Alpha-aminoamide derivatives used for treating lower urinary tract disorders

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to new and known α-aminoamides derived chemical class of blockers of sodium channels and their use for the treatment of disorders of the lower urinary tract and containing pharmaceutical compositions.

BACKGROUND of INVENTION

Disorders of the lower urinary tract (LUT), which from year to year affect the quality of life of millions of people around the world, include, without limitation overactive bladder (OAB), prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence.

OAB is the most common term currently used in clinical medicine to describe the set of symptoms in the lower urinary tract, accompanied or not accompanied by incontinence. Symptoms usually include urgent urge to urinate, frequent urination, nycturia, difficult or incomplete emptying and, occasionally, pain. Causes of overactive bladder include neurological disease or injury, syndrome infravesical obstruction, weakness of the external urethral sphincter, increased activity of the detrusor and reduced contractility in the elderly patient who, the risk of new reflexes emptying and the so-called idiopathic overactive bladder. Overactive bladder neurogenic nature caused neurological damage in such disorders as stroke, Parkinson's, diabetes, multiple sclerosis, peripheral neuropathy, or spinal cord injury. In contrast, OAB non-neurogenic nature may arise from violations of non-neurogenic nature, including stones in the bladder, muscle disease, urinary tract infections or side effects of drugs. OAB can be the result of hypersensitivity afferent neurons of the bladder as a result of various factors, including inflammatory conditions, hormonal imbalance and hypertrophy of the prostate gland.

Prostatitis is a term for inflammatory conditions of the prostate. It is believed that most cases of prostatitis is the result of a bacterial infection, but evidence of infection is not always detected. Infected or inflamed prostate gland may cause painful urination with severe difficulties. There are four types of prostatitis: acute bacterial prostatitis, XP is technical bacterial prostatitis, non-bacterial prostatitis and prostadynia, also called chronic pelvic pain syndrome, which is a condition associated with painful symptoms of chronic non-bacterial prostatitis without inflammation of the prostate gland.

Interstitial cystitis (IC) is a chronic inflammatory condition of the bladder that causes frequent, urgent and painful urination and discomfort in the pelvic area. Unlike ordinary cystitis (inflammation of the bladder caused by a bacterial infection) when IC bacterial agent is not found.

Benign prostatic hyperplasia (BPH) is a non-cancerous enlargement of the prostate gland, which is very common in men older than 40 years. The prostate gland grows in two different ways. One type of growth the cells to proliferate around the urethra, and at the second cells grow in the urethra and in the region of the outlet of the bladder. The specified second type of growth usually requires surgical intervention. Common symptoms of BPH include: blood in the urine, feeling of incomplete emptying of the bladder after urination, frequent urination, night floor is Uriah, persistent urge to urinate, incontinence. In severe cases of BPH another symptom is acute urine retention.

Function LUT is the accumulation and periodic elimination of urine. This requires a harmonious combination of reflexes and accumulation of urination, including the sympathetic and parasympathetic components of the autonomic nervous system and motor ways.

Urinary incontinence (UI) occurs when the urine does not remain in the lower urinary tract and is involuntary discharge of urine. There are 3 types of UI: acute, when the voltage and mixed type. It is believed that acute UI is due to an overactive bladder, while the UI when the voltage is due to the reduced resistance of the outlet of the urethra. UI mixed type includes both components. Symptoms are: frequent urination, urgent urination, nocturia, random urine. If conscious control of the parasympathetic reflex urination impaired, the increase of OAB symptoms and/or UI, creating a serious inconvenience in terms of health and social activity.

Drugs, suppressive reflex urination may be applicable for the treatment of OAB and UI. One of the goals when supression OAB are the primary affe entie neurons and their peripheral nerve endings in the bladder. It is expected that a therapeutic agent that cupressinum the initiation and/or propagation of action potential in primary afferent neurons through modulation of ion channels, increase the volume threshold activation of reflex voiding, and therefore reduce the hyperactivity of the bladder and persistent urge to urinate.

The currently used methods of treatment of OAB include antimuskarinovoe act occurs medicines, diet changes, exercise program bladder, electrical stimulation and surgery.

Currently there is no established treatments of prostatitis and prostadynia. Usually prescribed antibiotics, COX-2 inhibitors and α-adrenergic blockers, but their effectiveness has not been proven.

Methods of treatment of IC, which include the introduction of antihistamine drugs, pentosanpolysulfate sodium, dimethyl sulfoxide, steroids, tricyclic antidepressants and narcotic antagonists, as a rule, are ineffective.

Non-invasive ways to treat BPH include androgen deprivation therapy and the use of inhibitors of 5α-reductase inhibitors and α-adrenergic blockers with minimum efficiency.

Due to the fact that existing methods of treatment and treatment of disorders of the LUT associated with the limitations described above and, there is a need for new methods of therapy and treatment.

However, despite the large number of acceptable therapeutic agents, their use suffers from limited efficacy and side effects such as dry mouth, dry eyes, vaginal dryness, heart palpitations, irregular heartbeat, drowsiness, confusion, especially in elderly, and constipation, which are difficult tolerability.

Due to the fact that expressing the sodium channels sensitive afferent neurons hypersensibility when dysfunction of the bladder, it is reasonable to assume that blocking the activity of sodium channels may represent a new strategy in the treatment of disorders of the lower urinary tract.

The present invention relates to a rapid and highly effective methods for treating a number of disorders of the lower urinary tract using in vivo of some α-aminoamide compounds of the present invention for therapy as an alternative to current treatment methods.

In documents WO90/14334, WO94/22808, WO97/05102, WO97/0511 and WO99/35125, the contents of which are incorporated into this document by reference, discloses substituted benzylaminopurine compounds that are active in the Central nervous system and is applicable as an antiepileptic, protopectin onionskin, neuroprotective, antidepressant and protivoastmaticheskih hypnotics (see also Pevarello, P. et al. (1998), "Synthesis and anticonvulsant activity of a new class of 2-[(arylalkyl)amino]alkanamide derivatives", J. Med. Chemistry, 41:579-590). In the document WO99/35125 and WO99/35123 disclosed substituted benzylaminopurine compounds that are active in the Central nervous system and applicable as anesthetics (see also Veneroni O. et al. (2003) "Anti-allodynic effect of NW-1029, a novel Na+channel blocker, in experimental animal models of inflammatory and neuropathic pain", Pain 102 (1-2):17-25).

DETAILED description of the INVENTION

The present invention relates to the use of compounds of formula I to obtain drugs for treatment of disorders of the lower urinary tract. Compounds of the present invention are α-aminoamide derivatives of the formula (I):

in which:

R represents foreline, thienyl or peregrinae ring or a phenyl ring, optionally substituted by one or two substituents, independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifloromethyl;

R1represents hydrogen or C1-C6-alkyl or C3-C7-cycloalkyl;

R2and R3independently selected from hydrogen, C1-C4the alkyl, optional for EDINOGO hydroxy or phenyl, phenyl, phenyl ring, optionally substituted by one or two substituents, independently selected from C1-C6-alkyl, halogen, hydroxy, C1-C6-alkoxy or triptoreline; or R2and R3form together with the carbon atom to which they are attached, a C3-C6-cycloalkyl ring;

R4and R5independently represent hydrogen, C1-C6-alkyl or C3-C7-cycloalkyl; or R4and R5form together with the nitrogen atom to which they are attached, a 5-7 membered saturated heterocyclic ring;

X represents CH2, O, S;

Y and Z represent hydrogen or together form a 5-7 membered saturated or unsaturated carbocycle or heterocycle

or their isomers, mixtures and pharmaceutically acceptable salts.

Alkyl and alkoxygroup can be branched or unbranched.

Pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid additive salts with inorganic acids, e.g. nitric, hydrochloric, Hydrobromic, sulfuric and phosphoric acids, and the like, or with organic acids, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, tartaric, citric, succinic, benzoic, cinnamic, almond, methane is AlfaNova, pair-toluensulfonate and salicylic acids, and the like.

Some of the compounds of formula I contain asymmetric carbon atoms and can therefore exist in the form of racemic mixtures or individual optical isomers (enantiomers). Accordingly, the term "pharmaceutically acceptable salt" α-aminoamide formula (I) is also intended for inclusion in the scope of the present invention all possible isomers and their mixtures, and any pharmaceutically acceptable metabolite, biological predecessor and/or prodrugs, i.e. a compound which has a structural formula different from the one of the α-aminoamide formula (I) and when administered to a mammal, particularly a human, directly or indirectly converted in vivo into a compound of formula (I).

X and Y are preferably mutually located in the meta - or para-position.

The compounds of formula (I)in which Y forms together with Z dihydrobenzofuranyl or dihydrobenzofuranyl, or dihydrobenzo(thio)peranovic, or tetrahydrobenzo(thio)occupiedby the heterocycle are new and constitute a further object of the present invention.

Preferably, in the compound of formula I

R represents a phenyl ring, optionally substituted by one or two substituents, independently selected from halogen, is of reformatie, methoxy or thienyl ring;

R1represents hydrogen or C1-C4-alkyl;

one of R2and R3represents hydrogen and the other represents C1-C4-alkyl, optionally substituted by hydroxy or phenyl, optionally substituted by one or two halogen atoms, or R2and R3both represent methyl, or form together with the atom to which they are attached, cyclopropyl or cyclopentene ring; and

R4and R5represent hydrogen or C1-C4-alkyl, or form together with the nitrogen atom to which they are attached, pyrolidine or piperidino ring, and their pharmaceutically acceptable salts.

Examples of compounds for use in accordance with the present invention include:

2-(4-venetiancasino)propanamide;

2-(4-benzyloxyaniline)propanamide;

2-(3-benzyloxyaniline)propanamide;

2-(4-benzyldimethylamine)propanamide;

2-(4-benzyloxybenzyl)-3-N,N-dimethylbutyramide;

2-[4-(2-methoxybenzyloxy)benzylamino]propanamide;

2-[4-(2-forbindelse)benzylamino]propanamide;

2-[3-(2-forbindelse)benzylamino]propanamide;

2-[4-(2-forbindelse)benzylamino]propanamide;

2-[4-(2-forbindelse)benzylamino]-2-methylpropanamide;

2-[4-(2-forbindelse)benzylamino]-N-meth is propanamide;

2-[3-(3-forbindelse)benzylamino]propanamide;

2-[4-(3-forbindelse)benzylamino]propanamide;

2-[4-(3-methoxybenzyloxy)benzylamino]propanamide;

2-[4-(3-cyanobenzyl)benzylamino]propanamide;

2-[4-(3-forbindelse)benzylamino]propanamide;

2-[4-(3-forbindelse)benzylamino]-2-methylpropanamide;

2-[4-(3-forbindelse)benzylamino]-N-methylpropanamide;

2-[4-(4-forbindelse)benzylamino]propanamide;

2-[4-(3-forbindelse)benzylamino]-2-methylpropanamide;

2-[4-(2-chlorobenzoyloxy)benzylamino]propanamide;

2-[4-(3-chlorobenzoyloxy)benzylamino]propanamide;

2-(4-benzyloxybenzyl)-3-hydroxypropanoic;

2-[4-(2-forbindelse)benzylamino]-3-hydroxypropanoic;

2-[4-(3-forbindelse)benzylamino]-3-hydroxypropanoic;

2-(4-benzyloxybenzyl)-3-hydroxy-N-methylpropanamide;

2-[4-(2-forbindelse)benzylamino]-3-hydroxy-N-methylpropanamide;

2-[4-(3-forbindelse)benzylamino]-3-hydroxy-N-methylpropanamide;

2-[4-(2-chlorobenzoyloxy)benzylamino]-3-hydroxy-N-methylpropanamide;

2-[4-(3-cyanobenzyl)benzylamino]-3-hydroxy-N-methylpropanamide;

2-[4-(3-cyanobenzyl)benzylamino]-2-methyl-3-hydroxy-N-methylpropanamide;

2-[4-(3-chlorobenzoyloxy)phenylethylamine]propanamide;

2-{4-[2-(3-forfinal)ethyloxy]benzylamino}propanamide;

2-{4-[2-(3-forfinal)ethyl]benzylamino}propanamide;

2-[N-(4-Ben is eloxiertes)-N-methylamino]propanamide;

2-{4-[(3-chlorobenzoyloxy)phenylethyl]amino}propanamide;

2-[4-benzyldimethylamine]propanamide;

2-[4-(2-forbesii)benzylamino]propanamide;

2-[4-(3-forbesii)benzylamino]propanamide;

2-[4-(3-phenylpropoxy)benzylamino]propanamide;

2-[4-(4-phenylbutyrate)benzylamino]propanamide;

2-[4-(5-phenylmethoxy)benzoylamino]propanamide;

2-(4-benzyloxybenzyl)-3-phenyl-N-methylpropanamide;

2-(4-benzyloxybenzyl)-3-hydroxy-N-methylbutane;

2-(4-benzyloxybenzyl)-3-methyl-N-methylbutane;

2-(4-benzyloxybenzyl)-2-phenylacetamide;

2-[4-(2-forbindelse)benzylamino]-2-phenylacetamide;

2-[4-(3-forbindelse)benzylamino]-2-phenylacetamide;

2-[4-(2-forbindelse)benzyl-N-methylamino]-2-phenylacetamide;

2-[4-(3-forbindelse)benzyl-N-methylamino]-2-phenylacetamide;

2-[4-(3-chlorobenzoyloxy)benzylamino]-2-phenylacetamide;

2-[4-(2-forbindelse)benzylamino]-2-(2-forfinal)ndimethylacetamide;

2-[4-(2-forbindelse)benzylamino]-2-(3-forfinal)ndimethylacetamide;

2-[4-(3-forbindelse)benzylamino]-2-(2-forfinal)ndimethylacetamide;

2-[4-(3-forbindelse)benzylamino]-2-(3-forfinal)ndimethylacetamide;

2-[4-(3-chlorobenzoyloxy)benzylamino]-2-(3-forfinal)ndimethylacetamide;

2-(4-(2-titilate)benzylamino)propanamide.

Examples of the new compounds of the formula (I) include:

2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide;

2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-chlorophenacyl)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethylamino}-N-methylpropanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-6-ylmethyl)amino]propanamide;

2-[(4-phenethyl-2,3-dihydrobenzofuran-7-ylmethyl)amino]propanamide;

2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-torfin the Teal)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino-N-methylpropanamide

or their isomers, mixtures and pharmaceutically acceptable salts.

Preferred compounds of formula (I), which can be used separately or in combination with other compounds of formula (I)are

(S)-(+)-2-[3-(2-forbindelse)benzylamino]propanamide, (S)-(+)-2-[4-(2-forbindelse)benzylamino]propanamide (NW-1029), (S)-(+)-2-[4-(2-forbindelse)benzylamino]-N-methylpropanamide, (S)-(+)-2-[3-(3-forbindelse)benzylamino]propanamide, (S)-(+)-2-[4-(3-forbindelse)benzylamino]propanamide, (R)-2-(4-benzyloxybenzyl)-3-phenyl-N-methylpropanamide; (2R,3S)-2-(4-benzyloxybenzyl)-3-hydroxy-N-methylbutanoate; (S)-(+)-2-[4-(3-forbindelse)benzylamino]-N-methylpropanamide, (S)-(+)-2-(4-venetiancasino)propanamide, (R)-(-)-2-(4-benzyloxybenzyl)-3-N,N-dimethylbutyramide, (S)-(+)-2-(4-benzyldimethylamine)propanamide, and 2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide and (2R/3'S,R)-2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide, 2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide, 2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide, (2R/3'S,R)-2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide, (2R/3'S,R)-2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide.

Getting known is those compounds of formula I disclosed in WO90/14334, WO94/22808, WO97/05102, WO97/0511, WO99/35125 and WO99/35123.

The new compounds may be obtained by interaction of ester 4-hydroxy-3-iodobenzoic acid with the appropriate substituted 4-phenylbut-2-enivroment or amylcinnamaldehyde in the presence of bases (e.g., NaH) and a suitable catalyst such as a crown ether. The obtained esters of 3-iodine-4-{[(2E)-4-phenylbut-2-enyl]oxy}benzoate or 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate is then converted into the corresponding 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxylates or 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylates by ring closure in the presence of AIBN and anti-hydride. By restoring the known methods 5-carboxylate groups of up to 5-hydroxymethylene groups with subsequent oxidation to 5-carboxyaldehyde groups received intermediate compounds, which were subjected to reductive aminating an amine of the formula with other1-CR2R3CONR4R5where the values of R1-R5defined above, to obtain the required benzofuran derivatives. Appropriate benzothiophene derivatives can be obtained in a similar way, using as starting compounds are esters of 4-mercapto-3-iodobenzoic acid.

In one embodiment, receiving treatment, the patient represents lecapitaine, including man, in need of mitigation, prevention, or inhibition of symptoms of disorders of the lower urinary tract.

In particular, the needy in the above-mentioned treatment of the mammal is administered a specific higher α-aminoamide formula (I) in the dose, which is in the range of approximately 0.3 to approximately 100 mg/kg of body weight per day. Used in this document, the term "treatment" includes any procedures or applications in respect of a mammal, in particular humans, which is intended for a) preventing the onset of diseases or disorders in a subject having a predisposition to develop the disease/disorder, but do not have a diagnosis of the disease/disorder; (b) inhibiting the disease/disorder or condition, i.e., the cessation of its development; or (c) mitigation of the disease/disorder or condition, i.e., the induction of regression of the disease/disorder or condition.

Thus, disorders of the lower urinary tract in a mammal, including humans, can be ingibirovany, mitigated or prevented. Examples of disorders of the lower urinary tract in mammals that can be treated by introducing one or more α-aminoamide compounds of formula (I)include, without limitation: hyperactive is Ochiai bladder (OAB), prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence. In another aspect, the present invention relates to α-aminoamide formula (I)entered as the active ingredient, the pharmaceutically acceptable compositions effective for disorders of the lower urinary tract, which can be prepared by means known in the art of traditional methods, for example, by mixing the active ingredient with pharmaceutically acceptable, therapeutically neutral organic and/or inorganic carriers or fillers.

The term "combination therapy" (or "concomitant therapy") includes the introduction of α-aminoamides the compounds of formula (I) according to the present invention and at least a second agent as part of a specific treatment program designed to provide a positive effect from the combined action of these therapeutic agents. The advantages of such combinations include reducing the dose traditionally used therapeutic agents (i.e. funds excluding funds of the present invention) with the consequential reduction of side effects such traditionally used resources. The positive effect of the combination include but are not limited pharmacokinetic or pharmacode amichelle the combined effect of the combination of therapeutic agents. Introduction the combination of these therapeutic agents is usually carried out within a certain period of time (depending on the selected combination, usually within minutes, hours, days or weeks). The term "combination therapy" may be, but, as a rule, is not intended to include the introduction of two or more of these therapeutic agents as part of separate modes of monotherapy, which are randomly and arbitrarily result in the combinations covered by the present invention. The term "combination therapy" is intended to include the serial input of the above mentioned therapeutic agents, that is, introduction, wherein each therapeutic agent is administered at different times, and essentially simultaneous introduction of these therapeutic agents, or at least two of these therapeutic agents. Essentially simultaneous administration can be accomplished, for example, by the introduction of patient one capsule containing a constant ratio of each therapeutic agent, or several separate capsules for each of therapeutic agents. Sequential or substantially simultaneous introduction of each therapeutic agent can be any suitable way, including, without limitation, oral route, intravenous route, nutramigen path and direct absorption through mucous membrane tissues. A therapeutic agent can be administered in the same way or in different ways. For example, the first therapeutic agent from the selected combination can be administered by intravenous injection while the other therapeutic agent of the combination may be administered orally.

Alternatively, for example, all therapeutic agent can be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the injected therapeutic agent, is not precisely defined. The term "combination therapy" may also cover the introduction of the above-described therapeutic agents in combination with biologically active ingredients and non-drug treatments (such as surgery or radiation therapy). If combination therapy further includes a non-drug treatment, non-drug treatment can be carried out for any suitable period of time until achieved a positive effect from the combined action of the combination of therapeutic agents and non-drug treatment. For example, in suitable cases, the positive effect is still achieved when the infusion of therapeutic agents non-drug treatment is temporarily stopped, possibly for days or even n the week.

α-Aminoamide compositions of the present invention can be administered in the form of a number of forms, for example orally in the form of tablets, lozenges, capsules, tablets, sugar wafer or film-coated, liquid solutions, emulsions or suspensions; rectally in the form of suppositories; parenterally, e.g. by intramuscular or intravenous injection or infusion; and in the form of transdermal patch, ointment, emulsion, lotion, solution, gel, cream or nasal spray.

Suitable pharmaceutically acceptable therapeutically neutral organic and/or inorganic carriers or fillers, applicable for preparation of such compositions include, for example, water, gelatin, Arabic gum, lactose, starch, cellulose, magnesium stearate, talc, vegetable oils, cyclodextrins, polyalkylene glycols, and the like. α-Aminoamide compositions of formula (I) can be sterilized and may contain additional components that are well known to the person skilled in the art such as, for example, preservatives, stabilizing agents, wetting means and emulsifiers, for example, liquid paraffin, monooleate manned, salts for adjusting osmotic pressure, buffer mixtures, and the like.

In addition to the active ingredient in solid form for oral administration can in order to keep thinners, for example, lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium stearate or calcium and/or polyethylene glycols; binding agents, e.g. starches, Arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disintegrating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; hissing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, Polysorbate, laurylsulfate; and, in most cases, non-toxic and pharmaceutically inactive substances, used in pharmaceutical compositions. The pharmaceutical preparations can be prepared by any known method, for example by mixing, granulating, tabletting, sugar coating or coating film.

Compositions for oral administration include compositions with delayed release, which can be obtained by conventional methods, for example, by coating on tablets and granules Intercollege coverage.

Liquid dispersions for oral administration can consist, for example, syrups, emulsions and suspensions. Syrups can further comprise a carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suppositories in addition to the active ingredient may contain a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, surface-active ester of fatty acid and polyoxyethylenesorbitan or lecithin.

Compositions containing α-aminoamide formula (I), typically located in a unit dosage form containing, for example, from 20 to 7000 mg of active ingredient per unit dosage form. Receiving the appropriate medication is prescribed 1 or 2 or 3 times a day, depending on the speed of removing. Accordingly, the required dosage can be a single dose or can be divided into doses, administered with a suitable interval, the voltage is emer, 2-4 or more subdot in the day.

Pharmaceutical compositions containing α-aminoamide formula (I)may contain from about 20 to 7000 mg of the active ingredient in a unit dosage form, for example, in a capsule, tablet, powder mixture for the preparation of injections, measuring spoon, suppositories, and the like.

Optimal therapeutically effective dose can be easily determined by the expert in the art and can vary largely depending on the strength of the drug, route of administration and development of the exposed treatment of disorders of the lower urinary tract. In addition, factors associated with being treated the patients, such as age, weight, diet of the patient and the introduction can lead to the need for dose adjustment to a suitable therapeutically effective level.

There are many advantages associated with above defined applications and methods of the present invention, and they include the possibility of prevention and treatment of essentially all types of disorders of the lower urinary tract.

The effect is a specific example of the compounds of formula I, (S)-(+)-2-[4-(2-forbindelse)benzylamino]propanamide (NW-1029), a function of discharge was tested on rats with the use of models such as Acute irritation of the bladder in ssnoi acid" and "Irritation of the bladder derivative of cyclophosphamide (CYP)".

To measure the intervals between contractions (ICIs), which are a measure of bladder capacity, used cystometrogram with continuous filling (of 0.04 ml/min). For each animal was obtained characteristic curves for cumulative dose by intravenous injection of increasing doses of drugs.

Acute irritation of the bladder with acetic acid in rats

Method:

The experiment was carried out in adults shot female rats Sprague Dawley (170-200 g).

Through a midline abdominal incision, the catheter (PE-50) was inserted in the bladder through the arch of the bladder, and then measured intravesical pressure for tracking activity of the bladder in the process of its continuous filling of 0.15% solution of acetic acid. Before filling the bladder with a solution of acetic acid and after that processed NW-1029 rats was measured intervals between contractions (ICIs), the maximum pressure and the threshold pressure with reflex contraction of the bladder.

The results:

Continuous filling of the bladder with a solution of acetic acid irritates the bladder and reduces the value of the ICI have shot rats. Introduction NW-1029 (3, 10 and 30 mg/kg) leads to a significant reverse change from shot rats values ICI, reduced result is the introduction of acetic acid (Fig. 1).

The average irritation of the bladder with cyclophosphamide (CYP) in rats

Method:

The experiment was performed using adult generalizirovanny down and anesthetized female rats Sprague Dawley (170-200 g).

Chemical cystitis induced by the introduction of CYP, which has developed as a result of metabolism in acrolein, which is eliminated with urine stimulus. CYP (150 mg/kg) was administered intraperitoneally injected the day before the experiment.

NW-1029 was injected intravenously in the dose range from 0.1 to 10 mg/kg

The results:

Preprocessing CYP irritated bladder and frequent emptying with values ICI approximately 150-200 with between emptying. Intravenous NW-1029 in the dose range from 0.1 to 10 mg/kg significantly increased the value of ICI in generalizirovanny down and anesthetized rats (Fig. 2-3).

For a more complete explanation of the preferred embodiments of the present invention presents the following examples.

Example 1

2-[(3-Phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide

To a solution of the hydrochloride of N-methylalanine (0.50 g, 3.61 mmol) in methanol (10 ml) in the presence of molecular sieves (1,00 g) at room temperature was added cyanoborohydride sodium (0.36 g, 5,69 mmol) and a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxamide is Yes (0,90 g, 3.61 mmol) in methanol (10 ml). The reaction mixture was stirred in an argon atmosphere for 12 h and Then the solvent is evaporated in vacuum and the residue was purified by the method of flash chromatography on silica gel (elwira with ethyl acetate/methanol = 98/2) to obtain 0,93 g specified in the title compound (yield 77%).

1H-NMR (200 MHz, CDCl3); δ: of 1.30 (d, 3H, J=6.8 Hz); 1,76-2,19 (m, 2H); 2,64-2,87 (complex, 6H, J=7,7 Hz); 3,29 (square, 1H, J=7,0 Hz); 3,35-to 3.50 (m, 1H); 3,66 (s, 2H); 4,19-4.26 deaths (m, 1H); 4,57-of 4.66 (DD, 1H, J=9,2 Hz); 6,72 (d, 1H, J=8,2 Hz); 7,01-7,32 (complex, 7H).

13C-NMR (200 MHz, CDCl3); δ: 19,5; 25,9; 33,5; 36,6; 41,4; 52,3; 57,6; 77,0; 109,4; 124,4; 126,1; 128,4; 128,5; 130,8; 131,3; 141,4; 159,5; 175,0.

In a similar manner were also synthesized following connections:

2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(2-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-chlorophenacyl)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-6-ylmethyl)amino]propanamide;

2-[(4-phenethyl-2,3-dihydrobenzofuran-7-ylmethyl)amino]propanamide;

2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-perfe is ethyl)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-florfenicol)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide.

EXAMPLE 2

2-[(3-Benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide

To a solution of hydrochloride of (S)-N-methylalanine (0.50 g, 3.6 mmol) in methanol (10 ml) in the presence of molecular sieves (1,00 g) at room temperature was added cyanoborohydride sodium (0,44 g, 6,9 mmol) and a solution of 3-benzyl-2,3-dihydro-1-benzofuran-5-carbaldehyde (0.75 g, 3.6 mmol) in methanol (10 ml). The reaction mixture was stirred in an argon atmosphere for 12 h and Then the solvent is evaporated in vacuum and the residue was purified by the method of flash chromatography on silica gel (elwira-ethyl acetate) to obtain 0,58 g specified in the title compound (yield 50%).

1H-NMR (400 MHz, CDCl3); δ: of 1.32 (d, 3H, J=6.9 Hz); and 2.83-2.91 in (m, 4H); 3,05 (DD, J=2,4, 6.5 Hz, 1H); 3,26 (square, 1H, J=7,0 Hz); 3,62 (s, 2H); to 3.73 is 3.76 (m, 1H); 4,32 (DD, 1H, J=5,7, 8,9 Hz); 4,55 (t, 1H, J=9.0 Hz); 6,76 (d, 1H, J=8.1 Hz); 6,86 (user. s, 1H), 7,07 (d, 1H, J=8,1 Hz); 7,27 was 7.36 (m, 5H).

13C-NMR (400 MHz, CDCl3); δ: 19,72; 25,84; 41,04; 43,39; 52,29; 57,55; 109,42; 124,49; 126,51; 128,35; 128,53; 129,05; 130,68; 131,16; 139,06; 159,36; 175,37.

2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

<> 2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)-N-methylpropanamide;

2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]propanamide;

2-{3-[2-(2-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide;

2-{3-[2-(3-terbisil)]-2,3-dihydrobenzofuran-5-ylmethyl}amino)propanamide.

Examples 3-6: the production of intermediate products

Example 3

3-(2-Phenylethyl)-2,3-dihydro-1-benzofuran-5-carbaldehyde

To a suspension of PCC (3,69 g, 17,10 mmol) in methylene chloride (20 ml) at room temperature was added a solution of 3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-ylmethanol (of 3.32 g, 13,16 mmol) in methylene chloride (100 ml). After stirring for 12 h was added diethyl ether (300 ml), precipitated precipitated black solid was filtered and washed several times with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by the method of flash chromatography on silica gel (elwira petroleum ether/ethyl acetate = 95/5-9/1) to obtain the 0,202 g specified in the title compound (yield 67%).

1H-NMR (200 MHz, CDCl3); δ: 1,85-2,19 (m, 2H); 2,70 (DD, 2H, J=7.8 Hz); 3,44 of 3.56 (m, 1H); to 4.33 (DD, 1H, J=6,6, 9,2 Hz); 4.72 in (DD, 1H, J=9,2 Hz); 6,86 (d, 1H, J=8,2 Hz); 7,10-7,34 (m, 5H); 7,63-of 7.69 (m, 2H); 7,72-7,73 (m, 1H); 9,82 (s, 1H).

Similarly, using as starting compound 3-benzyl-2,3-d is hydro-1-benzofuran-5-ylmethanol, received 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxaldehyde with the release of 85%.

1H-NMR (200 MHz, CDCl3); δ: 1,17 (t, 3H, J=7,1 Hz); 2,77 (DD, 1H, J=13,8, and 9.4 Hz); 3,01 (DD, 1H, J=13,9 and 5.9 Hz); 3,68 of 3.75 (m, 1H); 4,32 (DD, J=9,1, 5,9 Hz, 1H); 4,56 (t, J=9.1 Hz, 2H); is 6.78 (d, 1H, J=8,3 Hz); 7,07-of 7.24 (m, 5H); 7,45 (user. s, 1H), to 7.61 (DD, 1H, J=8,1, 1.5 Hz); 9,71 (s, 1H).

Example 4

3-(2-Phenylethyl)-2,3-dihydro-1-benzofuran-5-ylmethanol

To a solution of ethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxylate (4,78 g, only 1,613 Torino mmol) in toluene (160 ml) at -30°C was added 1,5M solution of DIBAL in toluene (24 ml, 35,48 mmol). The reaction mixture was stirred in argon atmosphere at the same temperature for 30 minutes. Then added 3 N. HCl (100 ml) and separated the organic layer. The aqueous layer was extracted with ethyl acetate (3×50 ml), the collected organic layers were washed with saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was removed using a rotary evaporator. The crude product (of 4.05 g, yield 99%) was used at the previous stage without any further purification.

1H-NMR (200 MHz, CDCl3); δ: 1,66 (user. s, 1H); 1,75-of 2.21 (m, 2H); 2,70 (DD, 2H, J=7,6 Hz); 3,37-3,51 (m, 1H); to 4.23 (DD, 1H, J=6,6, and 9.0 Hz); 4,58 (s, 2H); 4.63 to (DD, 1H, J=8,8 Hz); 6,74 (d, 1H, J=8,2 Hz); 7,07-7,33 (m, 7H).

13C-NMR (200 MHz, CDCl3); δ: 33,4; 36,5; 41,4; 65,4; 77,0; 109,4; 123,7; 126,1; 127,7; 128,3; 128,5; 131,2; 131,1; 141,4; 159,7.

Similarly, using as starting compounds is of ethyl-3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate, received 3-benzyl-2,3-dihydro-1-benzofuran-5-ylmethanol with the release of 62%.

1H-NMR (200 MHz, CDCl3); δ: of 1.18 (t, 3H, J=7.2 Hz); is 2.74 (DD, 1H, J=13,8, and 9.3 Hz); 3,00 (DD, 1H, J=13,8, 6,1 Hz); 3,61-3,70 (m, 1H); is 4.21 (DD, 1H, J=8,9 and 5.9 Hz); 4,50 (m, 3H); of 6.68 (d, 1H, J=8,1 Hz); 6,93 (d, J=0.5 Hz, 1H); 7,01-from 7.24 (m, 6H).

Example 5

Ethyl-3-(2-phenylethyl)-2,3-dihydro-1-benzofuran-5-carboxylate

To a solution of ethyl-3-iodide-4-{[(2E)-4-phenylbut-2-enyl]oxy}benzoate (13,42 g, 31,73 mmol) and AIBN (0.52 g, 3,17 mmol) in benzene (900 ml) at room temperature was added the anti-hydride (12 ml, 44,43 mol) and heated the reaction mixture under reflux. After 2 h the solvent was removed in vacuum. The residue was purified by the method of flash chromatography on silica gel (elwira petroleum ether/ethyl acetate = 95/5) to obtain 9,14 g specified in the title compound (yield 97%).

1H-NMR (200 MHz, CDCl3); δ: of 1.36 (t, 3H, J=7.5 Hz); 1,80-of 2.26 (m, 2H); to 2.67 (DD, 2H, J=7.8 Hz); 3,39-of 3.54 (m, 1H); 4,27-4,34 (m, 3H); 4,69 (DD, 1H, J=9.0 Hz); 6,77 (d, 1H, J=7.4 Hz); 7,16-to 7.32 (m, 5H); a 7.85-of 7.90 (m, 2H).

13C-NMR (200 MHz, CDCl3); δ: 14,4; 33,3; 36,6; 40,8; 60,6; 77,7; 109,2; 123,7; 126,1; 128,4; 128,5; 131,2; 141,2; 163,1; 166,5.

Similarly, using as starting compound ethyl-3-iodide-4-[(2E)-3-phenylprop-2-enyl)oxy]benzoate, obtained ethyl-3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate with a yield of 90%.

1H-NMR (200 MHz, CDCl3); δ: of 1.27 (t, 3H, J=7,1 Hz); is 2.74 (DD, 1H, J=13,8, and 9.4 Hz); 3,03 (DD, 1H, J=13,9 and 5.9 Hz); 3,65-to 3.73 (m, 3H); 4,18-4,32 (m, H); 4,50 (t, J=9.1 Hz, 2H); 6,70 (d, 1H, J=8,3 Hz); 7,07-of 7.24 (m, 5H); 7,63 (user. s, 1H), 7,81 (DD, 1H, J=8,1, 1.5 Hz).

Example 6

Ethyl-3-iodide-4-{[(2E)-4-phenylbut-2-enyl]oxy}benzoate

To a suspension of NaH (0,82 g of 20.5 mmol) in THF (40 ml) at 0°C was sequentially added a solution of ethyl-4-hydroxy-3-iodobenzoate (5.0 g, 17,1 mmol) in THF (40 ml), then 15-crown-5 (4,0 ml, 25.6 mmol), and finally a solution of 4-phenylbut-2-arilbred (5,41 g, 25.6 mmol) in THF (50 ml). The reaction mixture was stirred at room temperature for 10 minutes and then was heated to 50°C within 6 hours After bringing to an equilibrium state at room temperature was added 3 N. HCl (30 ml) and poured the mixture into a separating funnel. Separated the organic layer and extracted the aqueous layer with ethyl acetate (3×30 ml). The collected organic layers were washed with saturated aqueous solution of sodium sulfate and dried over sodium sulfate. The solvent was removed using a rotary evaporator. The residue was purified by the method of flash chromatography on silica gel (elwira petroleum ether/ethyl acetate = 95/5) to obtain the 5,94 g specified in the title compound (yield 82%).

1H-NMR (200 MHz, CDCl3); δ: of 1.36 (t, 3H, J=7.2 Hz); 3.43 points (d, 2H, J=6.6 Hz); 4,33 (square, 2H, J=7.2 Hz); br4.61 (DD, 2H, J=1,2, 5,6 Hz); 5,67-x 6.15 (m, 2H); is 6.78 (d, 1H, J=8.6 Hz); 7,15-7,30 (m, 5H); of 7.96 (DD, 1H, J=2,0, 8.6 Hz); 8,44 (d, 1H, J=2.0 Hz).

13C-NMR (200 MHz, CDCl3); δ: 14,4; 38,7; 61,0; 69,6; 111,3; 125,1; 126,3; 128,5; 131,4; 134,1; 141,0.

Similar is cnym way using as a starting compound, ethylcinnamate received ethyl-3-iodide-4-{[(2E)-3-phenylprop-2-enyl]oxy}benzoate with a yield of 72%.

1H-NMR (200 MHz, CDCl3); δ: of 1.28 (t, 3H, J=7,1 Hz); 4,24 (square, 2H, J=7,1 Hz); 4,69 (DD, 2H, J=1,5-a 5.4 Hz); 6,24 to 6.35 (m, 1H), 6,68-6,76 (m, 2H); 7,16-7,34 (m, 5H); of 7.90 (DD, 1H, J=2,0, 8.6 Hz); scored 8.38 (d, 1H, J=1.8 Hz).

1. Applying at least one therapeutic agent, representing the α-aminoamide compound of formula (I):

in which:
R represents a phenyl ring, optionally substituted by one or two substituents, independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifloromethyl;
R1represents hydrogen or C1-C6-alkyl;
R2and R3independently selected from hydrogen, C1-C4-alkyl;
R4and R5independently represent hydrogen, C1-C6-alkyl;
X represents O or S;
Y and Z taken together with X and the phenyl ring, which is associated with Y and X, form a 5-7-membered saturated, the heterocycle containing the atoms are O or S, or Y and Z are hydrogen;
or its isomers, mixtures and pharmaceutically acceptable salts to obtain drugs for treatment of disorders of the lower urinary tract.

2. The use according to claim 1, in which the Association choose from:
2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide;
2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide.

3. The use according to claim 1 in which the compound is chosen from:
2-[4-(2-forbindelse)benzylamino]propanamide;
2-[4-(3-forbindelse)benzylamino]propanamide;
2-[4-(4-forbindelse)benzylamino] propanamide.

4. The use according to claim 1, where specified disorders of the lower urinary tract are overactive bladder (OAB), prostatitis and prostadynia, interstitial cystitis, benign prostatic hyperplasia and urinary incontinence as a consequence of the above pathologies.

5. The use according to any one of claims 1 to 4, where α is aminoamide represent
(S)-(+)-2-[4-(2-forbindelse)benzylamino]propanamide,
(S)-(+)-2-[4-(3-forbindelse)benzylamino]propanamide,
2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide,
(2R/3'S,R)-2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide.

6. α-Aminoamide compound of formula (I)

in which:
R represents a phenyl ring, optionally substituted by one or two substituents, independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifloromethyl;
R1represents a hydrogen Il is C 1-C6-alkyl;
R2and R3independently selected from hydrogen, C1-C4-alkyl;
R4and R5independently represent hydrogen, C1-C6-alkyl;
X represents O or S;
Y and Z taken together with X and the phenyl ring, which is associated with Y and X, form dihydrobenzofuranyl or dihydrobenzofuranyl, or dihydrobenzo(thio)peranovic, or tetrahydrobenzo(thio)occupiedby a heterocycle, its isomers, mixtures and pharmaceutically acceptable salts.

7. The compound of claim 6 selected from:
2-[(3-benzyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide;
2-[(3-phenethyl-2,3-dihydrobenzofuran-5-ylmethyl)amino]-N-methylpropanamide. or its isomers, mixtures and pharmaceutically acceptable salts.

8. Pharmaceutical composition having efficacy in relation to the function of emptying the bladder containing a pharmaceutically acceptable excipient and an effective amount of a compound according to claim 6 or 7 as the active ingredient.



 

Same patents:

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

The invention relates to new derivatives aminomethylpropanol acid formula 1

< / BR>
where Z represents (CH2)n, O or S; n is 0, 1 or 2; X represents 1-3 substituent, independently selected from hydrogen, halogen, (C1-6)alkyloxy,(C3-6)cycloalkane, (C6-12)aryloxy, (C6-12)aryl, teinila, CN, СООR6and (C1-4)alkyl, optionally substituted with halogen, or 2 substituent in adjacent positions together represent a condensed (C5-6)aryl group, or O-(CH2)m-O, where m is 1 or 2; Y is 1-3 selected from hydrogen, halogen, (C1-4)alkyloxy and (C1-4)alkyl, optionally substituted with halogen; R1represents COOR7; R2and R6are (C1-4)alkyl; R3, R4and R5independently represent hydrogen; R7, R8and R9independently represent hydrogen or (C1-4)alkyl; or pharmaceutically acceptable salts, and pharmaceutical compositions on their basis, with effect on the Central nervous system

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

The invention relates to novim retinoid compounds of General formula I, II, III, IV with retinoid negative hormone biological activity and/or activity of antagonist retinoids, compositions based on them, a method of determining the retinoid antagonists hormones,the method of treating a pathological state in a mammal, vospriimchivosti to treatment with retinoid antagonist or negative hormone by injection of compound I or II

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

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

The invention relates to new heterocyclic condensed to benzoylpyridine General formula I, where R1and R2denote independently from each other H or A; X denotes CR4R5; C=Z or O, Y represents CR6R7Z denotes O or CH2, R4, R5, R6or R7denote independently from each other H, A, HE or OA, or R5and R6or R7and R8indicate link together, with each molecule may receive a maximum of only one such bond, or R4and R5indicate together O-(CH2)2-O or O-(CH2)3-O, or R8and R9denote independently from each other H or A; And denotes alkyl with 1 to 6 C-atoms; n represents 0 or 1, and their physiologically acceptable salts

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to sulfamate derivatives of benzothiophene, obtained by method including stages: 1) conversion of 6-methoxybenzothiophene (3); , where R3 represents monobromine-derivative using N-bromosuccinimide and APTS in standard conditions; 2) conversion of said monobromine-derivative by interaction with Mg in Et2O in argon atmosphere into magnesium-organic bromide and its further condensation with ketone or aldehyde selected from group, consisting of cyclopentanone, cyclohexanone, cycldecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethylcyclopentanone, 2-adamantanone, propanal, hexanal, cyclohexane carboxaldehyde, cycloheptancarboxaldehyde in Et2O obtaining corresponding hydroxyl-substituted methoxybenzothiophene in standard conditions; 3) processing said hydroxy-substituted methoxybenzothiophene with triethylsilane in argon atmosphere in dichlomethane obtaining corresponding substituted methoxybenzothiophene; 4) optional alkylating of corresponding substituted methoxybenzothiophene using standard conditions obtaining corresponding substituted methoxybenzothiophene, carrying (C1-C6)alkyl or (C3-C12)cycloalkyl; removal of protective group from substituted methoxybenzothiophene, obtained at stage 3) or stage 4) in presence of tribromborane in standard conditions; conversion of obtained hydroxy-compound into corresponding sulfamate by processing with sodium hydrate and amidochlorsulfonic acid, or interaction with sulfamoylchloride in dimethylacetamide; 7) optional oxidation of obtained compound with hydrogen peroxide in trifluoracetic acid in standard conditions. Compounds can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders. Also described are pharmaceutical composition based on compounds I and application of the latter.

EFFECT: obtaining compounds which can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders.

43 cl, 1 dwg, 10 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.

EFFECT: new compounds possess useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

Ethynylbenzoate // 2079495
The invention relates to light-sensitive pesticides, specifically to some ethynylbenzoate

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel alkyl esters of 3-oxo-1,3-dihydrobenzo[c]oxepin-4-carboxylic acid of general formula , where R is methyl, ethyl, propyl, isopropyl, butyl, isopentyl, involving heating dialkyl esters of 2-(2-bromomethylbenzylidene)malonic acid, obtained through bromation of dialkyl esters of 2-(2-methylbenzylidene)malonic acid with N-bromosuccinimide to temperature of 190-220°C with simultaneous distillation of alkylbromide for 1-5 hours.

EFFECT: compounds can be used as intermediate products for synthesis of different organic compounds, particularly biologically active compounds.

1 cl, 6 ex

FIELD: medicine, cosmetology, organic chemistry.

SUBSTANCE: invention relates to a biologically active compound used for preparing agents promoting to hair growth. Compound is represented by the formula (I): wherein R1 and R2 are similar or different and each represents hydrogen atom, (C1-C6)-alkyl group or (C2-C6)-alkanoyl group; X represents hydrogen atom or halogen atom; R3a and R3b are different and each represents hydrogen atom or hydroxyl group; R4, R5, R6, R7 R8 and R9 are similar or different and each represents hydrogen atom, hydroxyl group, halogen atom or (C2-C6)-alkanoyloxy-group, or indicated group that are to be adjacent form in common π-bond or ester bond, or R5 and R8 or R5 and R9 form in common ester bond. Invention provides expanding assortment of chemical compounds possessing activity for inhibition of production of WNT-5A and stimulating growth of derma papilla cells.

EFFECT: valuable properties of tonic.

2 tbl, 8 dwg, 41 ex

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