N-(2-hydroxyethyl)-n-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl) piperidin-4-ylidene)methyl)benzamide, method for preparing and applying it for treating pain, anxiety and depression

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

 

The present invention relates to new compounds, process for the preparation of these compounds and related intermediate compounds, the use of the compounds and pharmaceutical compositions containing them. These compounds are useful in therapy, in particular for the treatment of pain, anxiety and depression.

Delta (δ) receptor was identified as a receptor that plays a role in many body functions, such as nociceptive, motor and cardiovascular system, as well as in the regulation of emotions. Therefore, the ligands of the δ receptor can find potential use as analgesics, anxiolytics and/or hypotensive agents. It was also shown that the ligands of the δ receptor possess immunomodulatory activities.

Currently, it identified at least three different populations of opioid receptors (µ, δ and κ), and all three are revealed in both the Central and peripheral nervous systems of many species, including humans. When you activate one or more than one of these receptors in various animal models have been observed analgesia and sedation. In General, selective ligands of the δ receptor have advantages over non-selective ligands of opioid receptors, causing less significant side effects.

Many compounds, representing the δ-agonist is, identified in the prior art have many disadvantages, which lies in the fact that the compounds have poor pharmacokinetics and do not have any anxiolytic or analytical steps in the introduction of the system paths.

In PCT publication WO 01/74806 describes some δ agonists.

However, there is still a need for improved δ-agonists.

The inventors have unexpectedly discovered that certain compounds exhibit one or more than one improved property, i.e. improved efficiency as δ-agonists, the efficiency of in vivo pharmacokinetics, bioavailability, stability, in vitro stability, in vivo, the penetration into the brain and/or lower toxicity.

In the present application is described N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide.

Further, in the present application is described N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, its pharmaceutically acceptable salts, its prodrugs, its solvate, and/or mixtures thereof.

In addition, in the present application is described tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate.

In addition, in the present application is described N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)Besame is.

In addition, this application also describes methods of obtaining N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate and N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide.

In addition, this application also describes a pharmaceutical composition comprising N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, its pharmaceutically acceptable salts, its prodrugs, its solvate, and/or mixtures thereof together with a pharmaceutically acceptable carrier.

In addition, this application also describes a method of treating pain, depression, anxiety, depression and/or Parkinson's disease in a warm-blooded animal, including the introduction of a specified animal in need of such treatment, a therapeutically effective amount of N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, and its pharmaceutically acceptable salts, prodrugs, solvate, and/or mixtures thereof.

The characteristics and advantages of the present invention can be more easily understood by the average of the experts in the art after reading the following detailed description. It should be understood that some of the s features of the invention, which for reasons of clarity, described above and below in the context of separate embodiments, can also be combined to form one embodiment. Conversely, various features of the invention, which for reasons of brevity, described in the context of a single embodiment, may also be combined with the education of their subcombination.

If not specifically mentioned in this description of the invention, reference is made in the singular may also include the plural. For example, terms that indicate an indefinite number, can refer either to one or to one or more than one.

Imply that the embodiment defined in this description of the invention as typical, are illustrative and not restrictive.

Unless otherwise noted, assume that any heteroatom with unsaturated valences has a sufficient number of hydrogen atoms to fill valences.

The definitions stated in this description of the invention, takes precedence over the definitions set forth in any patent, patent application and/or publication of a patent application that may be included in this description by reference.

"A warm-blooded animal" includes humans.

The term "protected" means that the compound, which is sent as secure protected aminosidine group. For example, protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide represents N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide, which has at least one amino group, protected aminosidine group.

The term "aminosidine group" refers to a generally recognized in the art groups that can join the amino group to prevent the involvement of the amino group in the reactions with any other portion of the molecule containing the amino group.

Suitable aminosidine groups include, for example, aminosidine groups described in "Protective Groups in Organic Synthesis" (2nd edition, John Wiley & Sons, 1991), but are not limited to. Aminosidine group may, for example, represent a protective group of the urethane type (also called urethane protective group), including, without limitation, arylalkylamine group, such as, for example, benzyloxycarbonyl, and alkoxycarbonyl groups, such as, for example, methoxycarbonyl and tert-butoxycarbonyl. Typically aminosidine group is a tert-butoxycarbonyl.

In one aspect of the present invention proposed N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, his farmaci is almost acceptable salt, its prodrug, its solvate and mixtures thereof.

In one of the embodiments of the compound of the present invention may be selected from N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, its pharmaceutically acceptable salt, solvate and mixtures thereof.

In another embodiment of the connection according to the present invention can be selected from N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, and its pharmaceutically acceptable salts and mixtures thereof.

In an additional embodiment, the compound of the present invention may be selected from N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide.

Also it will be clear that some compounds of the present invention may exist in solvated, for example hydrated, and resolutiony forms. In addition, it will be clear that the present invention encompasses all such solvated forms of the compounds.

In the scope of the invention also includes salts of this compound. In General, pharmaceutically acceptable salts of the compounds of the present invention can be obtained using standard techniques, well known in the art, for example by reacting a sufficiently basic compound, neprimirimaya, with a suitable acid, such as HCl or acetic acid, is able to provide a physiologically acceptable anion. You can also obtain the corresponding alkali metal salt (such as sodium, potassium or lithium) or alkaline earth metal (such as calcium) by treating the compounds of the present invention, with a suitable acidic proton, such as a carboxylic acid or a phenol with one equivalent of hydroxide or alkoxide (such as ethoxide or methoxide) alkali metal or alkaline-earth metal, or a suitable organic amine (such as choline or meglumine) in the aqueous medium, followed by purification by conventional methods.

In one of the embodiments described above, the connection can be converted into a pharmaceutically acceptable salt or MES, in particular salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluensulfonate.

Compounds of the present invention are useful in therapy, especially for the treatment of various pain States, such as, for example, chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain, and so forth. However, this list should not be understood as exhaustive.

Connect the means of the present invention are useful in the treatment of anxiety, such as, for example, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder in disorder, specific phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, disorders associated with stress, posttraumatic stress disorder, acute stress disorder, disorder generalized anxiety or disorder generalized anxiety due to a General medical condition.

At least one embodiment of the present invention is useful to treat depression, such as anxiety depression, major depressive disorder, delimitable disorder, bipolar depression and/or bipolar mania, bipolar disorder type I with manic, depressive or mixed episodes, bipolar II disorder, cyclothymic disorder, mood disorder due to General medical condition, manic episodes associated with bipolar disorder, and mixed episodes associated with bipolar disorder.

Compounds according to the invention are useful for the treatment of diarrhea, depression, anxiety and/or disorders associated with stress, such as post-traumatic stress R is stroisch, panic disorder, disorder generalized anxiety, social phobia and obsessive-compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as irritable bowel syndrome and functional dyspepsia, Parkinson's disease and other motor disorders, traumatic brain damage, shock, protection of the heart after myocardial infarction, for the treatment of spinal cord injury and addiction to the excessive use of drugs, including treatment of alcohol, nicotine, opioid and other drug dependence as well as for disorders of the sympathetic nervous system, such as hypertension.

Compounds according to the invention are useful as immunomodulators, particularly in autoimmune diseases, such as arthritis, transplant skin, organ transplants and similar surgical needs, when collagenoses, various allergies, for use as antitumor agents, and antiviral agents.

Compounds according to the invention are useful in disease States in which there is a place or involving degeneration or dysfunction of the OPI is innych receptors. This may include the use of labeled isotopes are variants of the compounds according to the invention in diagnostic techniques and in the implementation of imaging, such as positron emission tomography (PET).

Compounds according to the invention is useful as an analgesic agent for use during General anesthesia and anesthesia monitoring. Combinations of agents with different properties are often used to balance the effects required to maintain the state of anesthesia (e.g., amnesia, analgesia, muscle relaxation and sedation). In such a combination include inhalation anesthetics, sleeping pills, anxiolytics, myelomalacia and opioids.

In the scope of the invention includes the use of any of the compounds defined above to manufacture a medicinal product.

Also in the scope of the invention includes the use of any of the compounds according to the invention for the manufacture of a medicine for treatment of pain, including, without limitation, acute pain, chronic pain, neuropathic pain, back pain, cancer pain, and visceral pain.

Also in the scope of the invention includes the use of any of the compounds according to the invention for the manufacture of a medicinal product for the treatment of anxiety, including, without limitation, panic disorder, p. the clinical disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder in disorder, specific phobia, social phobia, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, disorder generalized anxiety or disorder generalized anxiety due to a General medical condition.

Also in the scope of the invention includes the use of any of the compounds according to the invention for the manufacture of drugs to treat depression, such as major depressive disorder, delimitable disorder, bipolar depression and/or bipolar mania, bipolar disorder type I with manic, depressive or mixed episodes, bipolar II disorder, cyclothymic disorder, mood disorder due to General medical condition, manic episodes associated with bipolar disorder, and mixed episodes associated with bipolar disorder.

Also in the scope of the invention includes the use of any of the compounds according to the invention for the manufacture of a medicinal product for the treatment of depression.

Also in the scope of the invention includes the use of any of the compounds according to the invention for manufacturing is the service of the medicinal product for the treatment of Parkinson's disease.

Also in the scope of the invention includes the use of any of the compounds of the present invention for the manufacture of a medicinal product for the treatment of any of the conditions discussed above.

An additional aspect of the invention is a method of treatment of a subject suffering from any of the conditions discussed above, whereby a patient in need of such treatment is administered an effective amount of the compounds of the present invention.

Thus, according to the invention proposed compound or its pharmaceutically acceptable salt or MES, such as defined above, for use in therapy.

In the context of the present description, the term "treatment" also includes "prevention"if no specific instructions to the contrary. The term "therapeutic" and "therapeutically" should be interpreted accordingly. The term "treatment" in the context of the present invention also covers the introduction of an effective amount of the compounds of the present invention to facilitate or pre-existing painful conditions, acute or chronic, or recurrent condition. This definition also includes prophylactic treatment for prevention of recurrent States and continuous treatment for chronic disorders.

In yet another embodiment of the connection nastasemarian or pharmaceutical composition or drug, containing at least one compound of the present invention, can be administered simultaneously, together, sequentially or separately with at least one other pharmaceutically active compound selected from the following:

(1) antidepressants, including, for example, agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, DULOXETINE, osasona, ESCITALOPRAM, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, sertraline, sibutramine, minisoccer, tranylcypromine, trazodone, trimipramine, venlafaxine, and equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(2) atypical antipsychotic drugs, including quetiapine and pharmaceutically active(e) isomer(s) and metabolite(s), but not limited to;

3) antipsychotic drugs, including, for example, amisulpride, aripiprazole, asenapine, benzisoxazol, bifeprunox, carbamazepine, clozapine, chlorpromazine, dibenzepin, divalproex, DULOXETINE, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapi, perphenazine, phenothiazines, privatelyoperated, pimozide, prochlorperazine, risperidone, certification is$, sulpiride, supraglan, thioridazine, trifluoperazine, trimeton, valproate, valproate acid, zopiclone, zotepine, ziprasidone and cash equivalents and pharmaceutically active(e) isomer(s) and metabolite(s), but not limited to;

(4) anxiolytics, including, for example, alnespirone, azaperone, benzodiazepines, barbiturates, such as adinazolam, alprazolam, balasan, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, lprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, postepu, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, kwazepam, reclusiam, tracazolate, crepidam, temazepam, triazolam, medazepam, zolazepam and cash equivalents and pharmaceutically active(e) isomer(s), and metabolite(s), but not limited to;

(5) anticonvulsants, such as carbamazepine, valproate, lamotrigine, gabapentin and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(6) medicines for the treatment of Alzheimer's disease, including, for example, donezepil, memantine, taken and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(7) medicines for the treatment of Parkinson's disease, including, for example, deprenyl, L-DOPA, Requip, irapex, inhibitors IAIA (monoamine oxidase B) (i.e. Telegin, rasagiline)inhibitors researcher (catechol-O-methyltransferase) (i.e. Tasmar)inhibitors A-2, inhibitors of reuptake of dopamine antagonists NMDA (N-methyl-D-aspartate), agonists nicotine, dopamine agonists and inhibitors of neuronal synthase nitric oxide and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(8) medicines for the treatment of migraine, including, for example, almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolid, pramipexol, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zolmitriptan and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(9) medicines for the treatment of stroke, including, for example, abciximab, activase, NXY-059, citicoline, kabinetten, desmoteplase, repinotan, traxoprodil and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(10) medicines for the treatment of urinary incontinence, including, for example, darifenacin, fluoxac, oxybutinin, propiverine, robalzotan, solifenacin, tolterodine and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(11) Lekarstvo the x means for the treatment of neuropathic pain, including, for example, gabapentin, LIDODERM, pregablin and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(12) medicines for the treatment of nociceptive pain, including, for example, celecoxib, etoricoxib, lumiracoxib, rofecoksib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to;

(13) medicines for the treatment of insomnia, including, for example, agomelatine, allobarbital, econimic, amobarbital, benzoctamine, butabarbital, capured, chloral, claparede, clarett, exclama, eszopiclone, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midfloor, Nizamabad, pentobarbital, phenobarbital, propofol, ramelteon, related, triclofos, secobarbital, zaleplon, zolpidem and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to them, and

(14) mood stabilizers, such as carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproate acid, verapamil and cash equivalents and pharmaceutically active(e) isomer(s)and metabolite(s), but not limited to.

In such combined products use with the organisations according to the present invention in the range of doses, open this description of the invention, and another pharmaceutically active compound or compounds in the agreed range of doses and/or in the doses described in relevantly publication.

When applying for treating a warm-blooded animal, such as man, the connection according to the invention can be introduced in the form of a conventional pharmaceutical composition by any route including oral, intramuscular, subcutaneous, local, intranasal, intraperitoneal, intracoronary, intravenous, epidural, intrathecal, intracerebroventricularly or by injection into the joints.

In one of the embodiments of the invention, the route of administration can be oral, intravenous or intramuscular.

"Therapeutically effective amount" and/or range of doses for the compounds of the present invention can be determined by the average expert in the art according to known criteria, including the age, weight and response of the individual patient, and interpreted in the context of a disease that should be treated and/or prevented. The number of typical (single or divided doses for a mammal can be from about 0.05 to about 300 mg/kg per day.

However, the specific dose level and frequency of dosing for each specific subject can vary, and they usually depend on the centre of the factors including, for example, the bioavailability of the compounds of the present invention in the input form; metabolic stability and length of action of specific compounds of the present invention; species, age, body weight, General health, sex and diet of the subject; mode and time of administration; rate of excretion, drug combination and the severity of the particular condition and any other factors normally considered by the attending physician when determining an individual mode and dose level that is most appropriate for a particular patient, but not limited to.

Also proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

In particular, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier for treatment, more specifically for the treatment of pain and anxiety.

In addition, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier for use in either the C States, above.

In addition, the proposed pharmaceutical composition comprising a compound of the present invention, its solvate or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier for the treatment of depression.

Inert pharmaceutically acceptable carriers for preparation of pharmaceutical compositions of the compounds of the present invention can be either solid or liquid. Drugs in solid form include powders, tablets, dispersible granules, capsules, pills and suppositories.

A solid carrier can be one or more than one substance, which can also act as diluents, corrigentov, solubilization, lubricants, suspendida agents, bonding agents or baking powder tablets; the carrier can also be an encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground connection according to the invention or an active component. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and compacted into a desired shape to the desired size.

To prepare suppozitornyj compositions of the low-melting wax such as a mixture of glycerides of fat what s acid and cocoa butter first melted and dispersed active ingredient, for example, by stirring. The molten homogeneous mixture is then poured into molds of suitable size and leave to stand until cool and hardened.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, carboxymethylcellulose sodium, low melting wax, cocoa butter and the like.

The term composition is also designed to enable the preparation of the active ingredient with encapsulating material as carrier providing a capsule in which the active component (with other carriers or without them) is surrounded by carrier, which thus is in Association with him. Similarly covered by the wafer.

Tablets, powders, pills and capsules can be used in solid dosage forms for oral administration.

Compositions in liquid form include solutions, suspensions and emulsions. For example, sterile water or water-propylene glycol solutions of the active compounds can be a liquid preparations suitable for parenteral administration. Liquid compositions can also be prepared in the form of a solution in water polietilenglikolja solution.

Aqueous solutions for oral maintenance could the t be prepared by dissolving the active component in water and adding, if required, suitable dye, corrigentov, stabilizers and thickeners. Aqueous suspensions for oral administration can be produced by dispersing finely ground active component in water with viscous material, such as natural synthetic gums, resins, methylcellulose, carboxymethylcellulose sodium and others suspendresume agents known in the field of preparation of pharmaceutical products.

Depending on the route of administration of the pharmaceutical composition will preferably contain from 0.05 to 99 wt.%, (percent by weight), more preferably from 0.10 to 50 wt.%, compounds according to the invention, all percentages by weight calculated with respect to the total weight of the composition.

In an additional aspect of the present invention, a method for producing compounds of the present invention.

In one of the embodiments of the invention, a method for obtaining N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, including the interaction of N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)benzamide with 4-thiazolecarboxamide in the presence of a reducing agent, such as triacetoxyborohydride sodium or borohydride sodium.

In another embodiment of the invention, a method for obtaining N-(2-hydroxy-ethyl) - N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)benzamide, including the interaction of the protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine 8-henrikromby acid with the formation of protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide and removing the protection from the specified protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide.

In a particular embodiment of the specified protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine-protected group, tert-Boc on position 1 of piperidine.

In a particular embodiment of the specified protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide protected group, tert-Boc on position 1 of piperidine.

In an additional embodiment of the invention, a method for obtaining a protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine, including the interaction of 2-(methylamino)ethanol-protected 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine.

In a particular embodiment of the specified protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine-protected group, tert-Boc on position 1 of piperidine.

In a particular embodiment of the specified protected 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-protected group, tert-Boc on position 1 of piperidine.

Another embodiment relates to STRs is also receiving protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide, including the interaction of the protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine 8-henrikromby acid.

Still one another embodiment relates to a method to unprotect protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide with the formation of N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide.

One additional embodiment relates to the interaction of N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide with a thiazole-4-carbaldehyde with the formation of N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide.

In one of the embodiments of the specified protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide protected group, tert-Boc on position 1 of piperidine.

In another embodiment of the specified protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine-protected group, tert-Boc on position 1 of piperidine.

One additional embodiment relates to a method for producing N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, including the interaction of 2-(methylamino)ethanol 4-((1-(tert-butoxycarbonyl)piperidine-4-ilidene)methyl bromide)benzoic acid with the formation of tert-butyl 4-((4-(N-(2-what hydroxyethyl)-N-methylcarbamoyl)phenyl)bromethalin)piperidine-1-carboxylate; the interaction of tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromethalin)piperidine-1-carboxylate 8-henrikromby acid with the formation of tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate; removing protection with tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate with the formation of N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide, and the interaction of N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide with thiazole-4-carbaldehyde with the formation of N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide.

Another embodiment relates to tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate.

Still one another embodiment pertains to N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide.

In General, the connection according to the invention can be obtained in accordance with the following schemes and General information known to the person skilled in the technical field and/or in accordance with the methods set forth in the following examples. Solvents, temperatures, pressures and other reaction conditions can be easily selected average expert in the field t is the transport. Starting materials are commercially available or can be easily prepared by a person skilled in the art. Upon receipt of the compounds can be used combinatorial methods, for example, in cases where the intermediate compounds possess useful for these methods groups.

where P represents aminosidine group.

Stage 1

The compounds of formula III can be obtained by reacting the compounds of formula II, which can be prepared by the method described in WO 2001/074806 for compounds 5, 2-(methylamino)ethanol in the presence of a catalyst, such as, for example, N-methylmorpholine and dimethylaminopyridine; solvent, such as DMF (dimethylformamide) and acetonitrile; and a suitable binding agent, such as, for example, tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea, hydrochloride N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide and carbonyldiimidazole.

Stage 2

The compounds of formula IV can be obtained by combining the compounds of formula III with 8-hinolinovogo acid in the presence of a catalyst, such as, for example, dihydro-dichloro-bis(di-tert-butyl-phosphinico-kP)palladate(2-), palladium acetate (II), PdCl2dppf ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)and (PdCl2(PPh3)2; bases, such as, in the example, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide; solvent, such as, for example, isopropyl alcohol and acetonitrile/water, at elevated temperatures; and, perhaps, with subsequent treatment with Si-Thiol (Si-Thiol), which is commercially available from SiliCycle, Inc. Quebec, Canada, in a solvent such as, for example, tetrahydrofuran. Further, the compounds of formula IV may be subjected to crystallization from a solvent.

Stage 3

The compounds of formula V can be obtained by treating compounds of formula IV acid, such as, for example, hydrochloric acid, in the presence of a solvent, such as, for example, dioxane, dichloromethane, methanol/dichloromethane and ether/dioxane, possibly followed by treatment with a base, such as, for example, sodium methoxide in a solvent such as, for example, methanol.

Stage 4

The compounds of formula I can be obtained by reacting the compounds of formula V with 4-thiazolecarboxamide in the presence of a suitable borohydride reagent, such as, for example, triacetoxyborohydride sodium in a solvent such as, for example, dichloroethane, tetrahydrofuran/methanol and dichloromethane/methanol.

More specifically, the compound of the present invention and intermediate compounds used to obtain it, can be obtained by synthetic routes, as Provillus is recorded in the following scheme 2.

Abbreviations:

TBTU - tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea,

POPd - dihydro-dichloro-bis(di-tert-butyl-phosphinico-kP)palladate(2-),

NMM is N-methylmorpholine,

DCE - dichloroethane.

More specifically, the compound of the present invention and intermediate compounds used to obtain it, can be obtained by synthetic routes, as illustrated in the following scheme 3.

Abbreviations:

TBTU - tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea,

NMM is N-methylmorpholine,

ACN - acetonitrile,

Pd(OAc)2- palladium (II)acetate,

K2CO3- carbonate of potash,

THF is tetrahydrofuran,

DCM - dichloromethane,

NaOCH3- sodium methoxide,

MeOH is methanol,

NaBH(OAc)3- triacetoxyborohydride sodium

DCE - dichloroethane.

BIOLOGICAL ASSESSMENT AND PROPERTY

It was found that the compounds according to the invention are active against δ receptor warm-blooded animal such as man. In particular, it was found that the compounds according to the invention are effective ligands δ receptors. The following in vitro tests prove these unexpected actions, especially the activity and effectiveness of compounds as agonists, as demonstrated in the functional analysis of the δ receptors person. This feature may be associated with activity in vivo and may not be in linear correlation with the binding affinity of. In these in vitro compounds are tested for their activity against δ receptors and receive IC50to determine the selective activity of the specific compound in respect to δ receptors. In this context IC50usually refers to the concentration of the compound, which was observed in 50%of the standard displacement of the radioactive ligand δ receptor.

Activity of compounds against κ (Kappa) and µ receptors also measured in the same analysis.

Models in vitro

Cell culture

The 293S cells expressing the cloned κ, δ and µ receptors of human and resistant to neomycin, grown in suspension at 37°C and 5% CO2in shake flasks containing DMEM (modified Dulbecco Wednesday Needle) without calcium, 10% FBS (fetal serum cows), 5% BCS, with 0.1% Pluronic F-68 and 600 μg/ml of geneticin.

Obtaining membranes

Cells precipitated by centrifugation and resuspended in lyse buffer (50 mm Tris Tris(hydroxymethyl)aminomethane, pH 7.0, 2.5 mm EDTA (ethylenediaminetetraacetic acid) with PMSF (phenylmethylsulfonyl), added immediately before use to 0.1 mm 0.1 M initial solution in ethanol), incubated on ice for 15 min, then homogenized by means of Poltrona within 30 seconds The suspension is centrifuged at 1000 g (max) for 10 min at 4°C. the Supernatant leave on ice, and precipitation resuspended and centrifuged as before. Supernatant after both zentrifugenbau combined and centrifuged at 46000 g (max) for 30 minutes Precipitation resuspended in cold Tris buffer (50 mm Tris/Cl, pH 7.0) and centrifuged again. The final precipitation resuspended in the buffer to membranes (50 mm Tris, of 0.32 M sucrose, pH 7.0). Aliquots (1 ml) in polypropylene tubes, frozen in a mixture of dry ice / ethanol and stored at -70°C until use. Protein concentration determined by the modified analysis Lowry with sodium dodecyl sulfate.

Analyses of the binding of the ligand

The affinity of binding of compounds in relation κ, δ or μ receptor is determined by measuring their activities in relation to the displacement of radioligand, bind to receptors in the membranes format SPA (analysis of scintillation proximity). Compounds dissolved in DMSO (dimethyl sulfoxide), perform 3-fold serial dilution using DMSO for 11 concentrations and transfer 2 μl per well in a white 96-well plate for analysis.

The cell membrane with κ, δ or μ receptors thawed at 37°C, cooled on ice, passed 3 times through a needle 25 gauge and then mixed with the suspension PVT SPA beads coated agglutinins R the measures of wheat (PVT-WGA SPA) in the buffer for binding (50 mm Tris, 3 mm MgCl21 mg/ml BSA (bovine serum albumin), a pH of 7.4, which is stored at 4°C after filtration through a 0.22 m filter). After incubation on ice for 30 min with 100 µl of a mixture of membranes and SPA beads added to each well of 96-hole tablet containing 2 μl of the diluted compounds.

The radio for the analysis of binding are125I Deltorphin II for the δ receptor, [3H]-U69593 for the κ receptor and [125I]-enkephalin for the µ receptor, respectively. To determine nonspecific binding of naloxone applied. The binding reaction initiated by adding radio (100 µl/well), diluted in buffer for binding, analysis tablet containing compounds, membranes and SPA beads. Final concentration of the ligands comprise 40 PM125I Deltorphin II, and 0.6 nm for [3H]-U69593 and 0.1 nm for [125I]-enkefalina. Tablets containing mixture to bind, leave with shaking at room temperature for a period of time from 60 to 120 minutes After rotation in a centrifuge at 2000 rpm for 5 min using a Topcount Reader (Perkin-Elmer Instrument) to measure the radioactivity in each well of the plates. Total (TV) and nonspecific (NS) binding determined in the absence and in the presence of 10 μm naloxone, respectively.

Functional tests

The activity of compounds as agonists measured by determining the Oia degrees, to which the compounds stimulate the binding of GTP[γ]35S (GTP-independent) complex membrane receptor-G-protein. The values of EC50and Emaxcompounds determined from the analysis of the curves of the concentration - response.

Compounds dissolved in DMSO, perform 3-fold serial dilution using DMSO for 11 concentrations and transfer 2 μl per well in a white 96-well plate for analysis.

The cell membrane with κ, δ or μ receptors thawed at 37°C, cooled on ice, passed 3 times through a needle 25 gauge and then mixed with the suspension PVT SPA beads coated agglutinin wheat germ (PVT-WGA SPA) in the buffer for GTPγS assay (50 mm HEPES (N-2-hydroxyethyl-piperazine-N-2-econsultancy acid), 150 mm NaCl, 5 mm MgCl2, 1 mm EGTA (ethylene glycol-tetraoxane acid), 0.2 mm DTT (dithiothreitol), 1 mg/ml BSA, pH 7,4). After incubation on ice for 30 min, 100 μl of a mixture of membranes and SPA beads added to each well of 96-hole tablet containing 2 μl of the diluted compounds.

GTP[γ]35S diluted with buffer to GTPγS analysis to a concentration of 0.2 nm, are mixed with 20 μm GDP (guanozintrifosfat) and add 100 ál of the mixture into each well of analysis tablet containing compounds, membranes and SPA beads. After shaking at room temperature for 45-60 min tablets spin in a centrifuge at 2000 rpm for 5 m is n and by measuring the radioactivity on the Topcount Reader (Perkin-Elmer Instrument) determine the activity of binding GTP[γ] 35S.

Data analysis

Specific binding (SB) was calculated as TB-NS, a SB in the presence of various test compounds was expressed as percentage of control SB. The values of the IC50and hill coefficient (nnfor ligands with specific displacement of the associated radioligand calculated using Excel Fit. Values were calculated from the equation of Cheng-Prusoff (Cheng-Prussoff). Mean±S.E.M (standard error of the mean).

PHYSICAL PROPERTIES AND METABOLISM AND PHARMACOKINETIC properties of DRUGS in vitro

On the basis of tests using the following analyses found that the compound according to the invention achieves one or more desired physical properties, as well as metabolic and pharmacokinetic properties of drugs in vitro.

Solubility

thermodynamic solubility of the compound(s) according to the present invention was determined by mixing a known quantity of the compound at 25°C for 24 hours in phosphate buffer with a concentration of 100 mm at a pH of 7.4. Then took an aliquot of the saturated solution and measured its concentration using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Experimental conditions and instrumental parameters of LC/MS/MS is described in detail in the section on LC/MS/MS.

LogD

Determination logD b the lo is based on the principle of "shake-flask". The compound(I) of the present invention suspended in octanol-saturated buffer solution and treated with ultrasound to facilitate dissolution. To remove any nerastvorimogo material solution was filtered. After selection of an initial sample volume of the solution was adjusted to 10 ml and add a known volume of octanol saturated with buffer. Two-phase solution is mixed and then separated by centrifugation. Then from the lower layer (water layer) select a second sample. Both of the sample, which consisted of a mortar concentration of the compound before and after the addition of octanol were analyzed using LC/MS/MS. Certain concentrations used to calculate the values of logD.

Metabolic stability

Metabolic stability of the compound(s) according to the present invention in vitro was determined using human liver microsomes as a source of enzyme. Compounds (final concentration 1 μm) incubated with human liver microsomes and NADPH (nicotinamide adenine dinucleotide phosphate). At various points since the beginning of the incubation take samples and analyze them using LC/MS/MS to determine the loss of the original connection. Own clearance (CLint) was determined on the basis of the rate of elimination of the source connection of the first order.

Analysis of LC/MS/MS

All obrazcy vivo were subjected to quantitative LC/MS/MS analysis using Micromass Quattro Ultima MS/MS (Waters, Milford, MA)equipped with a HPLC system Shimadzu LC-10 (Shimadzu Scientific Systems, Columbia, MD) and an automatic sampler CTC-Pal (Leap Technologies, Carrboro, NC). Specific LC/MS conditions that were used are summarized below:

MS ionization:elektrorazpredelenie
Other MS parameters:for automatic MS optimization used QuanOptimize
Flow rate:1.5 ml/min
Column:Phenomenex Max-RP, 30 mm×2 mm, 4 MK or equivalent
The temperature of the column:room temperature
Analysis time:2 min
Gradient:(A): 0.1% formic acid (10 mm ammonium formate and 0.02% (B): 90% ACN/10% methanol

Characteristics of the gradient of MS/MS
Time (min)AB
01000
0,31000
1,3595
1,5595
1,61000
2,01000

hERG ANALYSIS

The connection can be tested for inhibition of K+ channel encoded by the gene hERG man (human ether-a-go-go-related gene), using electrophysiological system average throughput (medium throughput) based on planar matrix (lonWorks™ HT). A detailed description of this analysis, made Bridelan-Taylor et al., it was published in the Journal of Pharmacological and Toxicological Methods (54 (2006), pages 189-199), which is incorporated herein by reference to the description lonWorks™ HT. The results of this test are presented in the table below.

Method Geller-Seifter (Geller-Siefter) - alarm model

In a conflict test the hungry animals are trained to press a lever press for food in a standard operant chamber under two conditions. According to the first condition, considered as nepotoplyaemyi component, the food is delivered on average after 17 pressure on lever press (also known as VR17 gr the FIC reinforcement). The second condition is considered as the suppressed component, indicated by the blinking lights inside the operant chamber, the food is also delivered on average after 17 pressure on lever press, but additionally on the floor of a cell separate VR17 graph is energized. Daily sessions consist of 5 interleaved presentations of each component type: suppressed (duration 3 minutes) and nepotoplyaemogo (duration 2 minutes). The amount of pressure on the lever press, published with the suppressed component, obviously low compared to nepotoplyaemyi component. Sedative agents, such as diazepam, increase the amount of pressure on the lever press, which animals do when the suppressed component in a certain interval of doses, but does not affect the amount of pressure on lever press produced when nepotoplyaemomu component. Some compounds according to the invention in this test have anxiolytic profile.

The following table presents some of the biological data for the compounds according to the invention, measured using one or more than one analysis described above.

Binding to Delta receptors, CR IC500.3 nm
Agonist Delta receptors, GTPgS, EC5011 nm
Agonist Delta receptors, GTPgS, %, maximum effect114%
Binding to mu receptors, IC50464 nm
The binding of the Kappa receptor, IC50620 nm
Solubilitymore than 500 μm
logD1,6
Microsome assay person, CLint@ 1E-06M35 µl/min/mg
hERG, Ion Works IC5018 microns
hERG, Ion Works, %, maximum effect62%

EXAMPLES

Hereinafter the invention will be disclosed in more detail using the following examples, describing the ways in which the compounds of the present invention can be obtained, purified, analyzed and subjected to biological testing and which should not be construed as limiting the invention.

All temperatures are given in degrees Celsius (°C). Unless otherwise stated, operations were carried out at room temperature or ambient temperature cf the water (18-25°C).

If not specifically mentioned, commercial reagents used in the preparation of the compound of example and intermediate compounds used in the form in which they were purchased, without further purification.

If not specifically mentioned, the solvents used in the preparation of the compound of example and intermediates, had anhydrous commercial grade and used without further drying or purification.

In this description of the invention uses the following abbreviations: aq.: water; CH2Cl2: dichloromethane, DMF: dimethylformamide; EtOAc: ethyl acetate; h: hour(s); HPLC: high performance liquid chromatography; HCl: hydrochloric acid; ISO-D: isopropyl alcohol; K2CO3: potassium carbonate; MeOH: methanol; NaHCO3: sodium bicarbonate; Na2SO4: sodium sulfate; NH3: ammonia; POPd: dihydro-dichloro-bis(di-tert-butyl-phosphinico-kP)palladate (2-); min: minutes; MS: mass spectrum; NMR: nuclear magnetic resonance and TBTU: tetrafluoroborate O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea.

Example 1

N-(2-Hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide

1A. tert-Butyl ester 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine-1-carboxylic acid.

N-Methylmorpholin (6,7 ml, about 60.6 mmol) and tert-butyl ester 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-CA the boom acid (obtained, as described in WO 2001074806 to connect 5) (20,0 g, and 50.5 mmol) in DMF (240 ml) was treated with TBTU (17.8 g, at 55.6 mmol) under nitrogen. After stirring for 10 min was added 2-(methylamino)ethanol (5,3 ml, and 65.7 mmol) and the solution was stirred for 2 h the Reaction mixture was diluted with EtOAc (350 ml), washed with 2%citric acid, 3%NaHCO3and brine. The aqueous washing was extracted with EtOAc (50 ml). The combined organic phases were dried over Na2SO4and then was concentrated in vacuo to obtain a solid substance. After stirring in a mixture of hexanol for 5 h white solid was collected by filtration and dried under high vacuum, receiving 21,0 g (92%) 1A.1H NMR (500,333 MHz, CDCl3): δ 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 3.91 (br s, 2H), 3.74 (br s, 2H), 3.54 (t, J=5.8 Hz, 3H), 3.34 (t, J=5.7 Hz, 2H), 3.09 (s, 3H), 3.01 (br s, 1H), 2.64 (t, J=5.9 Hz, 2H), 2.23 (t, J=5.8 Hz, 2H), 1.47 (s, 9H). MS IER+ (mass spectrometry with ionization by elektrorazpredelenie) 453.1.

1B. tert-Butyl ester 4-({4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-quinoline-8-ylmethylene)-piperidine-1-carboxylic acid.

Compound 1A (4.0 g, 8,8 mmol), 8-hinolinovogo acid (3.0 g, 17.6 mmol), POPd (0,088 g, 0.18 mmol) and K2CO3(3.6 g, 26 4 mmol) in ISO-D (90 ml) was stirred for 20 h under nitrogen in a pre-heated up to 100°C oil bath. The reaction mixture was filtered through celite and concentrated. The resulting material was purified what cromatografia on silica gel (gradient of 2-5% Meon in CH 2Cl2) to obtain yellow solid 1B (3,27 g, 74%).1H NMR (500,333 MHz, CDCl3): δ 8,91 (dd, J=4.0, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (dt, J=9.5, 3.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 2H), 7.37-7.33 (m, 5H), 3.86 (br s, 2H), 3.68 (br s, 2H), 3.59 (br s, 2H), 3.52-3.43 (m, 3H), 3.34-3.23 (m, 2H), 3.03 (s, 3H), 2.57-2.52 (m, 2H), 2.01 (dd, J=19.3, 7.6 Hz, 2H), 1.44 (s, N). MS IER+ 502,2.

1B. N-(2-Hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-ylmethyl)-benzamide.

Compound 1B (4.7 g, 9.3 mmol) was treated with 4n. HCl in dioxane (30 ml). After 10 min the mixture decantation and the solid was stirred in ether (40 ml) for 2 hours Then ether decantation and the remaining yellow solid was dried under high vacuum to obtain 3.7 g 1B (100%).1H NMR (300,132 MHz, DMSO, 90°C): δ 8.98 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.96 (d, J=6.6 Hz, 1H), 7.69-7.57 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H,), 3.23 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H), 2.92 (s, 3H), 2.63 (t, J=6.0 Hz, 2H), 2.15 (t, J=6.0 Hz, 2H). EAP-MS (time-of-flight mass spectrometry) IER+ 402,17.

1G. N-(2-Hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)-piperidine-4-ilidene)methyl)benzamide.

Compound 1B (3,3 g, 8.3 mmol) and 4-thiazolecarboxamide (1.4 g, 12.4 mmol) in dichloroethane (16 ml) was stirred under nitrogen for 30 minutes was Added triacetoxyborohydride sodium (5.3g, 24,9 mmol) and the reaction mixture was stirred for 20 hours the Mixture was diluted with CH2Cl2(20 ml) and washed with saturated aqueous NaHCO3. Organic is ABC was dried over Na 2SO4and concentrated. After column chromatography (120 g of silica gel, elution 4% 7h. NH3/MeOH in CH2Cl2) received a 2.01 g 1G in the form of a white solid (49%).1H NMR (500,333 MHz, CDCl3): δ 8 90 (dd, J=4.1, 1.7 Hz, 1H), 8.76 (d, J=1.9 Hz, 1H), 8.11 (dd, J=8.0, 1.5 Hz, 1H), 7.72 (dd, J=7.3, 2.3 Hz, 1H), 7.51-7.46 (m, 2H), 7.37-7.33 (m, 3H), 7.31-7.29 (m, 2H), 7.18 (s, 1H), 3.85 (s, br, 2H), 3.76 (s, 2H), 3.67 (br s, 2H), 3 26 (br s, 1H), 3.02 (s, 3H), 2.78-2.71 (m, 1H), 2.67-2.52 (m, 4H), 2.46-2.37 (m, 1H), 2.14-2.04 (m, 2H). EAP ITU+ 499,21.

1. N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, its pharmaceutically acceptable salt or their mixture.

2. The compound according to claim 1 for use as a drug for the treatment of pain, anxiety, depression, anxious depression or Parkinson's disease.

3. The use of compounds according to claim 1 in the manufacture of a medicine for treatment of pain, anxiety, depression, anxious depression or Parkinson's disease.

4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, for use in the treatment of pain, anxiety, depression, anxious depression or Parkinson's disease.

5. A method of treating pain, anxiety, depression, anxious depression or Parkinson's disease in a warm-blooded animal, comprising the stage of introduction of the specified animal in need of such is icenii, a therapeutically effective amount of a compound according to claim 1.

6. The method of obtaining N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide, including:
the interaction of the protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine 8-henrikromby acid with the formation of protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide
removing protection from the specified protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide.

7. A method of obtaining a protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine, including:
the interaction of 2-(methylamino)ethanol-protected 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine.

8. A method of obtaining a protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide, including:
the interaction of the protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine 8-henrikromby acid.

9. The method according to any of PP 8, wherein the specified protected 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine specified protected 4-(bromo-{4-[(2-hydroxy-ethyl)-methyl-carbarnoyl]-phenyl}-methylene)-piperidine and the specified protected N-(2-hydroxy-ethyl)-N-methyl-4-(piperidine-4-ilidene-quinoline-8-yl-methyl)-benzamide each independently protected group Tr is t-BOC on position 1 of piperidine.

10. The method of obtaining N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide, including:
the interaction of 2-(methylamino)ethanol 4-((1-(tert-butoxycarbonyl)piperidine-4-ilidene)methyl bromide)benzoic acid with the formation of tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromethalin)piperidine-1-carboxylate;
the interaction of tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromethalin)piperidine-1-carboxylate 8-henrikromby acid with the formation of tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate;
removing protection from tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinoline-8-yl)methylene)piperidine-1-carboxylate with the formation of N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide and
the interaction of N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide with thiazole-4-carbaldehyde with the formation of N-(2-hydroxyethyl)-N-methyl-4-(quinoline-8-yl(1-(thiazol-4-ylmethyl)piperidine-4-ilidene)methyl)benzamide.

11. Tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)-(quinoline-8-yl)methylene)piperidine-1-carboxylate.

12. N-(2-hydroxyethyl)-N-methyl-4-(piperidine-4-ilidene)(quinoline-8-yl)methyl)benzamide.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 and salts thereof, fungicidal compositions based on said compounds, a plant disease control method using compounds of formula , as well as intermediate compounds of formulae and . Values of radicals are given in the description.

EFFECT: high efficiency of the compounds.

14 cl, 20 dwg, 284 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted pyrimidine derivatives, having HIV replication inhibiting properties, or pharmaceutically acceptable salts thereof. In formula (1): R1 denotes hydrogen; R2 and R3 independently denote hydrogen; R7 and R8 denote C1-6alkyl; R4 denotes cyano; R9 denotes C1-6alkyl optionally substituted with cyano, C2-6alkenyl substituted with cyano, C2-6alkynyl optionally substituted with cyano; R5 denotes C1-6alkyl optionally substituted with Ar or Het; C2-6alkenyl optionally substituted with Ar or Het; C2-6alkynyl optionally substituted with Ar or Het; C3-7cycloalkyl; Ar; Het; R6 denotes H, Het; Y denotes -OR11, -NR12R13; R11 denotes hydrogen or C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy or pyridyl; R12 denotes hydrogen or C1-6alkyl; R13 denotes hydrogen or C1-6alkyl; or R12 and R13 together with a nitrogen atom, which is substituted by said two substitutes, form a morpholinyl; imidazolyl; X denotes -NR1-; Het denotes 5- or 6-member completely saturated ring, where one or two ring members are heteroatoms, each independently selected from nitrogen and sulphur, and where the rest of the ring members are carbon atoms; and where any member of the heterocycle with a nitrogen heteroatom can optionally be substituted with C1-6alkyl; where the 5- or 6-member ring can optionally be annelated with a benzene or thiophene ring; each aryl independently denotes phenyl or phenyl substituted with one substitute selected from C1-6alkoxy.

EFFECT: high efficiency of using said compounds.

7 cl, 4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula 1 or pharmaceutically acceptable derivatives thereof, where values of radicals X, W, R4, Ar1, Ar2, R3, R4, R20 are as described in paragraph 1 of the claim. The invention also describes a composition for treating or preventing pain, UI, ulcers, inflammatory bowel disease or irritable bowel syndrome.

EFFECT: compound which can be used in medicine is obtained and described.

46 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2-piperidino-5-(thienyl-2)-6H-1,3,4-thiadiazines, hydrobromides (of general formula I) and 2-piperidino-5-(thienyl-3)-6H-1,3,4-thiadiazines, hydrobromides (of general formula II) which possess antiaggregant action. wherein R=H; Cl; Br R1=H; Cl.

EFFECT: given compounds may be used for preparing cardiologic drugs and enable better treatment of various cardiovascular diseases, including myocardial infarction and thrombotic apoplexy.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel purified compound PM 181104 of formula I

(with molecular weight 1514 and molecular formula C69H66N18O13S5), pharmaceutically acceptable salts thereof, methods for synthesis via fermentation of a microorganism of the type Kocuria (ZMA B-1 / MTCC 5269), as well as pharmaceutical compositions.

EFFECT: high efficiency of using the composition to produce a medicinal agent for treating bacterial infections.

20 cl, 4 dwg, 4 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclic compounds with the following general formula I or II and to pharmaceutically acceptable salts thereof and to all stereo isomers and optical isomers thereof:

, , where n equals 1, X and Y are NH; R1 and R2 independently represent one substitute selected from a group consisting of aryl; 2-, 3-, or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; R3 and R4 independently represent one substitute selected from a group consisting of aryl; 2-, 3- or 4-pyridyl; aryl substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio; 2-, 3- or 4-pyridyl, substituted with one, two or three groups selected from C1-C4alkyl, nitro, carboxyl, aldehyde, alkoxy, amino, amido, carbamide, mercapto, methylthio, ethylthio. The invention also relates to a method of producing a range of substituted cyclic compounds and their salts in any of subclaims 1-4, to a pharmaceutical composition, to use, to a method of treating and preventing diseases as well as to an assembly.

EFFECT: obtaining new biologically active compounds suitable for treating or preventing diseases or symptoms, arising from or accompanied with violation of secretion and/or function of insulin.

13 cl, 4 ex, 3 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I: , their optical isomers or optical isomer mix, and pharmaceutically acceptable salts, where: R1 is independently selected out of group including: aryl, heteroaryl, arylcarboxyamido, heteroarylcarboxyamido, aryloxy, arylalcoxy or arylamino, and where indicated groups of aryl, aryalkyl or heteroaryl can be substituted by 0-3 substitutes R1a, where R1a is independently selected out of group including: halogen, alkyl, alkenyl, alcoxy, alcoxyalkyl, hydroxyalkyl, mono-, di- or trihalogenoalkyl, mono-, di- or trihalogenoalcoxy, mono- or disubstituted aminoalkyl, aminocarbonyl, mono- or disubstituted aminocarbonyl, cyclic aminocarbonyl, alkylsulfonyl, etherified carboxylic acid residue, arylcarbonylamino, carbamate, R1b-aryl or R1b-heteroaryl where R1b is H, halogen, OH, amino, mono- or disubstituted amino, mono-, di- or trihalogenoalkyl, alkcoxy, mono-, di- or trihalogenoalcoxy, hydroxyalkyl; R2 is independently selected out of group including: H, OH, cyano, halogen or aryl; optionally R1 and R2 can be linked to form spirocyclyl; R3, R4, R5 and R6 are H; optionally R1 and R3 can be cyclised to form carbocycle; optionally R3 and R4 or R5 and R6 are cyclised to form bicyclic bridge system including ethylene bridge; optionally R3 and R6 are cyclised to form bicyclic bridge system including methylene or ethylene group; R7 and R8 are independently selected out of group including hydrogen, OH, C1-C8alkyl, arylalcoxy, heteroarylalcoxy; optionally R7 and R9 can be cyclised to form spirocarbocycle or spiroheterocycle; and m=0-5; where "aryl" term denotes aromatic carbocyclic groups such as phenyl, biphenyl, indenyl, naphthyl, and aromatic groups condensed with heterocycles; where "heterocycle" term denotes aromatic and non-aromatic rings including 3 to 10 atoms in the ring, 1-4 of which are heteroatom selected out of oxygen, sulfur or nitrogen; where "alkyl" term, when used separately or as suffix, denotes branched or non-branched alkyl group including 1 to 8 carbon atoms in chain; where "alkenyl" term denotes non-saturated branched or non-branched alkyl group including 2 to 12 carbon atoms in chain.

EFFECT: compounds applicable as chemokine receptor activity modulators.

15 cl, 1 tbl, 372 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of pyridine [2,3-d] pyrimidine of general formula (I) and their pharmaceutically acceptable salts, which possess properties of KDR and FGFR inhibitors. Compounds can be applied to produce medications for treatment of cancer, for instance, of mammary gland, large intestine, lungs and prostate gland. In general formula (I) , Ar and Ar' independently on each other are selected from group that includes phenyl; phenyl substituted with 1-3 substituents selected from group C1-C4alkyl, hydroxy, halogen, halogen-substituted C1-C4alkyl, C1-C4alkoxy; 6-member nitrogen-containing heteroaryl and 6-member nitrogen-containing heteroaryl substituted with C1-C4alkoxygroup, on condition that Ar standing for heteroaryl does not represent 2-pyridyl, and standing for substituted heteroaryl does not represent substituted 2-pyridyl, R1 is selected from group including phenyl, C1-C10alkyl, C1-C10alkyl independently containing substituents selected from group that includes phenyl, C3-C6cycloalkyl. Invention also relates to intermediate compounds for compounds of general formula (I) and to pharmaceutical compositions.

EFFECT: obtaining derivatives and their pharmaceutically acceptable salts which possess properties of selective KDR and FGFR inhibitors.

21 cl, 2 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

The invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely neurology, and is applicable for the purpose of rehabilitation of the patients suffering acute cerebrovascular pathology with underlying posttraumatic stress disorder. That is ensured by prescribing on the tenth day from the onset of the disease cipralex 20 mg/day or paxil 20 mg/day for 5 months, and if observing pain syndrome, velaxin 75 mg/day for 6 months. It is combined with psychological tests for the presence of anxiety disorder on the scale of Spielberg, depression on the Zung depression scale, memory disorders by Luria's tests. The pain syndrome intensity is estimated by a visual analogue scale, while state of health, activity, mood are assessed by SAN tests modified by Leonova. The test results are used to conduct 5-month psychotherapy and cognitive psychotherapy. If observing a high level of anxiety, depression and/or manifested pain syndrome, psychotherapy is prescribed 7 days after testing. Starting from the first month of rehabilitation and before the completion of the 6-month course, occupational therapy is applied, and from the second month, a biofeedback control technique specified by static kinesiography is prescribed.

EFFECT: invention provides reduced length of treatment, reduced disabling of the patients with ischemic stroke.

4 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted heteroarylpiperidine derivatives of formula (I) and enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof, where R1 denotes -N(R10)-(C(R6)2)m-T, (C(R6)2)1-T or -O-(C(R6)2)m-T; R6 is independently selected from H, OCH3, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, and C3-6-cycloalkyl, possibly substituted with 1-3 substitutes which are halogen, T denotes NR7R8, , , , or ; R7 and R8 are independently selected from H, C1-6-alkyl; R9 is independently selected from OH, C1-6-alkyl, O-C1-6-alkyl, or NR12R13; R10 denotes H or C1-6-alkyl; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl and W denotes CH, O or NR10; B denotes CR2 or N; G denotes CR2 or N; D denotes CR2 or N; E denotes CR2 or N; provided that one or more of variables B, G, D and E must be N; R2 is independently selected from H, F, Cl, CH3, OCH3 and CF3; R3 denotes: H, CI, F or CH3; R4 denotes Cl, F or CH3, R5 denotes , morpholine, possibly substituted with 1-3 identical or different substitutes R14, a 4-7-member saturated or partially unsaturated heterocycle containing one nitrogen atom in the ring and possibly an additional heteroatom selected from O, N and S, where the heterocycle is possibly substituted with 1-4 identical or different substitutes R11, or NR12R13; R11 is indendently selected from halogen, OH, C1-6-alkyl, possibly substituted with 1-3 substitutes which are halogen, C2-6-alkynyl, -C0-6-alkyl-C3-6-cycloalkyl, -OC(O)C1-6-alkyl, -NH2, -NH(C1-6-alkyl) and -N(C1-6-alkyl)2; A denotes a 3-7-member saturated ring; R12 and R13 are independently selected from C1-6-alkyl, possibly substituted with OH, C2-6-alkylene-O-C1-6-alkyl; R14 denotes C1-6-alkyl; 1 equals 0, 1, 2, 3 or 4; m equals 0, 1, 2, 3 or 4; o equals 0, 1 or 2; p equals 0, 1, 2, 3 or 4; r equals 0, 1, 2, 3 or 4; s equals 1 or 2 and t equals 0 or 1. The invention also relates to use the compound of formula I to produce a drug for treating or preventing disorders, diseases or conditions responsible for inactivation or activation of the melanocortin-4 receptor in mammals, and to a pharmaceutical composition based on said compounds.

EFFECT: novel compounds which can be used as melanocortin-4 receptor modulators are obtained and described.

10 cl, 134 ex, 16 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition, particularly to a composition (versions) for treating depression. A pharmaceutical composition with a multipurpose post-receptor mechanism for treating depression containing ginsenosides Rg1 and Rb1; and a glycyrrhizic acid derivative being specified in a group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination taken in specific proportions. The multipurpose post-receptor pharmaceutical composition for treating depression containing ginsenosides Rg1 and Rb1; and the glycyrrhizic acid derivative being specified in the group consisting of glycyrrhizic acid, glycyrrhetinic acid and their combination; and a cyclic adenosine monophosphate jojoba (cAMP jojoba) taken in specific proportions.

EFFECT: pharmaceutical compositions shows substantial antidepressant efficacy.

13 cl, 17 tbl, 6 dwg, 8 ex

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