N-acyl-n' -benzylalylenediamno derivatives

FIELD: chemistry.

SUBSTANCE: invention relates to compounds and use of N-acyl-N'-benzylalkylenediamino derivatives of general formula I, where A is a linear or branched C2-C3 alkyl; X is oxygen; R1 is a linear or branched C1-C8 alkyl, optionally substituted with phenyl, phenoxy or naphthyl; or benzyl optionally substituted on the phenyl ring with one or more substitutes selected from halogen, C1-C4 alkyl, trifluoromethyl, C1-C4alkoxy group; R2 and R3 independently represent hydrogen, C1-C3 alkyl, halogen or C1-C4 alkoxy group; R4 is hydrogen or methyl; R5is hydrogen; R6 is a linear or branched C1-C6 alkyl or bonded to R5 to form a pyrrolidin-2-one ring; an their pharmaceutically acceptable salts which are active as sodium and/or calcium channel modulators.

EFFECT: wider field of use of the compounds.

7 cl, 13 ex

 

This invention relates to N-acyl-N'-benzylaminopurine following General formula I

and their pharmaceutically acceptable salts which are active as modulators of sodium and/or calcium channels and therefore applicable for preventing, alleviating and curing a wide range of pathologies, including, but not limited to, neurological, psychiatric, cardiovascular, inflammatory, ophthalmic, urology, metabolic and gastrointestinal diseases, where these mechanisms are described as playing a pathological role.

Malawska, etc. described the synthesis of new anti-arrhythmic and protivogipertonicheskoe derived pyrrolidin-2-it (Eur. J. Med. Chem. 37, 2002, 183-195).

It is well known that sodium channels play an important role in the neural network by sending electrical impulses rapidly through the cells and networks of cells, coordinating thus higher processes ranging from locomotion to cognition. These channels are large transmembrane proteins that are able to change between different States to provide selective permeability of sodium ions. This process requires bioelectric potential to be depolarized the membrane, and therefore, these channels are potentsialzavisimye. In the settlement of the tournament a few years formed a deeper understanding of the sodium channel and drugs interacting with them.

It became apparent that some drugs with unknown mechanism of action, in effect by adjusting the conductance of sodium channels, including local anesthetic, antiarrhythmic agent of class I and anti-convulsants. Neural blockers of sodium channels are used in the treatment of epilepsy (phenytoin and carbamazepine), bipolar disorder (lamotrigine), for the prevention of neurodegeneration and to reduce neuropathic pain. Various anti-epileptic drugs that stabilize neuronal excitability, effective against neuropathic pain (gabapentin).

In addition, the increased expression or activity of sodium channels observed in some models of inflammatory pain, confirming the role of sodium channels in inflammatory pain.

Calcium channels are Contracting (overlapping) membrane, consisting of many subunits proteins that allow you to control the flow of calcium ions into cells from the extracellular fluid. Typically, the calcium channels are dependent on capacities and are referred to as potentialization calcium channels (PSCC). PSCC distributed throughout the nervous system of mammals, where they regulate such diverse activities as the cell in which boudinot, the release of transmitter, intracellular metabolism, neurosecretory activity and gene expression. All "excitable" cells of animals, such as neurons of the Central nervous system (CNS), peripheral nerve cells and muscle cells, including cells of the skeletal muscles, heart muscle and arterial and venous smooth muscle, have potentialization calcium channels. Calcium channels have a Central role in regulating intracellular levels of calcium ions, which are important for the viability and function of cells. Intracellular calcium ion concentration involved in some life processes in animals, such as the release of neurotransmitter, muscle contraction, tempo activity and secretion of hormones. Probably calcium channels play a significant role in some painful conditions. Some compounds applicable in the treatment of various cardiovascular diseases in mammals, including humans, assumed to exert their beneficial effects by regulating the functions potentialization calcium channels present in cardiac and/or vascular smooth muscle. Compounds with activity against calcium channels are also involved for the treatment of pain. In particular, calcium channels, N-type (Cav2.2), responsible for regulirovanie neurotransmitters, presumably play a significant role in nociceptive transmission, as follows from the distribution in the tissues, as well as from the results of various pharmacological studies. This hypothesis is confirmed by the clinical application of thinocoridae, peptide isolated from the venom of the marine snail Conus Magus. Therapeutic application of the above peptide restricts what he requires intrathecal injection people (Bowersox SS and Luther R. Toxion, 1998, 36, 11, 1651-1658).

All these information show that the connection with the blockade of sodium and/or calcium channels have a high therapeutic potential for preventing, alleviating and curing a wide range of conditions, including neurological, psychiatric, cardiovascular, urological, metabolic and gastrointestinal diseases, where the above mechanisms are described as playing a pathological role.

There are many articles and patents that describe modulators or antagonists of sodium and/or calcium channels for the treatment or regulation of a variety of disorders such as their use as a local anesthetic, antiarrhythmic, antiemetics, antigenically depressants, agents for the treatment of unipolar depression, cardiovascular diseases, urinary incontinence, diarrhea, inflammation, epilepsy, neurodegenerative status is of any, neuronal cell death, anticonvulsants, anti-pain, migraine, acute hyperalgesia and inflammation, kidney disease, allergies, asthma, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, disorders of the urinary tract, disorders of gastrointestinal motility, premature birth, and obesity. By far not the full list below.

A broad and comprehensive overview of the prior art presented in WO 03/057219 (and references therein); additional sampling from the prior art described in the following references: Alzheimer's .Adv. Exp.Med. Biol. 2002, 513, 161-181; Vanegas H.; Schaible H. Pain 2000, 85, 9-18; U.S. patent 5051403; U.S. patent 5587454; U.S. patent 5863952; U.S. patent 6011035; U.S. patent 6117841; U.S. patent 6362174; U.S. patent 6380198; U.S. patent 6420383; U.S. patent 6458781; U.S. patent 6472530; U.S. patent 6518288; U.S. patent 6521647; WO 97/10210; WO 03/018561.

Description of the invention

This invention relates to compounds of formula I

where a represents a linear or branched C2-C8alkyl;

X represents methylene, oxygen, sulfur or NR7;

R1represents a linear or branched C1-C8alkyl or C3-C8albaniles or3-C8akinyan, optionally substituted CF3, phenyl, phenoxy or naphthyl, and aromatic rings, long is Ino substituted by one or more groups C 1-C4of alkyl, halogen, trifloromethyl, hydroxy or C1-C4alkoxy;

R2, R3independently represent hydrogen, C1-C3alkyl, halogen, trifluoromethyl, hydroxy or C1-C4alkoxygroup;

R4, R5independently represent hydrogen or C1-C6alkyl;

R6represents hydrogen or linear or branched C1-C8alkyl or associated with R5may form a five-semicolony lactam;

R7means hydrogen or C1-C6alkyl;

and their pharmaceutically acceptable salts, provided that, when A denotes-CH2CH2-, R1means X ortopedici, R2, R3and R5represent hydrogen and R6is methyl, R4is other than hydrogen or methyl (Nation, D.A. et al. J. Chem. Soc., Dalton Transactions: Inorganic Chemistry 1996, 14, 3001-3009); when A denotes-CH2CH2-, R1-X - 4-methoxy, R2- 2-methoxy, R3and R5is hydrogen and R6is methyl, R4is other than hydrogen (Saikawa, I. et al. Yakugaku Zasshi 1979, 99, 929-935) and

when A means-CH2CH2-, R1-X - 3-methoxy, R2- 5-methoxy, R3and R5is hydrogen and R6is methyl, R4is other than hydrogen (Menage, S. et al. J. Am. Chem. Soc. 1998, 120, 13370-13382).

This invention also relates to the use of compounds of General formula I, where A, X, 1, R2, R3, R4, R5, R6and R7have the above values, to obtain the drug with regulatory sodium and/or calcium channels activity.

Optional substituents R1-X, R2and R3in the phenyl ring can be in any position.

Pharmaceutically acceptable salts of compounds of formula I include acid additive salts, for example, with inorganic, such as hydrochloric, Hydrobromic, sulfuric and phosphoric acid, or organic, e.g. acetic, propionic, benzoic, cinnamic, almond, salicylic, glycolic, lactic, oxalic, malic, maleic, malonic, fumaric, tartaric, citric, and the like acids.

Preferred compounds according to the invention are the compounds of formula I in which A denotes an ethylene or propylene, X is oxygen, methylene, NH or NCH3, R1means C1-C8alkyl, optionally substituted CF3, phenyl or fenoxaprop, where the aromatic ring in R1is optionally substituted by one or two methoxy groups, fluorine or chlorine, or trifloromethyl, R2and R3represent hydrogen, methyl, methoxy, fluorine, chlorine or bromine, R4and R5represent hydrogen or methyl, R6represents methyl or ethyl or, boduch is related to R 5may form a five or six-membered lactam.

Examples of specific compounds are

N-2-(4-butylenediamine)ethylacetamide;

N-2-[4-(4-triptoreline)benzylamino]ethylacetamide;

N-2-(4-pentyloxybenzaldehyde)ethylacetamide;

N-2-[4-(5-cryptocentrus)benzylamino]ethylacetamide;

N-2-(2-benzyloxyaniline)ethylacetamide;

N-2-(3-benzyloxyaniline)ethylacetamide;

N-2-(4-benzyloxyaniline)ethylacetamide;

N-2-[4-(5-phenylmethoxy)benzoylamino]ethylacetamide;

N-2-[4-(2-phenethyl)benzylamino]ethylacetamide;

N-{2-[2-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;

N-{2-[3-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-2-methoxybenzylamine]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-2-methylbenzylamino]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-3-forbindelsen]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-3-chlorobenzylamino]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-3-methoxybenzylamine]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-3-methylbenzylamino]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]ethyl}ndimethylacetamide;

N-{2-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]ethyl}ndimethylacetamide;

N-3-(4-pentyloxybenzaldehyde)propylacetamide;

p> N-2-[4-(5-cryptocentrus)benzylamino]propylacetamide;

N-3-(4-benzyloxyaniline)propylacetamide;

N-3-[4-(2-phenethyl)benzylamino]propylacetamide;

N-3-[4-(5-phenylmethoxy)benzoylamino]propylacetamide;

N-{3-[4-(2-forbindelse)-2-methoxybenzylamine]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-2-methylbenzylamino]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3-forbindelsen]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3-chlorobenzylamino]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3-methoxybenzylamine]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3-methylbenzylamino]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3;5-dimethylbenzylamine]propyl}ndimethylacetamide;

N-{3-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]propyl}ndimethylacetamide;

1-[2-(4-butylenediamine)ethyl]pyrrolidin-2-he;

1-{2-[4-(4-triftormetilfullerenov]ethyl}pyrrolidin-2-he;

1-[2-(4-pentyloxybenzaldehyde)ethyl]pyrrolidin-2-he;

1-{2-[4-(5-triftormetilfullerenov]ethyl}pyrrolidin-2-he;

1-[2-(2-benzyloxycarbonylamino)ethyl]pyrrolidin-2-he;

1-[2-(3-benzyloxycarbonylamino)ethyl]pyrrolidin-2-he;

1-[2-(4-benzyloxyaniline)ethyl]pyrrolidin-2-he;

1-[2-(4-benzyldimethylamine)ethyl]pyrrolidin-2-he;

1-[2-(4-benzylaminopurine)ethyl]pyrrolidin-2-he;

1-{2-[4-(5-finalmente is hydroxy)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-phenoxyethoxy)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(naphthalene-1-ylethoxy)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[2-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[3-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(4-tert-butylbenzoate)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(4-triftormetilfosfinov)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2,6-DICHLOROSILANE)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(3,5-dimethoxybenzoate)benzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-2-methoxybenzylamine]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-2-methylbenzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-fluoro-benzyloxy)-3-forbindelsen]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-3-methoxybenzylamine]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-3-methylbenzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-3-chlorobenzylamino]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]ethyl}pyrrolidin-2-he;

1-{2-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]ethyl}pyrrolidin-2-he;

1-[3-(4-pentyloxybenzaldehyde)propyl]pyrrolidin-2-he;

1-[3-(2-benzyloxycarbonylamino)propyl]pyrrolidin-2-he;

1-[3-(3-benzilic is benzylamino)propyl]pyrrolidin-2-he;

1-[3-(4-benzyloxyaniline)propyl]pyrrolidin-2-he;

1-{3-[4-(5-phenylmethoxy)benzoylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2-phenoxyethoxy)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(naphthalene-1-ylethoxy)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(4-tert-butylbenzoate)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(4-triftormetilfosfinov)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2,6-DICHLOROSILANE)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(3,5-dimethoxybenzoate)benzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-2-methoxybenzylamine]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-2-methylbenzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-3-forbindelsen]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-3-methoxybenzylamine]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-3-methylbenzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-3-chlorobenzylamino]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]propyl}pyrrolidin-2-he;

1-{3-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]propyl}pyrrolidin-2-it.

Compounds according to the invention and their salts can be obtained by a method including:

a) interaction of the compounds of formula II

where R1, R2, R3and X have the above values,

with compounds of formula III in the presence of reductant

where R4, R5, R6and A have the previously indicated meanings, obtaining thus the compounds of formula I, or

(b) coordination compounds of the formula IV

where R1, R2, R3and X have the above meanings and Y represents a halogen atom or a group O-EC, where EC denotes electron-donating group, such as, for example, groups of methil, tosyl or TRIFLUOROACETYL, capable of converting the oxygen with which they are associated, in a good leaving group,

with compounds of the formula III with obtaining thus the compounds of formula I, or

(C) the interaction of the compounds of formula Ia

where R1, R2, R3, R5and R6, X and a have the abovementioned meanings, with compounds of formula V or VI

R4YR8CHO
VVI

where Y and R4have the above meanings and R8means hydrogen or C1-C5alkyl, receiving thus the connection to izobreteny is, in which R4means1-C6alkyl, and, if desired, converting the compounds according to the invention in another connection according to the invention, and/or, if desired, converting the compounds according to the invention in its pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound, and/or, if desired, separating a mixture of isomers of the compounds according to the invention to separate the isomers.

Compounds II, III, IV, V and VI are commercially available compounds or can be obtained from commercially available compounds using well known methods.

The interaction of compounds of the formula II with compounds of formula III and compounds of formula Ia to compounds of formula VI to form compounds of the formula I is the reaction of reductive amination, which can be carried out according to well known methods. According to a preferred embodiment of the invention it can be carried out in a nitrogen atmosphere in a suitable organic solvent, such as alcohol, for example a lower alcohol, in particular methanol, or acetonitrile, or tetrahydrofuran, at a temperature ranging from about 0°to about 70°C., in the presence of reductant, the most suitable is sodium borohydride or cyanoborohydride sodium. Sometimes isopropyl titanium IV and molecular sieves may be added to the reaction mixture to facilitate the reaction.

In the compound of formula IV and V halogen preferably represented by bromine or iodine. Alkylation reaction of compounds of formula IV with the compound of the formula III and the compounds of formula Ia with a compound of formula V can be carried out in a suitable organic solvent, such as alcohol, for example methanol, ethanol or isopropanol, in particular ethanol, at a temperature ranging from about 0°to about 50°C.

When in the compounds of this invention and their intermediate products are of the group that you want to protect before you expose them to these reactions, they can be protected before the reaction, and then the protection can be eliminated by well-known methods.

PHARMACOLOGY

The compounds of this invention exhibit an affinity for the binding sites of calcium and/or sodium channels, as demonstrated using selective radio research associate in vitro.

The compounds of this invention are blockers potentialization sodium channels and/or calcium channels. Therefore, these compounds displace 3H-batrachotoxin (VTH) with high affinity of the binding site on the sodium channel with IC50in the low micron or sub-micron range. Similarly, compounds displace 3H-nitrendipin from the binding site in the calcium channel with IC50/sub> in the low μm, or most commonly in the sub-μm range, and inhibiting calcium influx induced through calcium channels by cell depolarization.

Such substances find "dependence on the use of"when are blocked sodium channels, i.e. the maximum blockade of sodium channels is achieved only after repeated stimulation of the sodium channel. Therefore, the substance preferably bind to sodium channels, which are repeatedly activated. As a result, agents are able to be active mainly in the areas of the body that are pathologically overstimulated, as illustrated by experiments by the method of fixation potential (W.A.Catteral, Trends Pharmacol. Sci., 8, 57-65; 1987), which show that the compounds according to the invention inhibit electrically stimulated sodium channel dependent on application method.

Potencialzawisimae blockade of calcium and/or sodium channels by the compounds according to the invention is shown by fluorescence analysis of the inflow of calcium and electrophysiological studies.

Regulating calcium channels, N-type active N-acyl-N-benzylaminopurine General formula I is measured by fluorescence analysis influx of calcium.

Regulates sodium channel activity of N-acyl-N-benzylaminopurine total f is rmula I measured by electrophysiological analyses, using the method of fixing the voltage of the two electrodes (TEVC) on isolated Xenopus oocytes expressing the Na-channel Nav 1.3.

As a result of these mechanisms, the compounds according to the invention are active when administered orally in the range from 0.1 to 100 mg/kg, in a wide range of animal models and, in particular, in the MES test electrically caused convulsions, formalin model of prolonged pain and on carraginanous models of inflammation.

In view of the above-described mechanisms of action of compounds according to this invention is applicable for treating or preventing neuropathic pain. Syndromes of neuropathic pain include, but are not limited to diabetic neuropathy, sciatica, nonspecific pain, lower back pain, multiple sclerosis, fibromyalgia, related to HIV neuropathy, neuralgia, such as post herpetic neuralgia and trigeminal neuralgia, and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions.

Compounds according to the invention is also applicable to the treatment of chronic pain. Chronic pain includes, but is not limited to, chronic pain caused by inflammation or related to inflammation condition, osteoarthritis, rheumatoid arthritis, or as a complication of the disease, acute injury or trauma, and on which includes pain upper back or lower back area (which is the result of a systematic, regional or primary disease of the spine (such as radiculopathy), bone pain (due to osteoarthritis, osteoporosis, bone metastases or unknown reasons), pelvic pain, pain associated with spinal cord injury, cardiac chest pain, desertico pain in the chest associated with the Central nervous system pain after a stroke, myofascial pain, pain and cancer pain, pain caused by AIDS, pain associated with sickle erythrocytes, geriatric pain or pain caused by migraine, pain syndrome, temporomandibular joint, gout, fibrotic syndromes or syndrome compression of the brachial plexus and subclavian artery in the region of the first rib and clavicle.

Compounds according to the invention is also applicable to the treatment of acute pain (caused by a sharp defeat, disease, sports medicine injuries, carpal tunnel syndrome, burns, muscular-skeletal dislocations and sprains, muscle-tendon tension, neck and shoulder pain syndromes, dyspepsia, gastric cancer, duodenal ulcer, dysmenorrhea, endometriosis or surgery (such as surgical operations on the heart or bypass surgery), postoperative pain, pain from kidney stones, gallbladder pain, pain in gall-stone disease, obstetric pain or toothache.

Soy is inane according to the invention is also applicable to the treatment of migraine, such as headache type voltage, transformed migraine or developing a headache centered headache and secondary disorders headache, such as headaches arising from infections, metabolic disorders or other systemic disease, and other acute headaches, the paroxysmal hemicrania, and the like, resulting from the deterioration of these primary and secondary headaches.

Compounds according to the invention is also applicable to the treatment of neurological conditions and disorders cognitive abilities. Neurological conditions include, but are not limited to conditions such as epilepsy (including partial epileptic seizures, seizures of epileptic automatism, secondary generalized seizures, additionally including absences, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures and atonic seizures), degenerative dementia (including senile dementia, Alzheimer's disease, the disease Peak, Parkinson's disease and vascular dementia (including post-stroke dementia, stroke and cerebral ischemia), as well as dementia associated with damages, injuries, infections and other conditions affecting the intracranial space is about (including infection HIV), metabolism, toxins, anoxia, and the lack of vitamins, and a moderate deterioration in cognitive abilities associated with ageing, particularly age-related memory impairment, impaired movements (postencephalitic parkinsonism, progressive supranuclear paralysis, corticobasal degeneration), narcolepsy, a disorder of insufficient hyperactivity disorder (ADHD), amyotrophic lateral sclerosis, down's syndrome.

Compounds according to the invention is also applicable to the treatment of psychiatric disorders. Psychiatric disorders include, but are not limited to, manic depression also known as bipolar disorder (such as bipolar disorder type I, bipolar disorder type II), cycloamino disorder, bipolar depression with frequent intervals, ultrarational frequency of acute manic, manic, mixed manic, hypomanic or unipolar depression, schizophrenia, schizophrenic disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a prevailing medical condition caused by substances psychotic disorder or psychotic disorder not charac is risovannoe otherwise, anxiety disorders and, moreover, nicotine and drug dependence.

Compounds according to the invention is also applicable in the treatment of peripheral diseases such as ringing in the ears, muscle spasm, muscular sclerosis and other disorders, including, but not limited to, cardiovascular disease (such as cardiac arrhythmia, myocardial infarction or angina, hypertension, hypoxia, cardiac ischemia), endocrine disorders (such as acromegaly or diabetes insipidus), diseases in which the pathophysiology of the disorder involves excessive or hypersecretory or otherwise defective cell secretion of endogenous substances (such as catecholamine, hormone or growth factor).

Compounds according to the invention is also applicable in the treatment of liver disease, such as inflammatory liver disease, such as chronic viral hepatitis b, chronic viral hepatitis C, alcoholic liver disease, primary bilary cirrhosis, autoimmune hepatitis, nonalcoholic steatohepatitis, and transplant rejection liver.

Compounds of the invention inhibit inflammatory processes affecting all body systems. Therefore, they are applicable in the treatment of inflammatory processes of the muscular skeletal system, listed below, but do not cover all of the target disorder: podagricus is their status, such as ankylosing spondylitis, cervical arthritis, fibromyalgia, gut, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, psoriatic arthritis, rheumatic disease; disorders affecting the skin and related tissues: eczema, psoriasis, dermatitis, and inflammatory conditions such as sunburn; disorders of the respiratory system: asthma, allergic rhinitis and respiratory distress syndrome, pulmonary disorders that involve inflammation, such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and endocrine systems: polyarteritis polyarteritis, thyroiditis, aplastic anemia, sclerodoma, myasthenia gravis, multiple sclerosis, sarcoidosis, renal syndrome, Bechet syndrome, polymyositis, gingivitis.

Compounds according to the invention is also applicable in the treatment of disorders of the gastro-intestinal (GI) tract, such as inflammatory bowel disorders, including, but not limited to, ulcerative colitis, Crohn's disease, REIT, proctitis, coeliac disease, coeliac disease, microscopic or collagenous colitis, eosinophilic gastroenteritis, or reservoir REIT in the proctocolectomy and postranichnogo anastomosis, and irritable bowel syndrome, including any disorders associated with abdominal pain and/or abdomen is determined as being the discomfort, such as pilorospazm, nervous indigestion, spastic colon, spastic colitis, spastic colon, intestinal neurosis, functional colitis, mucous colitis, laxative colitis and functional dyspepsia; as well as for the treatment of atrophic gastritis, gastritis modified form, ulcerative colitis, peptic ulcers, pyresis, and other lesions of the GI tract, such as Helicobacter pylori, gastroesophageal reflux disease, gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders such as non-ulcer dyspepsia (NID); vomiting, diarrhea, and internal inflammation.

Compounds according to the invention is also applicable in the treatment of disorders of the urinary tract, such as overactive bladder, prostatitis (chronic bacterial and chronic non-bacterial prostatitis), prostadynia, interstitial cystitis, urinary incontinence and benign prostatic hyperplasia, anexity, pelvic inflammation, we have to stop spreading and vaginitis.

Compounds according to the invention is also applicable in the treatment of eye diseases such as pigmentosa, retinopathy, owein and acute damage of the eye tissue, degeneracy yellow spots or glaucoma, conjunctivitis.

Compounds according to the invention is also applicable in the treatment of obesity.

Compounds according to the invention is also applicable in the treatment of all the other States, mediated inhibition potentialization sodium channels and/or potentialization calcium channels.

You should take into account that the compounds according to the invention can be advantageously used in combination with one or more other therapeutic agents. Examples of suitable agents for combination therapy include agonist at 5HT1B/1Dsuch as triptan (e.g. sumatriptan or naratriptan); an agonist of the adenosine A1; ER ligand; a modulator of NMDA, such as a glycine antagonist; the antagonist of the substance P (for example, the antagonist NKI); cannabinoid; acetaminophen or phenacetin; inhibitor of 5-lipoxygenase; an antagonist of leukotriene receptor; DMARDs (e.g. methotrexate); gabapentin and related compounds; a tricyclic antidepressant (eg, amitriptyline); stabilizing neuronal anti-epileptic drug; inhibitor of monoaminergic consumption (e.g. venlafaxine); inhibitor of matrix metalloproteinase; synthase inhibitor of nitric oxide (NOS), such as an inhibitor of iNOS or nNOS; inhibitor of the release or action of factor alpha tumor necrosis; an antibody therapy, such as a monoclonal antibody therapy; an antiviral agent, such as an inhibitor of the nucleoside (e.g. lamivudine) or an immune system modulator (e.g. interferon); an analgesic, such as in hibitor cyclooxygenase-2; local anaesthetic; a stimulant, including caffeine; an H2-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminium hydroxide or magnesium; carminative agent (for example, simethicon); a decongestant (e.g., phenylephrine, phenylpropanolamine, pseudoephedrine, Oxymetazoline, epinephrine, nafazolina, Xylometazoline, propylhexedrine or left-desoxyephedrine), cough medicine (eg, codeine, hydrocodone, carmien, carbetapentane or dextromethorphan); a diuretic or a sedative or nesecarily antihistamine. It should be understood that this invention encompasses the use of compounds of formula (I) or its pharmaceutically acceptable salt in combination with one or more therapeutic agents.

Compounds according to this invention is applicable to humans and in veterinary medicine. It should be understood that reference to treatment includes the treatment of established symptoms and preventive measures, if otherwise is not specified in more detail.

N-acyl-N'-benzylaminopurine formula I, defined above, can be entered as "active ingredient" pharmaceutically acceptable composition that can be prepared by the conventional procedures, for example by mixing the active ingredient with pharmaceutically acceptable, therapeutically inert the organic and/or inorganic materials media.

The composition containing the N-acyl-N'-benzylaminopurine, can be introduced in various forms, for example orally in the form of tablets, pills, capsules, tablets coated with sugar or film, liquid solutions, emulsions or suspensions; rectally in the form of suppositories; parenterally, e.g. by intramuscular or intravenous injection or infusion, and percutaneous.

Suitable pharmaceutically acceptable, therapeutically inert organic and/or inorganic materials media applicable for the preparation of such composition include, for example, water, gelatin, gum Arabic, lactose, starch, cellulose, magnesium stearate, talc, vegetable oils, polyalkylene glycols and the like. The composition containing the N-acyl-N'-benzylaminopurine formula I, defined above, can be sterilized and may contain additional well-known compounds such as, for example, preservatives, stabilizers, wetting or emulsifying agents, such as paraffin oil, monooleate manned, salts for regulating the osmotic pressure, buffers and the like.

For example, solid forms for oral administration may contain together with the active ingredient, diluents, for example lactose, dextrose, saccharose, cellulose, corn starch or potato to Ajmal; lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; binding agents, for example starches, gum Arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; dezintegriruetsja agents, for example starch, alginic acid, alginates or sodium salt starch glycolate; gas-emitting mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, Polysorbate, laurylsulfate, and, as a rule, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be produced in the usual manner, for example by mixing, granulating, tabletting, sugar coating or film coating.

Compositions for oral administration contain compositions with delayed release, which can be prepared in the usual way, for example by applying the enteric coating on tablets and granules.

Liquid dispersion for oral administration may be, for example, in the form of syrups, emulsions and suspensions.

The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example the EP, natural gum, agar, sodium alginate, pectin, methylcellulose, carboximetilzellulozu or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound in pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, such as propylene glycol, and, if desirable, a suitable quantity of the hydrochloride lidocaine. The solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic saline solutions.

Suppositories may contain together with the active ingredient pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, surfactants based on esters of fatty acids of polyoxyethylenesorbitan or lecithin.

Appropriate treatment involves the introduction of 1, 2 or 3 times a day depending on the rate of clearance. Accordingly, the desired dose may be presented in a single dose or as divided doses, administered at appropriate intervals, for example from two to four or more subdot in the day.

Pharmaceutical compositions containing N-acyl-N'-benzylaminopurine formula I, which is defined to enter the, will contain per dosage, such as a capsule, tablet, powder for injection, teaspoonful, suppository and the like, from about 0.1 to about 500 mg of active ingredient, most preferably from 1 to 10 mg.

Optimal therapeutically effective dose for injection can easily be determined by experts in this field and will vary depending on the strength of the drug, route of administration and progression of the condition or disorder that is treated. In addition, factors related to a specific subject, which is treated, including age, weight, diet and time of administration, will cause the necessity of bringing the dose corresponding to a therapeutically effective level.

The following examples further clarify the invention.

Example 1

N-{2-[4-(2-Forbindelse)for 3,5-dimethylbenzylamine]ethyl}ndimethylacetamide

2 M solution of N-(2-amino-ethyl)ndimethylacetamide (664 mg, 6.5 mmol) in dry THF is added to a 1 M solution of 4-(2-forbindelse)for 3,5-dimethylbenzaldehyde (1.84 g, 7,15 mmol), obtained as described in example 4, in dry THF. To this mixture is added dropwise a 2 M solution of Ti(O-iPr)4(2,77 g of 9.75 mmol) in dry THF and the reaction mixture was stirred for 12 hours at room temperature in a nitrogen atmosphere.

Add a 0.75 M solution of sodium borohydride (690 mg, 18.2 mmol) in absolute ethanol and the resulting mixture is agreat at 70°C for 6 hours. After cooling, add water (8 ml) and the resulting white precipitate is removed by filtration. The crude compound is purified using the cartridge SCX (strong cation exchange resin). Pure product is removed by elution with 3% solution of ammonia in methanol. Specified in the header connection (1,93 g) obtained after evaporation of the solution under vacuum to yield 86,0%.

MS (ESI positive dispersion 3.5 kV; Skimmer 20 V; probe 250°C): 345 [MH+].

1H-NMR (DMCO-d6): 7,75 (ushort, 1H), 7,60 (DD, 1H), 7,45 (m, 1H), 7,25 (m, 2H), 6,99 (s, 2H), to 4.81 (s, 2H), only 3.57 (s, 2H), 3,48 of 3.28 (m, 3H), 3.15 in (dt, 2H), of 2.21 (s, 6H), to 1.79 (s, 3H).

Example 2

1-{3-[4-(2-Forbindelse)-3-chlorobenzylamino]propyl}pyrrolidin-2-he

2 M solution of 1-(3-aminopropyl)pyrrolidin-2-she (920 mg, 6.5 mmol) in dry THF is added to a 1 M solution of 3-chloro-4-(2-forbindelse)benzaldehyde (1,87 g, 7.1 mmol), obtained as described in example 5, in dry THF. To this mixture is added dropwise a 2 M solution of Ti(O-iPr)4(2,77 g of 9.75 mmol) in dry THF and the reaction mixture was stirred for 12 hours at room temperature in a nitrogen atmosphere.

Add a 0.75 M solution of sodium borohydride (690 mg, 18.2 mmol) in absolute ethanol and the resulting mixture heated at 70°C for 6 hours. After cooling, add water (8 ml) and the resulting white precipitate is removed by filtration. The crude compound is purified using the cartridge SCX (strong cation exchange resin). Clean the product removed by elution with 3% solution of ammonia in methanol. Specified in the header of the connection of 2.27 g) obtained after evaporation of the solution in vacuum with the release of 89.3 per cent.

MS (ESI positive dispersion 3.5 kV; Skimmer 20 V; probe 250°C): 391 [MH+].

1H-NMR (DMCO-d6): of 7.55 (DD, 1H), and 7.4 (m, 2H), 7,22 (m, 4H), and 5.2 (s, 2H), 3,6 (c, 2H), 3,2 (t, 4H), 2,4 (m, 2H), 2,18 (m, 2H), to 1.87 (m, 2H), 1.55V (m, 2H).

Example 3

1-{3-[4-(2-Forbindelse)-3-methoxybenzylamine]propyl}pyrrolidin-2-he

2 M solution of 1-(3-aminopropyl)pyrrolidin-2-it (924 mg, 6.5 mmol) in dry THF is added to a 1 M solution of 4-(2-forbindelse)-3-methoxybenzaldehyde (1.86 g, 7,15 mmol), obtained as described in example 6, in dry THF. To this mixture is added dropwise a 2 M solution of Ti(O-iPr)4(2,77 g of 9.75 mmol) in dry THF and the reaction mixture was stirred for 12 hours at room temperature in a nitrogen atmosphere.

Add a 0.75 M solution of sodium borohydride (689 mg, 18.2 mmol) in absolute ethanol and the resulting mixture heated at 70°C for 6 hours. After cooling, add water (8 ml) and the resulting white precipitate is removed by filtration. The crude compound is purified using the cartridge SCX (strong cation exchange resin). Pure product is removed by elution with 3% solution of ammonia in methanol. Specified in the title compound (2.30 g) obtained after evaporation of the solution under vacuum to yield of 91.6%.

MS (ESI positive dispersion 3.5 kV; Skimmer 20 V; probe 250°C): 387,1 [MH+].

1NAMR (DMSO-d 6) δ: at 7.55 (DD, 1H), and 7.4 (m, 1H), 7,22 (m, 2H), 6,95 (m, 2H), 6,8 (DD, 1H), 5,1 (s, 2H, in), 3.75 (s, 3H), and 3.6 (s, 2H), 3,2 (t, 4H), 2,4 (m, 2H), 2,18 (m, 2H), to 1.87 (m, 2H), 1.55V (m, 2H).

Example 4

4-(2-Forbindelse)for 3,5-dimethylbenzaldehyde

a 0.5 M solution of 1-methyl bromide-2-fervently (1.51 g, 8.0 mmol) in DMF is added dropwise to a suspension containing 1.1 g of 4-hydroxy-3,5-dimethylbenzaldehyde (7,3 mmol), 1.51 g K2CO3(11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml of DMF. The reaction is accompanied by the same procedure as described in example 3. The residue is purified on silica gel, obtaining quantitative yield specified in the title compound (1.88 g).

Example 5

4-(2-Forbindelse)-3-chlorobenzaldehyde

a 0.5 M solution of 1-methyl bromide-2-fervently (1.5 g, 8 mmol) in DMF is added dropwise to a suspension of 3-chloro-4-hydroxybenzaldehyde (1,14 g, 7,3 mmol), K2CO3(1.51 g, 11 mmol) and KI (120 mg, 0.73 mmol) in DMF (100 ml). The reaction mixture was stirred at 90°C during the night. After cooling, the solid residue is filtered off and the solvent is evaporated in vacuum. The residue is dissolved in ethyl acetate and the organic layer washed twice in 1 M NaOH, dried over Na2SO4and evaporated to dryness. The residue is purified on silica gel, receiving 1,91 g specified in the title compound, yield 100%.

Example 6

4-(2-Forbindelse)-3-methoxybenzaldehyde

a 0.5 M solution of 1-methyl bromide-2-fervently (1.5 mg, 8 mm is l) in DMF is added dropwise to a suspension of 3-methoxy-4-hydroxybenzaldehyde (1.1 g, 7,3 mmol), K2CO3(1.51 g, 11 mmol) and KI (120 mg, 7,3 mmol) in DMF (100 ml). The reaction mixture is treated as described in example 4. The residue is purified on silica gel, receiving 1,89 g (quantitative yield) specified in the title compound, yield 100%.

Example 7

In vitro binding3H-batrachotoxin on the membranes of the brainrat brain

Membrane preparations (P2 fraction).Male Wistar rats (Harlan, Italy-175-200 g) death under light anesthesia and the brain quickly removed and the cortex of the brain is cut off, homogenized in 10 volumes of ice 0.25 M sucrose buffer (50 mm Tris·HCl, pH 7,4). The crude homogenate was centrifuged at 3250 rpm for 10 min and the supernatant removed. The pellet homogenized and centrifuged again and the two supernatant is drained and centrifuged at-machine-Constitution 14750 rpm for 10 min, +4°C. the resulting pellet stored at -20°C until use.

The analysis of binding. The pellet re-suspended in 50 mm Hepes buffer, pH of 7.4, containing 0.8 mm MgSO4, 5.4 mm KCl, 5.5 mm glucose and 130 mm choline, using a transmitter station PT10. Analysis of the binding is carried out in final volume of 0.25 ml containing 50 μl of membrane preparation (200 μg protein), 50 μl of ligand3N-batrachotoxin (10 nm), 50 μl of TTX (1 μm), 50 μl of Scorpion toxin (37,5 mg/ml) and 50 μl of the test compounds or buffer or 300 μm veratridine, h is usually used to define nonspecific binding. Analysis of the binding is carried out at 37°C for 30 min and stop rapid vacuum filtration through filters made of glass fiber Whatman GF/b Filters (pre-soaked polyethylenimine 0,1%) was washed with 3×5 ml ice buffer and placed in picoampere containing scintillation cocktail (Filter Count, Packard). The bound radioactivity is measured liquid scintillation spectrometry at an efficiency of 45%.

Data analysis. IC50calculated from the curves of transferring a computer program LIGAND (McPherson, J. Pharmacol. Methods, 14, 213. 1985). Curves of the transfer receiving, using at least 9 concentrations, each in two copies, covering 100000-fold range.

Example 8

In vitro binding3H-nitrendipine on the membranes of rat brain

Membrane preparations.Male Wistar rats (Harlan, Italy - 175-200 g) death under light anesthesia and the brain quickly removed and the cortex of the brain is cut off, homogenized in 10 volumes of ice 50 mm Tris·HCl, pH 7,7 using transmitter station PT10. The crude homogenate was centrifuged at 50000×g for 10 min. and the Pellet homogenized and centrifuged twice in fresh buffer at 50000×g for 10 min, +4°C. the resulting pellet stored at -20°C until use.

The analysis of binding. The pellet re-suspended in 50 mm Tris·HCl, pH 7,7, using a transmitter station P10. Analysis of the binding is carried out in final volume of 1 ml, containing 900 μl of membrane preparation (about 700 μg of protein), 50 μl of3H-nitrendipine (0,15 nm) and 50 μl of the test compounds or buffer or 1 µm nifedipine, to determine the nonspecific binding. Analysis of the binding is carried out at 25°C for 45 min and stop rapid vacuum filtration through filters made of glass fiber Whatman GF/b Filters, washed with 3×5 ml ice buffer and placed in picoampere containing scintillation cocktail (Filter Count, Packard). The bound radioactivity is measured liquid scintillation spectrometry at an efficiency of 45%.

Data analysis. IC50calculated from the curves of transferring a computer program LIGAND (McPherson, J. Pharmacol. Methods, 14, 213. 1985). Curves of the transfer receiving, using at least 9 concentrations, each in two copies, covering 100000-fold range.

Example 9

Analysis of the inflow of calcium

Cells IMR32 human neuroblastoma have an integral channels and L-and N-type. In terms of differentiation IMR32 predominantly Express on the membrane surface calcium channels, N-type. The remaining calcium channels, L-type block using a selective blocker of L-type, nifedipine. In these experimental conditions, only the channels of the N-type can be found.

The cell is IMR32 subjected to differentiation, using 1 mm dibutyryl-camp and 2.5 μm bromosuccinimide, within 8 days (4 times) in a flask with a capacity of 225 cm3, then separated, seeded at 200,000 cells/well on 96-well plates, coated with polylysine, and additionally incubated for 18-24 h in the presence of buffer differentiation before using.

Use a test kit CA2+(molecular devices) based on the wavelength 485-535 nm fluorescent calcium indicator.

The differentiated cells are incubated with a saturating dye for 30 min at 37°C, then for the next 15 min add one or nifedipine (1 μm), or in the presence of ω-conotoxin or test compounds.

Fluorescence (485-535 nm) was measured using a tablet reader Victor (Perkin Elmer) before or after (30-40 c) automated injection of 100 mm KCl depolarizing solution.

Curves of inhibition calculated from 5 concentrations, each in triplicate, and the IC50determine, using linear regression analysis.

Preferred compounds of General formula I inhibit calcium channels, N-type with the value of the IC50less than 10 microns.

Example 10

Electrophysiological analysis

Experiments to determine the tonic block is performed on isolated Xenopus oocytes expressing the Na-channel Nav 1.3. Currents recorded using the method of fixation of n is two voltage electrodes (TEVC).

Preparation of oocytes:

Frog (Xenopus Laevis) anaesthetize in solution with complex ethyl ester, 3-aminobenzoic acid (1 g/l), after 25 minutes she laid on his back on the frozen bed." The skin and other tissues are cut, ovarian lobe extract and incubated in ND96⌀Ca2+(NaCl 96 mm, KCl 2 mm, MgCl21 mm, Hepes 10 mm, pH of 7.85 with NaOH).

After removal of the oocytes muscles and the skin stitched separately.

Ovarian fraction is crushed to clusters of 10/20 oocytes are placed in a test tube with a solution of collagenase (1 mg/ml) and kept in motion for about 1 h in the incubator.

At the end of this stage, when oocytes are well separated from each other, they are washed three times ND96⌀Ca2+and three times NDE (ND96⌀Ca2++CaCl20.9 mm, MgCl20.9 mm, 2.5 mm pyruvate, gentamicin 50 mg/l).

The retrieved oocytes are in various stages of development. Only cells at stages V or VI are selected for subsequent experiments with the introduction of RNA.

A day after cooking in oocytes injected (Drummond Nanoject) 20 ng Nav 1.3 cRNA and keep in NDE.

Starting from 48 h after injection of mRNA, complete cell currents recorded using dvuhmegapikselnoy automatic workstation commit voltage. Typical microelectrodes have a resistance of 0.5 to 1 Mω and filled with 3 M KCl

The control solution bath contains (mm): NaCl 98, MgCl21, CaCl2a 1.8, Hepes 5 (pH 7,6).

Connection th ovat in the mother solution (20 mm) and diluted to final concentrations in the external bath solution.

Registration currents:

First, examine the ratio of current/voltage (I/V) for currents Nav 1.3, expressed in oocytes to determine membrane (diffusion-adsorption) the potential of causing maximum activation. Nav 1.3 show the maximum activation at 0 mV, which is used as the test potential (Vtest) for studies of tonic block.

In steady-state inactivation properties of currents Nav 1.3 then examined to determine the membrane potential to the resting state (Vrest), in which the efficiency of the channel is the maximum (Imax), and the membrane potential for half-maximal inactivation (V 1/2), which produces half of the maximum current (I 1/2), respectively. These state of the two voltages is then used to assess potencialzawisimae tonic block.

In conclusion, the two-stage Protocol is used to determine potencialzawisimae unit Nav 1.3: oocytes fixed at -80 mV, the currents activate 100 MS step pulse to 0 mV (Vtest) 3000 MS preconditioning potential at -80 mV (at rest, the state of Imax) and -40 mV (depolarized, the state of I 1/2), respectively.

The amplitude of the currents in the two States recorded in the absence and presence of different concentrations of compounds (lavage make between them), so op is adelite concentration curves - inhibition and value of the IC50for tonic block in the depolarized (the presence of half of the maximum current) conditions.

Preferred compounds of General formula I inhibit sodium channels Nav 1.3 with the value of the IC50lower than the comparative sodium channel blocker ralfinamide.

Example 11

Test maximal electroshock in rats and mice

Rat Wistar get through inserted into the ears of the clamping electrodes electroshock (160 mA for 0.2 s with a sequence of pulses of 60 Hz, with pulse duration of 0.4 MS; EATS a single model 7801, Ugo Basile, Comerio, Italy), sufficient to produce the tonic response of the extensor hindquarters at least 97% of the control animals.

Mouse get the shock 28 mA for 0.7 s with a sequence of pulses 80 Hz, with a pulse duration of 0.4 MS. Different doses of the test compounds and standard AED administered to groups of 10-20 mice or rats at a dose volume of 0.5 ml/kg for 60 minutes r.o. or 30 min I.P. Pavlova. to induce MES to calculate the value of the ED50. Complete suppression of the tonic component of the hind limb extensor seizures take as a sign of anticonvulsant activity.

Example 12

Formalin test in mice

According to the modified Protocol from Rosland and others (1990) mice injected p is dcone (s.c.) 20 ml of a 2.7% solution of formalin in the surface of the sole of the left hind paws and immediately placed in a clear PVC surveillance cameras (23×12×13 cm). Pain behavior is quantitatively evaluated by calculating the total number of oblizyvanie feet, in which an injection was used. Measurements carried out during the early phase (0-5 min) and late phase (30-40 min) after formalin injection (Tjolsen and others 1992).

The test compound is administered r.o. for 15 min before formalin injection in a volume of 10 ml/kg body weight in groups of 10 mice per dose. The control group is treated by the media.

Example 13

Karragenana model of inflammation

Using male Wistar rats weighing 175-200 g

In the left hind paw injected 100 μl of carrageenan (2% wt./about. in physiological solution). Compounds according to the invention (30 mg/kg), indomethacin (5 mg/kg) or control media (such as distilled water) was administered orally 1 h before the injection of carrageenan. The volume of paw was measured by plethysmometer (Ugo Basile) immediately before injection (primary) and after 1, 2, 3, 4 and 5 hours after injection of carrageenan.

1. The compound of the formula I

where a represents a linear or branched C2-C3alkyl;
X represents oxygen;
R1represents a linear or branched C1-C8alkyl, optionally substituted phenyl, phenoxy or naphthyl; or benzyl, optionally substituted on the phenyl ring by one or more substituents selected and is halogen, With1-C4of alkyl, trifloromethyl,1-C4alkoxygroup;
R2, R3independently represent hydrogen, C1-C3alkyl, halogen or C1-C4alkoxygroup;
R4represents hydrogen or methyl;
R5represents hydrogen;
R6represents a linear or branched C1-C6alkyl or associated with R5forms a ring pyrrolidin-2-it;
and their pharmaceutically acceptable salts,
provided that when a represents-CH2CH2-, R1-X - 4-methoxy, R2- 2-methoxy,
R3and R5is hydrogen and R6is methyl, R4is other than hydrogen, and when a represents-CH2CH2-, R1-X - 3-methoxy, R2- 5-methoxy, R3and R5is hydrogen and R6is methyl, R4is other than hydrogen.

2. The compound of General formula I according to claim 1, where a represents ethylene or propylene, X is oxygen, R1means C1-C8alkyl, optionally substituted phenyl or fenoxaprop; or benzyl, optionally substituted on the phenyl ring by fluorine, chlorine, R2and R3represent hydrogen, methyl, methoxy, fluorine, chlorine or bromine, R4represents hydrogen or methyl, R5is hydrogen, R6represents methyl or ethyl, or being associated with R5forms pyrrolidin-2-it.

3. With the Association according to claim 1, selected from the group consisting of the following members:
N-2-(4-butylenediamine)ethylacetamide;
N-2-(4-pentyloxybenzaldehyde)ethylacetamide;
N-2-(2-benzyloxyaniline)ethylacetamide;
N-2-(3-benzyloxyaniline)ethylacetamide;
N-2-(4-benzyloxyaniline)ethylacetamide;
N-2-[4-(5-phenylmethoxy)benzoylamino]ethylacetamide;
N-{2-[2-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;
N-{2-[3-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)benzylamino]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-2-methoxybenzylamine]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-2-methylbenzylamino]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-3-forbindelsen]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-3-chlorobenzylamino]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-3-methoxybenzylamine]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-3-methylbenzylamino]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]ethyl}ndimethylacetamide;
N-{2-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]ethyl}ndimethylacetamide;
N-3-(4-pentyloxybenzaldehyde)propylacetamide;
N-3-(4-benzyloxyaniline)propylacetamide;
N-3-[4-(5-phenylmethoxy)benzoylamino]propylacetamide;
N-{3-[4-(2-forbindelse)-2-methoxybenzylamine]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)-2-methylbenzylamino]propyl}ndimethylacetamide;
N-{3-[4-(2-f is urbaniacs)-3-forbindelsen]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)-3-chlorobenzylamino]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)-3-methoxybenzylamine]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)-3-methylbenzylamino]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]propyl}ndimethylacetamide;
N-{3-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]propyl}ndimethylacetamide;
1-[2-(4-butylenediamine)ethyl]pyrrolidin-2-he;
1-[2-(4-pentyloxybenzaldehyde)ethyl]pyrrolidin-2-he;
1-[2-(2-benzyloxycarbonylamino)ethyl]pyrrolidin-2-he;
1-[2-(3-benzyloxycarbonylamino)ethyl]pyrrolidin-2-he;
1-[2-(4-benzyloxyaniline)ethyl]pyrrolidin-2-he;
1-{2-[4-(5-phenylmethoxy)benzoylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-phenoxyethoxy)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(naphthalene-1-ylethoxy)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[2-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[3-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(3-forbindelse)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(4-tert-butylbenzoate)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(4-triftormetilfosfinov)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2,6-DICHLOROSILANE)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(3,5-dimethoxybenzoate)benzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-2-methoxybenzylamine]ethyl}pyrrolidin-he;
1-{2-[4-(2-forbindelse)-2-methylbenzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-3-forbindelsen]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-3-methoxybenzylamine]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-3-methylbenzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-3-chlorobenzylamino]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]ethyl}pyrrolidin-2-he;
1-{2-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]ethyl}pyrrolidin-2-he;
1-[3-(4-pentyloxybenzaldehyde)propyl]pyrrolidin-2-he;
1-[3-(2-benzyloxycarbonylamino)propyl]pyrrolidin-2-he;
1-[3-(3-benzyloxycarbonylamino)propyl]pyrrolidin-2-he;
1-[3-(4-benzyloxyaniline)propyl]pyrrolidin-2-he;
1-{3-[4-(5-phenylmethoxy)benzoylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(2-phenoxyethoxy)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(naphthalene-1-ylethoxy)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(4-tert-butylbenzoate)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(4-triftormetilfosfinov)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(2,6-DICHLOROSILANE)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(3,5-dimethoxybenzoate)benzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-2-methoxybenzylamine]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-2-methylbenzyl is but]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-3-forbindelsen]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-3-methoxybenzylamine]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-3-methylbenzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-3-chlorobenzylamino]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)for 3,5-dimethoxyphenethylamine]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)for 3,5-dimethylbenzylamine]propyl}pyrrolidin-2-he;
1-{3-[4-(2-forbindelse)-3-bromo-5-methoxybenzylamine]propyl}pyrrolidin-2-he;
or their pharmaceutically acceptable salts.

4. The method of obtaining the compounds of formula I according to claim 1,

where a represents a linear or branched C2-C3alkyl;
X represents oxygen;
R1represents a linear or branched C1-C8alkyl, optionally substituted phenyl, phenoxy or naphthyl; or benzyl, optionally substituted on the phenyl ring by one or more substituents selected from halogen, C1-C4of alkyl, trifloromethyl,1-C4alkoxygroup;
R2, R3independently represent hydrogen, C1-C3alkyl, halogen or C1-C4alkoxygroup;
R4represents hydrogen or methyl,
R5represents hydrogen;
R6represents a linear or branched C1-C6and the keel or associated with R 5forms a ring pyrrolidin-2-it;
and its pharmaceutically acceptable salts, provided that
when a represents-CH2CH2-, R1-X - 4-methoxy, R2- 2-methoxy, R3and R5is hydrogen and R6is methyl, R4is other than hydrogen, and
when a represents-CH2CH2-, R1-X - 3-methoxy, R2- 5-methoxy, R3and R5is hydrogen and R6is methyl, R4is other than hydrogen,
including
the interaction of compounds of formula II

where R1, R2, R3and X have the above values,
with compounds of formula III in the presence of a reducing agent

where R4, R5, R6and have these values, obtaining thus the compounds of formula I and/or, if desired, converting the compounds according to the invention in its pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound.

5. Pharmaceutical composition having modulating activity against sodium and/or calcium channels containing an effective amount of the compounds of formula I according to claim 1 or its pharmaceutically acceptable salt in a mixture with a suitable carrier and/or diluent.

6. The compound of formula I according to claim 1 or its pharmaceutically acceptable salt for use in the operation of the active therapeutic substance, having modulating activity against sodium and/or calcium channels.

7. The use of the compounds of formula I according to claim 1 or its pharmaceutically acceptable salts for the preparation of drugs having modulating activity against sodium and/or calcium channels.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound (1S,4aR,5S,6R)-methyl- 5{2-[1-(2-amino-2-oxoethyl)-2-oxopyrrolidin-2-yl]ethyl}-1,4a,6-trimethyldecahydronaphthalene-1-carboxylate of formula (I) , having anticonvulsant and analgesic activity. The compound is obtained from plant material - needles or sap of Siberian cedar.

EFFECT: obtaining a novel compound with anticonvulsant and analgesic activity.

3 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-substituted (1S,4aR,5S)-methyl-5-[2-(2'-oxo-2',5'-dihydro-1H-pyrrol-3'-yl)ethyl]-1,4a-dimethyl-6-methylenedecahydronaphthalene-1-carboxylates of formula (I) having anticonvulsant activity. The compounds are obtained from plant material - needles or sap of Siberian cedar.

EFFECT: obtaining novel compounds with anticonvulsant activity.

2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

or

or to their pharmaceutically acceptable salts, where ring A, R2, R3, R4 and X are as defined in the description. The disclosed compounds are useful as 11βHSD1 inhibitor. The invention also relates to a pharmaceutical composition, an agent for treating or preventing pathology related to glucocorticoids, a 11βHSD1 inhibitor containing the disclosed compound or its pharmaceutically acceptable salt, and use of the disclosed compounds.

EFFECT: compounds are highly effective.

40 cl, 48 tbl, 191 ex

FIELD: chemistry.

SUBSTANCE: invention concerns levorotatory enantiomer for compound of the formula (B) and its pharmaceutically acceptable salts, where R1 is methyl, X is -COOMe; and levorotatory enantiomer for compound of the formula (B) and its pharmaceutically acceptable salts, where R1 is methyl, X is -COOEt. Additionally invention concerns methods of obtaining indicated enantiomers by asymmetrical hydration of respective source compounds in the form of Z and E isomers.

EFFECT: intermediary compounds for obtainment of levetiracetam medicine.

4 cl, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in novel derivatives of 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone of formula I , X represents O, R1 represents C1-C8alkyl, C3-C8cycloalkyl, C8-C16arylalkyl, C8-C16arylalkenyl, in which alkenyl fragment contains up to 5 carbon atoms, C4-C16cycloalkylalkyl, R2 represents C1-C4alkyl, unsubstituted or substituted with one or more halogens, R3 represents C3-C8cycloalkyl, C7-C16arylalkyl, substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, cyano or CF3, C3-C8alkoxyalkyl, -C(O)R4 or -CH2CONHR5; R4 represents C6-C14aryl, substituted with one or more substituents from halogen line, C1-C8alkoxy or nitro; R5 represents C6-C14aryl, unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, nitro or amino, heterocyclic group, saturated, partially saturated or fully unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, or additionally second atom is represented with heteroatom, selected from N, O and S, heterocyclic group is unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, or their combinations; or heterocyclylC1-C5alkyl, saturated, partially saturated or unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, O or S, and which is unsubstituted or substituted in heterocyclic fragment with C1-C8alkyl or C1-C8alkoxy group, and their physiologically acceptable salts, in each case compound can be in form of enantiomer mixture, such as racemate, or mixture of diastereomers, or can be in form of one enantiomer or one diastereomer; on condition that if R1 represents cyclopentyl and R2 represents methyl, R3 does not represent benzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl or 4-cyanobenzyl. Compounds I inhibit activity of PDE-4 enzyme, which allows using them in pharmaceutical compositions.

EFFECT: increase of composition and treatment method efficiency.

38 cl, 11 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to derivatives of 4-pyrrolidine phenyl benzole ether of formula where X-Y stands for -CH2-O-; R1, R1.1 and R1.2 independently on each other are selected from group, including H, haloid, haloid (C1-C6)alkyl, R21, R22 and R23 independently on each other stand for H; R24 stands for H; R3 stands for H; R4 stands for -CONHR5, -CN or -NHR6; R5 stands for H, (C1-C6)alkyl; R6 stands for -CO-H, -CO-(C1-C6)alkyl, -CO-NH2, -SO2-(C1-C6)alkyl; as well as its individual isomers and racemic and non-racemic mixtures. Compounds 1 inhibit monoaminooxidase B, which allows to apply them in pharmaceutical composition and for production of medications, intended for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

15 cl, 7 dwg, 21 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to novel pyrrolidone derivatives of formula I where Q stands for =N- or =C(R24)-; X-Y stands for -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 independent on each other stand for halogen, C1-C6alkyl, halogen(C1-C6)alkyl, cyano, C1-C6alkoxy, halogen(C1-C6)alkoxy; R21, R22 and R23 independent on each other stand for H and halogen; R24 stands for H, CH3, halogen; R3 stands for -C(O)N(H)CH3, -CH2CN; R4 stands for H; as well as its individual isomers, racemic or non-racemic mixtures of isomers. Compounds inhibit monoaminooxidase, which allows to use them in pharmaceutical compositions for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

19 cl, 5 dwg, 49 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidone of the formula (I): wherein Q means =N, =C(R24)-; X-Y means -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 are chosen independently from group comprising hydrogen atom (H), halogen atom, halogen-(C1-C6)-alkyl, -CN, (C1-C6)-alkoxy group; R21, R22 and R23 are chosen independently of one another from group comprising H, halogen atom; R24 means H; R3 means -NHR6; R4 means H; R6 means -C(O)H, -C(O)-(C1-C3)-alkyl, -C(O)-halogen-(C1-C3)-alkyl, -C(O)O-(C1-C3)-alkyl, -C(O)-NH2, -SO2-(C1-C3)-alkyl, and also its individual isomers, racemic and nonracemic mixtures. Proposed compounds inhibit activity of monoamine oxidase B that allows its using in prophylaxis and treatment of disease mediated by monoamine oxidase B inhibitor, in particular, Alzheimer's disease and senile feeble-mindedness.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

15 cl, 4 sch, 31 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of dodecanoic acid of formula where R- represents CI- in form of hydrates.

EFFECT: obtaining compounds, which have antiseptic properties and smaller toxicity than already known, for instance myramistine.

2 cl, 1 ex, 6 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound (1S,4aR,5S,6R)-methyl- 5{2-[1-(2-amino-2-oxoethyl)-2-oxopyrrolidin-2-yl]ethyl}-1,4a,6-trimethyldecahydronaphthalene-1-carboxylate of formula (I) , having anticonvulsant and analgesic activity. The compound is obtained from plant material - needles or sap of Siberian cedar.

EFFECT: obtaining a novel compound with anticonvulsant and analgesic activity.

3 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel N-substituted (1S,4aR,5S)-methyl-5-[2-(2'-oxo-2',5'-dihydro-1H-pyrrol-3'-yl)ethyl]-1,4a-dimethyl-6-methylenedecahydronaphthalene-1-carboxylates of formula (I) having anticonvulsant activity. The compounds are obtained from plant material - needles or sap of Siberian cedar.

EFFECT: obtaining novel compounds with anticonvulsant activity.

2 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to phenyl substituted pyrrolidones of formula: , where R1 and R5 represent substitutes, which are independently chosen from a group which contains H, CN, halogen, C1-C4alkyl and OR8, where R8 represents C1-C4alkyl, R2 and R4 represent substitutes, which are chosen from a group which contains H, halogen, CN and C1-C4alkyl, R3 represents H, R6 represents a condensed phenyl heterocyclic ring system, chosen from , where R16 represents a substitute, chosen from a group which contains H, C(O)NR18R19 and S(O)2R20, where R18 and R19 represent H or C1-C6alkyl; R20 represents C1-C6alkyl or phenyl; and R17 represents a substitute, which is chosen from a group which contains H, NH2, (CH2)mOH, C(O)NR21R22, SO2R23 and NHSO2R23; where R21 and R22 represent substitutes, which are independently chosen from a group which contains H and substituted or unsubstituted C1-C6alkyl, or, together with a nitrogen atom to which they are bonded, optionally form a ring; R23 represents C1-C6alkyl; and m equals 1; or R6 represents a group, where R9 and R11 represent substitutes, which are independently chosen from a group which contains H, halogen, CN, C(O)NR12R12, NR12R12 and OR12, where each R12 represents H or C1-C4alkyl, and under the condition that, at least one of substitutes R9 and R11 is not hydrogen; R10 represents CN, NR13R14, SO2NHR13, NHSO2R13, O(CH2)nSO2R15, SO2R15, SO2(CH2)nNR13R14 or C(O)NR13R14, where R13 and R14 represent H or C1-C4alkyl; R15 represents C1-C4alkyl, n equals 1-2, and R7 represents halogen, C1-C4alkyl, C2-C4alkenyl or C2-C4alkynyl.

EFFECT: design of compounds and a pharmaceutical composition for inhibiting HIV growth.

19 cl, 12 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: in formula (1) compound, cysteinprotease is cathepsin K, cathepsin S, cathepsin L or cathepsin B. In formula (I) R is , AA1 is a bond, AA2 is a bond, R7 and R8 each independently represents hydrogen, C1-8 alkyl, CycA or C1-8 alkyl, substituted CycA, R9 is hydrogen, values of the rest of the radicals are given in the formula of invention. The invention also relates to a pharmaceutical composition, containing a formula (I) compound as an active ingredient, to a cysteinprotease inhibitor, method of inhibiting cysteinprotease, use of formula (I) compound in obtaining cysteinprotease inhibitor.

EFFECT: compound has inhibitory activity towards cysteinprotease.

10 cl, 16 tbl, 8 dwg, 224 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, arthrology. Said therapy includes application of ointment on the joint area. The ointment contain includes Diclofenac, Lydasa, Indometacin, Cinnarizine, Allomaron, Baralgin, a Cerebrolysin, Nootropil, calendula extract, chestnut extract, Dalargin, Solbrol, Extrapone, Eftillinum, sulphidic silt mud in certain quantitative ratio. Ointment is kept for 20-30 minutes. Sessions are daily, once a day. Therapeutic course includes 10-12 procedures.

EFFECT: method improves clinical effectiveness ensured by improved absorbability of sulphide silt mud and other biologically active substances.

8 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely to neurology and can be used at treatment of chronic diseases of brain, in particular toxic encephalopathy. For this purpose transcranial electrical stimulation of a brain is performed; it is spent in two stages with 15-20 minutes duration of each stage; the first stage has average frequency of 77 Hz, the second stage has average frequency of 10 Hz. Pyracetam is administered intravenously 10-15 minutes prior to the beginning of electrical stimulation.

EFFECT: maintenance of effective treatment of an encephalopathy at the expense of intensifying tranquilizing and nootropic effect of the spent therapy.

1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition on the basis of a Vinpocetine and Pyracetamum combination in the form of a solution for injections possessing cerebrovasodilating and nootropic activity and the method of its reception are offered. The solution contains 0.1-0.5 wt % of Vinpocetinum and 5-40 wt % of Pyracetamum and auxiliary substances.

EFFECT: maintenance of more expressed synergy at treatment of the diseases bound to acute or chronic insufficiency of a cerebral circulation in a combination to stability of the form.

12 cl, 4 ex, 3 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: formulation contains N-carbamoyl-methyl-4-phenyl-2-pyrrolidone as active principle and solubilising neutral organic component selected from the group that comprises diamide of carbonic acid, and/or monosaccharides, and/or disaccharides, and/or polyatomic spirits or their homogeneous mixture, with mass relation of N-carbamoyl-methyl-4-phenyl-2-pyrrolidone and specified solubilising component 1:(0.15-5). Method for preparation of pharmaceutical formulation consists in the fact that formulation components are simultaneously and separately evaporated in depressurised gas medium, and produced vapors are cocondensated on the surface of sedimentation cooled down to negative temperature. The second version of method for preparation of pharmaceutical formulation consists in the fact that formulation components are previously dissolved in water, solution is frozen to the temperature of not higher than - 60°C, then frozen solution is sublimated in depressurised gas medium, and adsorbed water remainder is removed in prepared pharmaceutical formulation. Invention provides for preparation of water-soluble pharmaceutical formulation on the basis of N-carbamoyl-methyl-4-phenyl-2-pyrrolidone.

EFFECT: formulation is suitable for preparation of injection, suspension dosage forms.

3 cl, 8 dwg, 4 ex

Up!