alkyl or trifluoromethyl.

8. The compound according to any one of paragraphs.1 to 7, in which x is zero.

9. Connection on p. 3, representing (2-methoxy-5-tetrazol-1-yl-benzyl)-(2S-phenylpiperidine-3S-yl)amine or its pharmaceutically acceptable salt, or MES.

10. Connection on p. 3 representing [2-methoxy-5-(5-cryptomaterial-1-yl)benzyl] -(2S-phenylpiperidine-3S-yl)amine or its pharmaceutically acceptable salt, or MES.

11. Connection on p. 9 or 10 in the form of its dihydrochloride salt.

12. The compound according to any one of paragraphs.1 - 11 for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinin.

13. The compound according to any one of paragraphs.1 - 11 with antiemetic activity.

14. Pharmaceutical composition for use in the treatment of conditions mediated by tachykinins, including substance P and other n is the number of the active ingredient it contains from 0.1 to 99% of the compound according to any one of paragraphs.1 - 11 or its pharmaceutically acceptable salt, or MES.

15. The pharmaceutical composition according to p. 14, characterized in that it further comprises NT3antagonist.

16. The pharmaceutical composition according to p. 15, wherein R1represents a C1-4alkoxy group; R2does

< / BR>
where R6represents a hydrogen atom, a group WITH1-4alkyl, cyclopropyl or trifluoromethyl;

x is equal to zero;

R3, R4and R5each is a hydrogen atom.

17. The pharmaceutical composition according to p. 15, characterized in that T3antagonist selected from ondansetron, granisetron or metoclopramide.

18. The pharmaceutical composition according to p. 16, characterized in that T3antagonist selected from ondansetron, granisetron or metoclopramide.

19. The method of obtaining the compounds of formula I

< / BR>
where R1stands WITH1-4alkoxygroup;

R2represents a

< / BR>
R3denotes a hydrogen atom or halogen;

R4and R5independently from each other represent a hydrogen atom or halogen or the group WITH1-4alkyl, C1-4alkoxy or trifluoromethyl;
-4
alkyl, phenyl, NR7R8CH2C(O)CF3or trifluoromethyl;

R7and R8independently from each other represent a hydrogen atom or a group1-4alkyl or acyl;

x represents 0 or 1;

n represents 0, 1 or 2;

m represents 0 or 1,

or its pharmaceutically acceptable salt, or MES, in which the compound of formula II

< / BR>
subjected to interaction with the compound of the formula III

< / BR>
with subsequent recovery.

20. The method according to p. 19, wherein R1represents a C1-4alkoxygroup; R2does

< / BR>
where R6represents a hydrogen atom, a group WITH1-4alkyl, cyclopropyl or trifluoromethyl;

x is equal to zero;

R3, R4and R5each is a hydrogen atom.

21. The method of obtaining the compounds of formula I

< / BR>
where R1stands WITH1-4alkoxygroup;

R2represents a

< / BR>
R3denotes a hydrogen atom or halogen;

R4and R5independently from each other represent a hydrogen atom or halogen or the group WITH1-4alkyl, C1-4alkoxy or trifluoromethyl;

R6the group WITH1-4alkyl, or acyl;

x represents 0;

n represents 0, 1 or 2;

m represents 0 or 1,

or its pharmaceutically acceptable salt, or MES, in which the compound of formula XXIII

< / BR>
subjected to interaction with ammonium chloride or sodium azide.

22. The method of obtaining the compounds of formula I

< / BR>
where R1stands WITH1-4alkoxygroup;

R2represents a

< / BR>
R3denotes a hydrogen atom or halogen;

R4and R5independently from each other represent a hydrogen atom or halogen or the group WITH1-4alkyl, C1-4alkoxy or trifluoromethyl;

R6denotes a hydrogen atom, a group WITH1-4alkyl, (CH2)mcyclopropyl, -S(O)nWITH1-4alkyl, phenyl, NR7R8CH2C(O)CF3or trifluoromethyl;

R7and R8independently from each other represent a hydrogen atom or a group1-4alkyl, or acyl;

x represents 0 or 1;

n represents 0, 1 or 2;

m represents 0 or 1,

or its pharmaceutically acceptable salt, or MES, which restores the compound of formula XXIV.

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the

 

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The invention relates to the derivatives of cinoxacin used in therapy

The invention relates to new compounds of formula I, where b and E are independently selected from CH or N; R4is hydrogen, halogen, hydroxy; G represents the compounds of formula II (a, b, c) and their optical and geometric isomers; and nontoxic pharmaceutically acceptable acid salt additive

The invention relates to new compounds of formula I, where b and E are independently selected from CH or N; R4is hydrogen, halogen, hydroxy; G represents the compounds of formula II (a, b, c) and their optical and geometric isomers; and nontoxic pharmaceutically acceptable acid salt additive

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The invention relates to the derivatives of triazole, exhibiting antifungal activity

The invention relates to compounds of the formula

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and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid
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