Substituted derivatives of 2-phenylaminoimidazoline phenylketone as ip antagonists

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

 

The invention relates to compounds of General formula

where R1means optionally substituted aryl, and R1optionally substituted by one, two or three substituents, independently selected from the row containing alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl,

R2means hydrogen,

And means-C(O)-(CH2)n- or-C(O)-CH2-O-, and the subscript n means an integer from 2 to 6, inclusive,

or their pharmaceutically acceptable salts or solvate.

It has been unexpectedly found that the compounds of formula I are antagonists of the prostaglandin receptor I2(IP).

Prostaglandins or prostanoids (PG) are a group of biologically active compounds formed from membrane phospholipids and is built of essential fatty acids containing 20 carbon atoms and three, four or five double bonds, and a cyclopentane ring. These compounds are divided into seven major classes, which are indicated by the letters D, E, F, G, H or I, and differ only in the substituents in the cyclopentane ring. In addition, the main classes are divided into subgroups marked with subscript indices 1, 2 or 3, which correspond to their fatty acid predecessors. That is they way PGI2has a bicyclic structure, and subscript 2 means that it contains arachidonic acid.

PGI2(also known as prostacyclin) acts on platelets and blood vessels, inhibiting aggregation and causing expansion of vessels, and is thought to play an important role in vascular homeostasis. It is assumed that PGI2regulates anti-platelet properties of intact blood vessels. It is also believed that PGI2is a physiological modulator of vascular tone, i.e. has an effect opposite to vasoconstrictor agents. The importance of impacts on the vessels is of particular importance due to the participation of PGI2in hypotension caused by septic shock. Although it was established that prostaglandins have no direct effect on vascular permeability, PGI2significantly speeds up the formation of edema and infiltration of leukocytes through the active flow of blood in the focus of inflammation. Therefore, antagonists of the IP receptor can reduce hypotension caused by septic shock, to reduce the degree of swelling and prevent violations associated with profuse bleeding, such as, but not limited to, hemophilia and bleeding.

Several studies on analgesia in rodents in vivo suggest that PGI2plays an important fu is the Ktsia in the induction of hyperalgesia. Similarly, in vitro studies have clearly shown that the "preferred PGI2" IP receptors, act as key modulators of the function of the sensory neuron. Because sensory neurons associated with activation of adenylate cyclase and phospholipase C and, consequently, of camp-dependent protein kinase and protein kinase C, these receptors can affect the activity of ion channels and thus to release neurotransmitter. The proof of the key role of IP receptors in the pain associated with the inflammatory process, obtained in recent studies using transgenic mice defective in the IP receptor (T.Murata and others, Nature, 388, 678-682 (1997)).

Along with the fact that prostaglandins are mediators of hyperalgesia, it is known that these compounds are produced locally in the bladder in response to a physiological stimulus, such as stretching of the smooth muscle of the detrusor, injury makeuserkey mucosa and stimulation of the nerve (K.Anderson, Pharmacological Reviews, 45(3), 253-308 (1993)). PGI2is the major prostaglandin, which is released into the bladder of a man. There is evidence that prostaglandins are the link between the stretching of the smooth muscle of the detrusor caused by bladder filling, and activation of C-fiber afferents in the stretching of the bladder. It is assumed that prostaglandins can PR who take part in the pathophysiology of disorders of the urinary bladder. Therefore, it is expected that antagonists of prostaglandin IP receptor can be used in the treatment of such conditions.

It is also expected that antagonists of the IP receptor can be used for respiratory allergies, where PGI2produced in response to an allergen, or respiratory disorders such as asthma.

Additional information related to the prostaglandins and their receptors, is contained in the monograph Goodman & Gillman''s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, GL, s-616 (1996).

Compounds related to the compounds of General formula I, is described in the following literature. In the patent US 6184242 (Bley and others) described some derivatives of 2-(substituted phenyl)aminoimidazole. US 5364944 and 5218124 (Failli and others) are related to certain derivative substituted benzoylbenzene-, biphenyl - 2-oxazolidinone acids, which are claimed as inhibitors of lipoxygenase inhibitors of phospholipase A2 and leukotriene antagonists, and are used as anti-inflammatory, antiallergic and cytoprotective agents. US 5326776 (Winn and others) refers to some derivative of the substituted phenyl, which claimed as receptor antagonists angiotensin II, primenewswire in the treatment of hypertension, edema, renal failure, benign prostate hypertrophy, diabetic nephropathy, diabetic retinopathy, Alzheimer's disease or congestive heart failure, glaucoma, atherosclerosis, stroke, various disorders associated with obesity, and disorders of the Central nervous system. In the US 4889868 and US 4588737 (Huang) describes derivatives of bis-imidazolidine as inhibitors of lipoxygenase and phospholipase C, as well as receptor antagonists of platelet activating factor, which have anti-inflammatory, anti-asthmatic and anti-allergic properties and, in addition, are used for the treatment of myocardial infarction. In the US 4396617 and US 4374143 (Dolman and Kuipers) described some 2-arylaminomethylidene, which are claimed as fungicides against bean rust, brown rust of wheat and powdery mildew of cereals. Some derivatives of 2-(substituted phenylamino)imidazolidine stated in US 4287201 (Olson and others), is applied to delay the onset of egg laying in young chickens, when interrupted laying eggs in Mature chickens and the stimulation of artificial molt.

The method of obtaining derivatives of 2-arylamino-2-imidazoline described in US 3931216 (Franzmair). British patent application GB 2038305 (owned by Duphar International Research) relates to certain compounds of imidazolidine, which are claimed as inhibitors of the growth of lateral shoots of tobacco or tomato, or inhibitors overgrown lawn, or inhibitors of the growth of dwarf (dwarf) ornamental plants. European published application 0017484 (owned Fijisawa Pharmaceutical) refers to some who m a derivative of 2-imidazoline, which are claimed for use in the treatment of hypertensive inflammatory and gastro-intestinal disorders and for the relief of pain of various etiologies. Some derivatives of 1-[4-(4,5-dihydro-1H-imidazol-2-yl)AMINOPHENYL]-3-substituted phenyl)-2-propen-1-she claimed as agents for the treatment of Parkinson's disease (V.K. Srivastava and others, Pharmazie, 41, 598-599 (1986)).

In article Bley and others, Trends in Pharmacological Sciences, 19(4), 141-147 (1998)described the role prostanoid IP receptors in the occurrence of inflammatory pain. Article Smith and others, British Journal of Pharmacology, 124(3), 513-523 (1998), refers to the study of the response prostanoid receptor in sensory neurons of the rat. About the change in pain perception and inflammatory response in mice defective in prostacyclin receptors, the paper reported Murata and others, Nature, 388 (6643), 678-682 (1997). Article Anderson K-E., Pharmacological Review, 45(3), 253-308 (1993), refers to the pharmacology of smooth muscles of the lower urinary tract and the cavernous tissue of the penis. Classification prostanoid receptors (properties, distribution, and structure prostanoid receptors and their subtypes) are described in the review of Coleman and others, Pharmacological Review, 46(2), 205-229 (1994).

All publications, patents and patent applications, cited above or below, are included as references in the text of the application.

The object of the present invention are derivatives of substituted phenylketone General formula I as antagonis the s receptor prostaglandin I 2(IP), containing their pharmaceutical compositions, their use as therapeutic agents and the method of obtaining such compounds.

The present invention relates to compounds of formula I

where R1means optionally substituted aryl, and R1optionally substituted by one, two or three substituents, independently selected from the row containing alkoxy, aryl, aryloxy, aralkylated, halogen, halogenated, hydroxy, hydroxyalkyl, nitro, cycloalkyl, amino, alkylamino, dialkylamino, methylenedioxy, Ethylenedioxy, or optionally substituted heterocyclyl,

R2means hydrogen,

And means-C(O)-(CH2)n- or-C(O)-CH2-O-, and the subscript n means an integer from 2 to 6, inclusive,

or their pharmaceutically acceptable salts or solvate.

Of the claimed compounds can be prepared pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt or solvate in a mixture with at least one suitable carrier. In a preferred embodiment of the invention, pharmaceutical compositions are applied to the respective injection to a patient with the disease, the intensity of the symptoms which is reduced during treatment with antagonist IP receptor.

Saedinenie formula I, or their pharmaceutically acceptable salt, or solvate because of its properties can be used for treatment or prevention of pathological conditions, the intensity of the symptoms are reduced during treatment with antagonist IP receptor. In a preferred embodiment of the invention, the subject in need of such treatment, is a pathological condition associated with pain, such as pain caused by inflammation, neuropathic pain, pain associated with cancer, acute pain, chronic pain, postoperative pain, dental pain, premenstrual pain, visceral pain, pain caused by burns, migraine or histamine headache, neuralgia, post-traumatic injuries, pain associated with functional bowel disorder such as irritable bowel syndrome (mucous colitis), hyperalgesia or integrated local syndromes. In another preferred embodiment of the invention, the subject in need of such treatment, is a pathological condition associated with inflammation, such as bacterial, fungal infection, viral infection, idiopathic inflammation of the bladder, overdose, old age, lack of nutrition, prostate trouble or pain when conjunctivitis is.

In yet another preferred embodiment of the invention, the subject in need of such treatment, is a pathological condition associated with diseases of the genitourinary tract, such as the syndrome infravesical obstruction, incontinence, lack of functional activity of the bladder, frequent urination, urgency incontinence, stress incontinence, increased reactivity of the bladder, benign prostatic hypertrophy (DBH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturnal polyuria, urgent urination, increased activity of the bladder, increased sensitivity of the renal pelvis, urgency, urethritis, prostatitis syndrome pain in the renal pelvis, prostatodynia, cystitis or idiopathic hypersensitivity of the bladder. In yet another preferred embodiment of the invention, the subject in need of such treatment, is a pathological condition associated with respiratory disease caused by allergies or asthma. In yet another preferred embodiment of the invention, the subject in need of such treatment, is a pathological condition associated with the formation of edema or hypertensive vascular disease.

In addition,the present invention describes a method for the compounds of formula I, moreover, this method involves reacting the compounds of formula

where a1means -(CH2)n- or-CH2O-, a R1, R2and n have the meanings indicated in claim 1,

with the compound of the formula

where X means halogen,

obtaining the compounds of formula

where R1, R2and a have the meanings indicated in claim 1,

and, if necessary, conversion of the compounds of formula I in a pharmaceutically acceptable salt.

Unless otherwise stated, the following terms used in the text of the application, including the description and claims have the meanings specified below. It should be noted that ispolzovanie in the description and claims, the singular number include the plural forms unless the context clearly indicated otherwise.

"Acyl" (or alkanol) means the radical-C(O)-Rawhere Rameans (ness.)alkyl, with the values specified in the proposal. Examples of acyl radicals include, but are not limited to, formyl, acetyl, propionyl, butyryl etc.

"Alkoxy" means the radical-O-Rbwhere Rbmeans radical (ness.)alkyl, with the values specified in the proposal. Examples of alkoxy radicals include, without limitation listed the th, methoxy, ethoxy, isopropoxy etc.

"Alkoxycarbonyl" means the radical-C(O)-ORcwhere Rcmeans radical (ness.)alkyl, with the values specified in the proposal. Examples of radicals alkoxycarbonyl include, without limitation, methoxycarbonyl, etoxycarbonyl, isopropoxycarbonyl etc.

"Alkylaminocarbonyl" means the radical-C(O)-otherewhere Remeans radical (ness.)alkyl, with the values specified in the proposal. Examples of radicals alkylaminocarbonyl include, without limitation, methylaminomethyl, ethylaminomethyl, isopropylaminocarbonyl etc.

"Alkylsulfonyl" means a radical-SO2Rfwhere Rfmeans radical (ness.)alkyl, with the values specified in the proposal. Examples of the alkylsulfonyl radicals include, without limitation, methanesulfonyl, econsultancy, propanesulfonyl etc.

"Aralkylated" means the radical-O-Riwhere Rimeans radical aralkyl with the values specified in the proposal. Examples of radicals of aralkylated include, without limitation, benzyloxy, phenylethylene etc.

"Aryl" means the monovalent aromatic carbocyclic radical containing one cycle or one or more condensed cycles, of which at least one cycle is and what maticheskim, which optionally may be substituted by one, two or three substituents, independently selected from the row containing alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl, which means a monovalent saturated carbocyclic radical containing from 3 to 7 atoms in the cycle, comprising one or two heteroatoms independently selected from nitrogen, oxygen, and which optionally may be substituted by one or more substituents independently selected from the range, including alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylsulfonyl, furanose. Examples of aryl radicals include, without limitation, phenyl, naphthyl, biphenyl, indanyl etc.

"Aryloxy" means the radical-O-Rjwhere Rjmeans an aryl radical having the values specified in the proposal. Examples of radicals of aryloxy include, without limitation, phenoxy etc.

"Dialkylaminoalkyl" means the radical-C(O)-NRmRnwhere Rmand Rneach independently means a radical (ness.)alkyl, with the values specified in the proposal. Examples of radicals dialkylaminoalkyl include, without limitation, dimethylaminoethyl, diethylaminoethyl, methylpropylamine etc.

"Atlantix is" means the radical-co 2CH2Oh.

"Halogen" means a fluorine radical, bromine, chlorine and/or iodine.

"Heterocyclyl" means a monovalent saturated carbocyclic radical containing from 3 to 7 atoms in the cycle, consisting of one or more cycles and comprising one, two or three heteroatoms, independently selected from the series nitrogen, oxygen and sulfur. Radical heterocyclyl optionally may be substituted by one or more substituents independently selected from the range alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, carbylamine, alkylsulfonyl, heteroaromatic (furanose) or otherwise. Examples of radicals heterocyclyl include, without limitation, morpholinyl, piperazinil, methylpiperazine, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholine etc. Preferred substituents in the heterocyclic moiety include, without limitation, acyl, alkoxycarbonyl, alkylaminocarbonyl or alkylsulfonyl.

"Optional" or "optionally" means that a subsequent event or circumstance may occur, but will not necessarily occur, and that the description includes instances when the event or circumstance occurs and instances where it does not happen. For example, optional (chemical) bond" means the bond may be present, and may otsutstvuet, and that the description includes single, double and triple bond.

"Optionally substituted phenyl" means phenyl cycle, which is optionally substituted by one or more substituents independently.

"Optionally substituted phenyl" means phenyl cycle, which is optionally substituted by one or more substituents independently selected from the number of alkoxy, halogen, aryloxy and others, above.

The new compounds may be obtained in the form of their isomers, as well as racemic and prizemistoj mixture. "Isomer" means different compounds with the same molecular formula, but differ in the nature or sequence of chemical bonds or by the spatial arrangement of atoms. Isomers that differ in the spatial arrangement of atoms, called "stereoisomers". Stereoisomers that are mirror images of each other and possess optical activity, are called "enantiomers"and stereoisomer that are not mirror images of each other, are called "diastereoisomers".

"Tropicheskii isomer" means isomers that exist due to the slow rotation of volume groups around a Central connection.

"Chiral isomer" means a compound with one chiral center. This connection has two enantiomeric forms with FR is the opposite chirality and can exist in the form of an individual enantiomer or as a mixture of enantiomers. A mixture containing equal quantities of specific enantiomeric forms of opposite chirality, is called a "racemic mixture". Compounds having more than one chiral center may exist as a single diastereoisomer or mixture of diastereoisomers, which is called "diastereomers mix." If there is one chiral center stereoisomer can be characterized by the absolute configuration (R or S) of this chiral center. The absolute configuration means the spatial arrangement of the substituents at the chiral center. These deputies associated with the chiral center, classified by rule Kahn, Ingold and Prelog (Cahn and others, Angew. Chem., Inter. Edit., 5, 385 (1966) (errata s), Cahn and others, Angew. Chem., 78, 413 (1966), Cahn and Ingold., J. Chem. Soc. (London), 612 (1951), Cahn and others, Experientia, 12, 81 (1956), Cahn, J. Chem. Educ., 41, 116 (1964)).

"Geometric isomer" means the diastereomers, existing due to the slow rotation around double bonds. These configurations differ in the prefixes in the names of CIS - and TRANS -, or Z and E, which means that the groups are located on the same or on different sides of the plane of the double bond according to the rules of Cahn-Ingold-Prelog.

"Leaving group" means a group whose name is usually associated with its use in synthetic organic chemistry, i.e. the mean atom or is the Rupp, which is substituted in the conditions of the alkylation reaction. Examples of leaving groups include, without limitation, halogen, alkane - or arensulfonic, such as methanesulfonate, econsultancy, thiomethyl, benzosulfimide, tosyloxy, titilate, dialoginterface, optionally substituted benzyloxy, isopropoxy, acyloxy etc.

"Protective group" has the meaning associated with it in synthetic organic chemistry means a group which selectively blocks the reactive center in a multifunctional compound such that the reaction can be performed selectively at another unprotected reactive center. Some methods of the present invention is designed so that the protective group blocking reactive oxygen atoms in the reactants. Suitable protective groups for the alcoholic or phenolic hydroxyl groups, which can be easily and selectively removed include protective group as acetates, gelegenheitsarbeit, benzyl ethers, alkylsilane ethers, heterocyclyl ethers, methyl or other alkyl ethers, and other Protective or blocking groups for carboxyl groups similar protective groups for hydroxyl groups, preferably tert-butile the first, benzyl or methyl esters. Examples of protective groups can be found in the monographs .W.Green and other Protective Groups in Organic Chemistry, J.Wiley, 2 ed. (1991)and Harrison and others, Compendium of Synthetic Organic Methods, V.1-8, J.Wiley and Sons (1971-1996).

"Aminosidine group" or "N-protective group" means a protective group, which refers to the groups intended to protect nitrogen atom against undesirable reactions when conducting syntheses. Such groups include, without limitation, benzyl, benzyloxycarbonyl (carbobenzoxy, CBS), para-methoxybenzeneboronic, para-nitrobenzenesulfonyl, tert-butoxycarbonyl (BOC), TRIFLUOROACETYL, etc.

"Release" or "removing the protective group" means a method of removing the protective group after completion of the selective reactions. Some protective groups are preferred due to the simple reaction conditions and relative ease of removal. Deblokiruyuschee reagents for removal of the protective groups for hydroxyl or carboxyl group include the carbonates of potassium or sodium, lithium hydroxide in alcohol solution, the zinc in methanol, acetic acid, triperoxonane acid, palladium catalysts or tribromide boron, etc.

"Inert organic solvent" or "inert solvent" mean a solvent inert under the conditions described reaction, such as benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, etc. Unless otherwise stated, solvents used in reactions of the present invention are inert solvents.

"Pharmaceutically acceptable" means a material, which is used in obtaining pharmaceutical compositions and which is generally safe, non-toxic, harmless to biological or other respects and includes material that is acceptable in veterinary medicine and in the pharmaceutical industry.

"Pharmaceutically acceptable carrier" means a carrier, which is used in obtaining pharmaceutical compositions and which is usually compatible with other ingredients of the composition, it has no negative effect on the patient is safe in biological or other respects and includes a carrier that is acceptable in veterinary medicine and in the pharmaceutical industry. "Pharmaceutically acceptable carrier"used in the description and claims, includes one or more media.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the necessary Pharma the ideological activity of the parent compound. For example, such salts include:

(1) acid additive salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate econsultation, 1,2-ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, 2-naphthalenesulfonate, 4-methylbicyclo[2,2,2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like;

(2) salts formed when replacing the acidic proton present in the original compound, metal ion, such as alkali metal ion, ion, alkaline earth metal, aluminum ion, or in the formation of proton coordination the coordinating compound with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc.

It is assumed that the reference to the pharmaceutically acceptable salt includes solvated or crystalline form, especially solvate and polymorph modifications. The solvate contain stoichiometric or non-stoichiometric amount of solvent and are often formed during crystallization. Hydrates are formed in the case, if the solvent is water, and the alcoholate is formed in the case, if the solvent is alcohol. Polymorphic modifications include different crystalline forms of compounds of the same elemental composition. Polymorphic modifications usually have different x-ray diffraction patterns, different infrared spectra have different melting points, density, hardness and shape of the crystals, optical and electrical properties, stability, and solubility. Education the predominant crystalline form is affected by various factors, such as the solvent used for recrystallization, crystallization rate and temperature of storage.

The term is pharmacological action used in the text of the application, includes the effects on the subject, which achieved the intended goal of therapy. In one of the preferred embodiments of the invention pharmacological action means the treatment of a subject in need of such treatment. For example, pharmacological action can lead to predotvrasenie, to alleviate or reduce the symptoms of a pathological condition associated with pain, inflammation, pathological condition of the urinary tract or asthma in a patient in need of such treatment. In a preferred embodiment of the invention pharmacological effect means that the activation of the IP receptor is associated with therapeutically beneficial effects on the subject with a pathological condition that can be cured with the introduction of the modulator IP receptor, primarily antagonist IP receptor.

"Subject" means a mammal and namecapital. Examples of mammals include, without limitation, any representative of the family of mammals: human, non-human primates, such as chimpanzees and other apes and monkeys, farm animals such as cattle, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and mo the ski mumps, etc. Examples of memleketim include, without limitation, birds, etc. the Term does not refer to a specific age or sex.

"Therapeutically effective amount" means an amount of compound that when administered to a subject for treatment of a pathological condition is sufficient to ensure such treatment of a pathological condition. Therapeutically effective amount may vary depending on the type of connection, the pathological condition to be treated, the severity or the nature of the disease, the age and relative health of the subject, method and form of administration, from the opinion of the attending physician or practitioner veterinarian and other factors.

"Therapy" or "treatment" of the disease condition includes:

(1) preventing the disease, i.e. the suppression of clinical symptoms of the disease in the subject, which is exposed to or predisposed to the disease but which are not detected or do not manifest symptoms of the pathological condition;

(2) the suppression of pathological conditions, such as suppression of the development of the disease or its clinical symptoms;

(3) the weakening of the disease, such as stimulation of temporary or long-term regression of the disease or its clinical symptoms.

"Pathological condition" means any disease, drug is the solution, the condition, symptom or indication.

"A pathological condition associated with urinary tract" or "disease of the urinary tract" or "uropathy" or "symptoms of the urinary tract", used interchangeably, mean pathological changes in the urinary tract or the dysfunction of the smooth muscle of the bladder or its innervation caused by rasagulla accumulation and excretion of urine. Symptoms of urinary tract (also known as hyperactivity of the detrusor) include obstruction of the outlet, the failure of the outlet and a sensitivity of the renal pelvis.

"The failure of the outlet" includes, without limitation, increased urethral mobility, congenital failure of the sphincter or mixed incontinence. Simptomaticeski this is usually manifested in the form of incontinence with tension.

"Obstruction of the outlet" includes, without limitation, benign hypertrophy of the prostate, disease urethral stricture, tumor, etc. Simptomaticeski this is usually manifested in the form of obstruction (low flow rate, difficulty in initiating mocheispuskanija etc) and irritation (urgency, suprapubic pain, etc.).

"Increased activity of the bladder" or "hyperactive detrusor" R is t, without limitation, changes that symptomatically appear in the form of urgency, frequency, reduced bladder capacity, incontinence and the like; in the process of urodynamics changes are manifested in the form of changes in bladder capacity, threshold bladder, unstable bladder contractions, muscle spasms of the sphincter and the like, and the symptoms usually manifest themselves in the form of detrusor hyperreflexia (neurogenic bladder), in conditions such as obstruction of the outlet, the failure of the outlet, hypersensitivity, renal pelvis, or idiopathic conditions such as detrusor instability, etc.

"Increased sensitivity of the renal pelvis" includes, without limitation, pain, renal pelvis, interstitial (cell) cystitis, prostadynia, prostatitis, vulvodynia, urethritis, orchialgia etc. it Symptomatically manifested as pain, inflammation or discomfort in the renal pelvis and usually includes symptoms of increased activity of the bladder.

"Pain" means more or less localized sensation of discomfort, attack or suffering arising from stimulation of specific nerve endings. There are many types of pain, including, without limitation, releasee pain, phantom pain, jerking pain, acute pain, pain caused by inflammation, neuropathic pain, complex local pain, neuralgia, neuropathy, etc. (Dorland's Illustrated Medical Dictionary, 28thEdition, W.B.Saunders Company, Philadelphia, PA). Healing from the pain is to reduce the severity of pain experienced by the subject to be treated.

"Neuropathic pain" means pain, resulting from functional disturbances and/or pathological changes, as well as non-inflammatory disorders of the peripheral nervous system. Examples of neuropathic pain include, without limitation, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic neuropathy pain, pain caused by a pinched nerve, etc.

"Modulator" means a compound that interacts with the target. Interaction includes, without limitation, an action of type agonist, an action of type antagonist, etc. as specified in the description of the application.

"Agonist" means a compound, a drug, an activator of the enzyme or hormone, which enhances the activity of another compound or portion of the receptor.

"Antagonist" means a compound, a drug, an inhibitor of the enzyme or hormone, which reduces or blocks the activity of another compound or parcel of cocktail recipes. is and.

The range of connections

The names of the compounds of the present invention are illustrated below.

In General, the nomenclature used in the description, based on Autonom system, computerized Institute Beylshtein to use systematic IUPAC nomenclature. However, since strict adherence to these guidelines leads to a significant transformation of names when replacing only one substituent, the compounds are named in such a way as to ensure that the items within one molecule.

For example, the compound of formula I, where a represents-C(O)-(CH2)2-, R1means 4-forfinal, and R2means hydrogen, is called 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-on.

For example, the compound of formula I, where a represents-C(O)-CH2O-, R1means 4-methoxyphenyl and R2means hydrogen, is called 2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenoxy]-1-(4-methoxyphenyl)Etalon.

It is known that imidazolin-2-luminograph in compounds such as the compounds of formula I, is in tautomeric equilibrium with imidazolin-2-ylideneamino.

For convenience, all of the compounds of formula I are imidazolin-2-laminography, but it is assumed that the volume of izobreteny which includes both tautomeric forms.

Among the compounds of the present invention, are listed in the brief description, some preferred compounds of formula I, or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt or solvate.

In each case And independently and preferably denotes-C(O)-(CH2)n-.

The subscript n in each case independently and preferably denotes an integer from 2 to 4 inclusive, more preferably an integer of 2.

R1in each case, independently and preferably means aryl, optionally substituted one, two or three substituents, independently selected from a number alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl, more preferably phenyl, optionally substituted one, two or three substituents, independently selected from the series halogen, alkoxy, or optionally substituted heterocyclyl, most preferably phenyl, optionally substituted one, two or three substituents, independently selected from the series chlorine, fluorine, ethoxy, methoxy, or optionally substituted morpholine-4-yl, or optionally substituted piperazine-4-yl.

R2in each case mean a hydrogen.

Preferred compounds of formula I are those compounds which tion, in which a represents-C(O)-(CH2)n-, a n is 2. Preferred above all such compounds in which a represents-C(O)-(CH2)n-, n is 2 and R1means aryl, optionally substituted one, two or three substituents, independently selected from a number alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl.

More preferred compounds of formula I in which a represents-C(O)-(CH2)n-, n is 2, R1means phenyl, optionally substituted one, two or three substituents, independently selected from the series halogen, alkoxy, or optionally substituted heterocyclyl. In a preferred embodiment of the invention R1means phenyl, optionally substituted one, two or three substituents, independently selected from the series halogen or alkoxy. More preferably, a represents-C(O)-(CH2)n-, n is 2 and R1means phenyl, optionally substituted one, two or three substituents, independently selected from the series chlorine, fluorine, ethoxy or methoxy; more preferably a represents-C(O)-(CH2)n-, n is 2 and R1means phenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 4-forfinal, 2,4-differenl or 2-fluoro-4-methoxyphenyl.

In addition, preferred compounds of formula I in which a represents-C(O)-CH 2)n-, n is 2 and R1means phenyl substituted one, two or three substituents, independently selected from a number of optional substituted heterocyclyl or halogen. More preferably, a represents-C(O)-(CH2)n-, n is 2 and R1means phenyl substituted one, two or three substituents, independently selected from a number of optional substituted morpholine-4-yl, optionally substituted piperazine-4-yl, chlorine or fluorine, and more preferably a represents-C(O)-(CH2)n-, n is 2 and R1means 4-morpholine-4-ylphenyl, 2-fluoro-4-morpholine-4-ylphenyl, 4-piperazine-4-ylphenyl, 4-(ethylaminomethyl)piperazine-4-ylphenyl, 4-(etoxycarbonyl)piperazine-4-ylphenyl, 4-(methanesulfonyl)piperazine-4-ylphenyl or 4-(n-propanesulfonyl)piperazine-4-ylphenyl.

Preferred primarily compounds of the formula I in which a represents-C(O)-(CH2)n-, n is 2 and R1means aryl, optionally substituted one, two or three substituents, independently selected from the range of C1-C6alkyl, alkoxy, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl, a R2means hydrogen. An example of such a compound is the compound in which a represents-C(O)-(CH2)n-, n is 2, R1means 4-forfinal, and R2means hydrogen.

in Addition, preferred compounds of formula I in which a represents-C(O)-CH2O-. Preferred above all such compounds in which a represents-C(O)-CH2O-, and R1means aryl, optionally substituted one, two or three substituents, independently selected from the number of alkoxy, aryloxy, aralkylated, halogen, Ethylenedioxy, or optionally substituted heterocyclyl. More preferably, a represents-C(O)-CH2O-, R1means phenyl, optionally substituted one, two or three substituents, independently selected from a number alkoxy or Ethylenedioxy. Even more preferred compounds in which a represents-C(O)-CH2O-, R1means phenyl, optionally substituted one, two or three substituents, independently selected from a number alkoxy or Ethylenedioxy, and R2means hydrogen.

Examples of the first preferred compounds include the following compounds of formula I, or individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt or solvate:

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-he,

1-(2,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

1-(4-chloro who enyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

1-(2,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(phenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-methoxyphenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-morpholine-4-ylphenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(ethylaminomethyl)piperazine-4-ylphenyl]propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-1-ylamino)phenyl]-1-[4-(etoxycarbonyl)piperazine-4-yl-2-forfinal]propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(methanesulfonyl)piperazine-4-ylphenyl]propane-1-he,

(m) 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(n-propanesulfonyl)piperazine-4-ylphenyl]propane-1-on.

Compounds of the present invention can be obtained by the methods shown in the schemes of reactions.

Starting materials and reagents used in the preparation of these compounds are generally commercially and drugs produced, for example, Aldrich Chemical Co., or they can be obtained by methods known to the person skilled in the art, for example according to the methods described in the guidelines for organic synthesis, such as Fieser and Fieser''s Reagents for Organic Synthesis, Wiley & Sons, New York, V.1-15 (1991), Rodd''s Chemistry of Carbon Compounds, Elsevier Science Publishers, vol. 1-5 and Applications (1989), Organic Reactions, Wiley & Sons, New York, Vol.1-40 (1991). The following scheme of reactions are only illustrative of some methods of synthesis of compounds of the present invention, and various modifications to these schemes reactions can be developed and offered by a person skilled in the art with reference to the materials of the present application.

Raw materials and intermediate compounds in these schemes reactions can be obtained and if necessary cleaned with suitable means, including, but not limited to, filtration, distillation, crystallization, chromatography and the like, Such materials can be characterized using appropriate methods, including physical constants and spectral data.

Unless otherwise described in the text of the reaction is preferably carried out at atmospheric pressure at a temperature of from about -78°With up to approximately 150°S, more preferably from approximately 0°With up to approximately 125°With the most preferred and acceptable at about room tempera is ur (or ambient temperature), for example, when approximately 20°C.

In the diagrams a and B shows an alternative method of obtaining the compounds of formula I.

Scheme And

On the scheme And shows how to obtain the compounds of formula I, particularly compounds of formula Ia, where a represents-CO(CH2)n-, a n, R1and R2have the values specified above.

Method And

In the way As the parent compound, ketone 1A (where R means (ness.)alkyl) and benzaldehyde 2A are commercial preparations, for example, the company Aldrich Chemical Company or known compounds or can easily synthesize a specialist in this field.

Stage 1A interaction of ketone 1A with benzaldehyde 2A leads to the formation of compounds of formula 3 (where aameans a chemical bond or -(CH2)p-p means an integer from 0 to 4). The reaction is carried out in a known manner, for example Alderney condensation catalyzed by base. Suitable solvents include proton organic solvent, such as methanol, ethanol, 2-methoxyethanol etc.

Stage 2A selective hydrogenation of the double carbon-carbon links and restore the nitro group in the compound of formula 3 to the amino group leads to the formation of compounds of formula 4. Suitable reaction conditions recovery include the catalytic gidrirovanie is by using a catalyst based on platinum or palladium (for example, PtO2or palladium on charcoal, preferably 10% palladium on coal) in an inert organic solvents, such as ethyl acetate, tetrahydrofuran, methanol or ethanol.

In stage 3A, the treatment of compounds of formula 4 halogenated 4,5-dihydro-1H-imidazole (III) leads to the formation of compounds of formula Ia. The reaction is carried out by boiling under reflux, usually in an atmosphere of inert gas. Suitable solvents include inert organic solvents such as methanol, ethanol, 2-propanol, dichloromethane, acetonitrile or tetrahydrofuran, preferably 2-propanol. Halogenated 4,5-dihydro-1H-imidazole is a known compound or can easily synthesize the person skilled in the art, for example, the synthesis of 2-chloro - 4,5-dihydro-1H-imidazole described in article A. Trani, Bellasio E., J.Het. Chem., 11, 257 (1974).

An alternative way And

In the alternative method And the source connection, optional substituted or unsubstituted aryl 1b and allelochemic 2b are commercial preparations, for example, the company Aldrich Chemical Company or known compounds or can easily synthesize a specialist in this field.

Stage 1b interaction optional substituted aryl 1b with allelochemical 2b leads to the formation of compounds of formula 5. The reaction is carried out by way of swetnam specialist in this field, for example, under the reaction conditions of Friedel -. The reaction is carried out in the presence of an acid catalyst Lewis, such as aluminum chloride, in an inert organic solvent such as carbon disulfide, nitrobenzene, hexane, etc.

In stage 2B, the restoration of the nitro group in the compound of formula 5 to the amino group leads to the formation of compounds of formula 6. The reaction can be conducted under conditions similar to those described in method A, stage 2A.

In stage 3b, the treatment of compounds of formula 6 halogenated 4,5-dihydro-1H-imidazole leads to the formation of compounds of formula Ia. The reaction can be performed in the same way as described in method A, stage 3A.

Examples obtain the compounds of formula Ia according to the reactions shown in the diagram And described in detail in examples 1-8.

Scheme B

In scheme B shows an alternative method of obtaining the compounds of formula I, particularly compounds of formula Ib, where a represents-C(O)-CH2O-, a R1and R2have the values specified above.

Usually the parent compound, alkylhalogenide 1 and alcohol 2 are commercial preparations, for example, the company Aldrich Chemical Company, or known compounds or can easily synthesize a specialist in this field.

In stage 1 interaction alkylhalogenide 1 with with alcohol 2 leads to the formation of soy is inane formula 7. The reaction is carried out by a method known to the person skilled in the art, for example under the reaction conditions of Williamson, in the presence of a base such as potassium carbonate, sodium carbonate or cesium carbonate. Suitable solvents include aprotic organic solvents such as N,N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide.

In stage 2 recovery of nitro group in the compound of formula 7 to the amino group leads to the formation of the compound of formula 8. Suitable reaction conditions recovery include catalytic hydrogenation using a catalyst based on platinum or palladium or tin chloride (II), preferably of tin halide (II). Suitable solvents include inert organic solvents such as ethyl acetate, N,N-dimethylformamide, tetrahydrofuran, etc.

In stage 3, the treatment of compounds of formula 8 halogenated 4,5-dihydro-1H-imidazole leads to the formation of compounds of formula Ib. The reaction can be performed in the same way as shown in the diagram And, stage 3a.

Examples obtain the compounds of formula Ib according to the reactions shown in scheme B, described in detail in examples 9 and 10.

Compounds of the present invention are modulators of the IP receptor, primarily antagonists IP receptor, and have antagonistic activity against IP receptor. predpolagaetsya, these compounds (and compositions containing them are useful for the prevention and treatment of various diseases in mammals, especially humans.

Compounds according to the invention first of all have anti-inflammatory and/or analgesic properties in vivo, and accordingly it is assumed that they will find application in the treatment of pathological conditions associated with pain of various etiologies, including, without limitation, pain caused by inflammation, postoperative pain, visceral pain, dental pain, premenstrual pain, Central pain, pain from burns, migraine or histamine headache, nerve damage, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, pain associated with cancer, viral, parasitic or bacterial infection, post-traumatic injuries (including fractures and sports injuries), and pain associated with functional bowel disorder such as irritable bowel syndrome (mucous colitis).

In addition, the compounds of the present invention can be used in the treatment of inflammatory conditions of various etiologies, including, without limitation, bacterial, fungal or viral infections, rheumatoid arthritis, osteoar the RIT, post-operative condition, a bladder infection or idiopathic inflammation of the bladder, overdose, old age or lack of power, prostatitis and conjunctivitis.

In addition, the compounds of the present invention can be used in the treatment of pathological conditions associated with obstruction of the bladder and urinary incontinence, such as obstruction of the outlet of the bladder, urinary incontinence, reduced bladder capacity, frequent urination, urgency incontinence, stress incontinence, increased reactivity of the bladder, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, urinary frequency, nocturnal polyuria, urgent urination, increased activity of the bladder, increased sensitivity of the renal pelvis, urgency, urethritis, prostatitis syndrome pain in the renal pelvis, prostatodynia, cystitis or idiopathic hypersensitivity of the bladder and other symptoms associated with hyperactivity of the bladder.

In addition, the compounds of the present invention can be used in the treatment of hypertensive vascular diseases, such as hypotension associated with septic shock.

In addition, the compounds according to the present from which retenu can be used in the treatment of respiratory diseases, such as allergies and asthma.

These and other areas of therapeutic applications are described, for example, in the book, Goodman & Gillman''s The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, New York, GL, s-616 (1996), and article R.A. Coleman, Pharmacological Reviews, 46, 205-229 (1994).

The affinity of binding of these compounds with the intended target was determined by tests on linking IP receptor of human platelets in vitro, as described in detail in example 18. The values of the PKipreferred compounds comprise from 7.1 to 9.6.

The binding constants of some specific compounds according to the invention with an IP receptor of human platelets in vitro in the following table.

2
ConnectionExample No.Affinity with the IP receptor of human platelets (PKi)
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-he19,50
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-he38,28
2-[4-(imidazolidin-2-ylideneamino)phenoxy]-1-(4-methoxyphenyl)alanon108,56
ethyl ester of 4-(4-{3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propionyl}phenyl)piperazine-1-carboxylic acid58,03
1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(imidazolidin-2-ylideneamino)phenoxy]alanon97,35
ethylamide 4-(4-{3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propionyl}phenyl)piperazine-1-carboxylic acid77,41
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-he6at 7.55
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-{4-[4-(furan-2-carbonyl)piperazine-1-yl]phenyl}propan-1-he7was 9.33
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-isopropoxyphenyl)propane-1-he29,36
1-(2,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he27,25
ethyl ester of 4-(4-{3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propionyl}-3-forfinal)piperazine-1-carboxylic acid77,17
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-morpholine-4-ylphenyl)propane-1-he47,74
propyl ether of 4-(4-{3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propionyl}phenyl)piperazine-1-carboxylic acid7of 7.23
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-Mei the piperazine-1-yl)phenyl]propan-1-he 78,15
1-[4-(4-acetylpiperidine-1-yl)phenyl]-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he78,20
1-(4-chlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he29,40
1-(2,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he2of 9.55
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-phenylpropane-1-he28,50
1-(4-benzyloxyphenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he27,95
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-methoxyphenyl)propane-1-he29,00
oxalate 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-phenoxyphenyl)propane-1-it27,70
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-naphthalene-2-improper-1-he28,31
1-biphenyl-4-yl-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he28,83
1-(3,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he2the 7.65
1-(3,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he8,02
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2,3,4-trichlorophenyl)propane-1-he28,76
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-forfinal)propane-1-he29,35
1-(2,4-dichloro-5-forfinal)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he29,15
4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)butane-1-he88,51
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(3-forfinal)propane-1-he29,17
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(6-methoxynaphthalene-2-yl)propane-1-he29,37
1-(3,5-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he29,13
3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-naphthalene-1-improper-1-he28,99

Anti-inflammatory/analgesic activity of the compounds of the present invention can be determined by tests in vivo, such as analysis of mechanical hyperalgesia of the paw in rats induced carrageenan, and analysis of mechanical hyperalgesia in rats, induced complete adjuvant-blockers, which are described in more detail in PR the measures 19 and 20, respectively. Activity against inhibition of contractions of the bladder may be determined by in vivo analyses, such as analysis of inhibition of contractions of the urinary bladder in rats induced isovolumetric stretching of the bladder, and the analysis of inhibition of contractions of the urinary bladder in rats induced by change of fluid volume, which are described in more detail in examples 21 and 22, respectively. Activity against inhibition of septic shock can be determined by analysis of in vivo, such as the analysis of correct hypotension in rats induced by endotoxin, described in more detail in example 23.

The present invention includes pharmaceutical compositions containing at least one compound according to the invention or its individual isomers, racemic or nerezisca mixture of isomers, or pharmaceutically acceptable salt or solvate, in a mixture with at least one pharmaceutically acceptable carrier and optionally other therapeutic and/or prophylactic ingredients.

Typically, compounds of the present invention is administered in a therapeutically effective amount by any acceptable route of administration, accepted for agents of similar purpose. Suitable doses typically range from 1 to 500 mg per day, preferably 1-100 mg per day and most predpochtitelno-30 mg per day, depending on many factors, such as the weight of curable diseases, the age and relative health of the subject, the activity of the used connection method and form of administration, indications, on the basis of which is assigned to the administration of a medicinal product, opinion and qualifications of the doctor. Specialist on these diseases without special experiments on the basis of their experience and descriptions of the present invention can determine therapeutically effective amount of the compounds of the present invention, necessary for the treatment of this disease.

Typically, compounds of the present invention is administered in the form of pharmaceutical compositions, including compositions suitable for oral (including transbukkalno and sublingual (sublingual) methods), rectal, nasal, local, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) routes of administration or in a form suitable for administration by inhalation method or injection. The preferred method of administration is generally oral when appropriate daily regimen of medicines, which is assigned according to the severity of disease.

Connection or connection to the present is the invention in a mixture with one or more suitable adjuvants, carriers or diluents can be produced in the form of pharmaceutical compositions and standard doses. Pharmaceutical compositions and standard doses can include the necessary ingredients in the appropriate proportions, can contain or not contain additional active compounds or components, and the standard dose can contain any acceptable effective amount of the active ingredient in accordance with the assigned daily scheme of a medicament. The pharmaceutical compositions can be used in the form of solid dosage forms such as tablets or filled capsules, in the form of a semi-solid, powder formulations with prolonged action, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral administration, or in the form of suppositories for rectal or vaginal administration, or in the form of sterile injectable solutions for parenteral administration. For standard doses suitable are compounds containing per tablet approximately 1 mg of active ingredient or, more generally from about 0.01 to about 100 mg

Compounds of the present invention can be prepared in many forms for oral administration. Pharmaceutical compositions and dosage can include to the operation of the active ingredient the compound or compounds of the present invention or their pharmaceutically acceptable salts. Pharmaceutically acceptable carriers may be solid or liquid consistency. Solid form preparations include powders, tablets, pills, capsules, starch wafers, suppositories, and dispersible granules. A solid carrier can be one or more substances, which can act as diluents, flavoring agents, soljubilizatory, wetting, suspendresume agents, binding agents, preservatives, dezintegriruetsja agents or encapsulating material. In the manufacture in the form of powders, the carrier is typically a finely powdered solid substance that is mixed with finely ground active ingredient. In the manufacture of tablets, the active ingredient is usually mixed with a carrier containing a binder component in the appropriate proportions, and pressed into tablets of the desired shape and size. The powders and tablets preferably contain from about one (1) to approximately seventy (70) percent of the active compounds. Suitable carriers include, without limitation, magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, coconut oil, etc. it is Assumed that the term "drug (drug)" which concludes the composition of the active compound with encapsulating material carrier, provided that the capsule containing the active ingredient with the carriers, or without them, surrounded by carrier, which is in close contact with the active component. A similar definition applies to the wafers and cakes. Tablets, powders, capsules, pills, wafers and cakes are solid forms suitable for oral administration.

Other forms suitable for oral administration, are liquid forms of drugs, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid forms of drugs, which immediately before use translate into liquid form. The emulsion can be obtained in solutions, for example aqueous solutions of propylene glycol, or they may contain emulsifying agents such as lecithin, monooleate sorbitol or Arabian gum. Aqueous solutions prepared by dissolving the active component in water and adding the appropriate colors, flavors, stabilizers and thickeners. Aqueous suspension prepared by dispersing finely ground active ingredient in water containing a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium salt of methyl cellulose and other known suspendresume agents. Liquid form preparations include solutions, suspensions and emulsions and moghtaderi, along with the active component, colorants, flavors, stabilizing agents, buffering agents, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents, etc.

Compounds of the present invention can be prepared for parenteral administration (e.g. by injection, for example by injection of a test dose or continuous infusion) and may be put in the form of standard doses in capsules filled syringes, small containers for infusion or containers with multiple doses containing preservative. Compositions can take the form of suspensions, solutions or emulsions in oily or aqueous binder, such as a solution in aqueous polyethylene glycol. Examples of oil or non-aqueous carriers, diluents, solvents or binders include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil), esters of organic acids for injection (for example, etiloleat) and may contain additional components, such as preserving, wetting, emulsifying or suspendida, stabilizing and/or dispersing agents. In another embodiment, the active ingredient may be in powder form, obtained by release of sterile solids in aseptic conditions or lyophilization of a solution, to make laugh the project before use with an appropriate carrier, for example sterile, pyrogen-free water.

Compounds of the present invention can be prepared for topical application to the epidermis as ointments, creams or lotions, or as a transdermal patch. For example, ointments and creams produce water-or oil-based adding suitable thickeners and/or gelling agents. Lotions produce water-or oil-based, in addition, usually containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickeners or dyes. Compositions for the local introduction of the oral cavity represent the pellet containing the active agent in a mixture with a filler having a pleasant flavor, usually sucrose and the Arabian gum or tragakant; tablets containing the active ingredient in a mixture with an inert basis such as gelatin and glycerin or sucrose and Arabian gum; a rinsing solution containing the active ingredient in an appropriate liquid medium.

Compounds of the present invention can be prepared for administration in the form of suppositories. Low-melting wax such as a mixture of glycerides of fatty acids or coconut oil, is first melted, and then it is uniformly dispersed active component, for example, by stirring. The molten homogeneous is mesh poured into forms appropriate size and then cooled to purchase solid consistency.

Compounds of the present invention can be prepared for vaginal administration. Suitable are vaginal suppositories, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient carriers known in the art.

Compounds of the present invention can be prepared for nasal administration. The solution or suspension is applied directly to the nasal cavity by conventional means, for example, a dropper, pipette or spray. The composition can be delivered in form, containing one or more doses. In the case of a dropper or pipette, the patient is given a certain volume of solution or suspension. Sprays injected dosing gun.

Compounds of the present invention can be prepared for aerosol administration, primarily in the respiratory tract and including intranasal administration. Usually particles connections are small, for example approximately five (5) microns or less. Such a particle size of get known methods, for example by grinding to a fine state micronization. The active ingredients are manufactured in a sealed package with the appropriate gas propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other priemel the range of the gas. The aerosol may also contain surfactants, such as lecithin. The dose of the drug is regulated by a metering valve. In another embodiment, the active ingredients in the form of a dry powder, for example a powder mix of the compound with an appropriate powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). In the nose powdered carrier forms a gel. The powdered composition can be manufactured in a standard dose, for example, capsules or cartridges, for example, gelatin or blister packs from which the powder can be entered inhaler.

Optionally, the composition can be obtained with intersolubility coating for Vvedenie with a slow or controlled release of the active ingredient.

The pharmaceutical preparations are preferably represent a standard dose. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. The standard dose can be a packaged preparation, the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the standard dose may be a capsule, tablet, wafer and is and cake or can be a package, containing a certain number of any of the above forms.

Other pharmaceutically acceptable carriers and their formulations are described in the book Remington The Science and Practice of Pharmacy, ed. by E.W.Martin, Mack Publishing Company, 19th edition, Easton, Pensilvania (1995). Typical pharmaceutical compositions containing the compound of the present invention, described in examples 11-17.

The following preparations and examples are given with the purpose of enabling the person skilled in the art will be familiar with the proposed invention and use it in practice. Examples are given to illustrate the invention and do not limit its scope.

In the examples the authors sought to ensure accuracy in compliance (specified) parameters (e.g., quantities, temperatures and the like), however, there may be minor experimental errors and discrepancies due to inaccuracies, for example, in the calibration, the rounding of figures, etc. Elemental composition is given in percent.

Example 1

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-he

1A), 1-(4-Forfinal)-3-(4-nitrophenyl)propane

A solution of 4-fortetienne (11,05 g, 80 mmol) and 4-nitrobenzaldehyde (12,08 g, 80 mmol) in ethanol (120 ml) was cooled in an ice bath. Then the reaction mixture was treated with a solution of potassium hydroxide (9,86 g, 176 mmol) in water(80 ml), was stirred for 30 min, concentrated in vacuo and diluted with water. The precipitation was separated by filtration and washed with water. Specified in the title compound was obtained by crystallization from ethyl acetate/hexane in the form of crystalline substances orange (16,98 g, 82.5 per cent), tpl.167,6-168,0°C.

Elemental analysis for C15H10FNO3:

est.: With 66,40, N. And 3.72, N 5,16;

calc.: WITH 66,48, N 3,65, N OF 5.29.

1B) 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-he

A mixture of 1-(4-forfinal)-3-(4-nitrophenyl)propenone (10 g, 38.9 mmole) and 10% palladium on coal (1.0 g) in tetrahydrofuran (100 ml) and ethyl acetate (100 ml) was first made at ambient temperature for 5 h under pressure using a balloon with hydrogen. The catalyst was removed by filtration through a layer of celite and the filtrate was concentrated in vacuum. The product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane)indicated in the title compound was obtained in the form of oil, solidified during storage (8,17 g, 86%), tpl.54-55°C.

1B) 3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-he

A mixture of 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-it (1,17 g, 4,81 mmole) and sulfate of 2-chloro-4,5-dihydro-1H-imidazole (1,95 g, 9,62 mmole) (obtained according to the method described Trani A. and Bellasio E., J. Het. Chem., 11, 257 (1974)) in 2-propanol (20 ml) was boiled under reflux for 15 minutes the Reaction is th mixture was cooled, was diluted with ethyl acetate (150 ml), washed with 5%sodium hydroxide solution, water and brine. The organic layer was separated, dried over potassium carbonate and evaporated in vacuum. The product was purified by chromatography on silica gel (eluent: 10% methanol/dichloromethane containing 1% ammonium hydroxide), was obtained 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-it is in the form of oil (1.01 g, 76.5 per cent). The oil was converted into the hydrochloride, tpl.190,2-190,8°C.

Elemental analysis for C18H19ClFN3O•0,2H2O:

est.: With 61,52, 5,56 N, N 11,96;

calc.: WITH 61,40, N 5,47, N OF $ 11.97.

Example 2

The following compounds of formula Ia was obtained according to the methods described in example 1, replacing 4-fortetienne described in example 1A, to the corresponding compounds of formula Ia.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-isopropoxyphenyl)propane-1-it, tpl.134-137°C.

Elemental analysis for C21H26ClN3O•0,2H2O:

est.: With 64,42, N 6,80, N of 10.73;

calc.: WITH 64,49, N 6,69, N 10,86.

Hydrochloride of 1-(2,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.154-157°C.

Elemental analysis for C18H18ClF2N3O•0,2H2O:

est.: With 58,52, N 5,02, N 11,37;

calc.: WITH 58,56, N 4,89, N 11,47.

Hydrochloride of 1-(4-chlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]ropan-1-it, tpl.189-192°C.

Elemental analysis for C18H19Cl2N3O:

est.: With 59,35, N 5,26, N 11,54;

calc.: WITH 59,74, N 5,33, N 11,70.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(phenyl)propane-1-it, tpl.154-155°C.

Elemental analysis for C18H20ClN3O:

est.: With 65,55, N 6,11, N 12,74;

calc.: WITH 65.42 PER, N 6,09, N 12,81.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-benzyloxyphenyl)propane-1-it, tpl.157-159°C.

Elemental analysis for C25H25N3O2:

est.: With 76,16, N Of 6.31, N 10,52;

calc.: WITH 74,90, N 6,21, TO 10.62 N.

Oxalate 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-phenoxyphenyl)propane-1-it, tpl.176,8-178,5°C.

Elemental analysis for C26H25N3O6:

est.: With 65,67, N. And 5.30, N 8,84;

calc.: WITH 65,24, N 5,22, N 8,83.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-phenylphenyl)propane-1-it, tpl.157-160°C.

Elemental analysis for C24H24ClN3About•0,8H2O:

est.: With 68,58, N 6,14, N 10,00;

calc.: WITH 68,39, N OF 5.92, N 10,02.

Hydrochloride of 1-(3,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.187-189°C.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-forfinal)propane-1-it, tpl.133-135°C.

Elemental analysis for C18H18FN3O:

est.: With 69,44, N Of 5.83, N 13,50;

calc.: WITH 69,19, N 5,77, N 13,55.

-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(3-forfinal)propane-1-it, tpl.138-140°C.

Elemental analysis for C18H18FN3O:

est.: With 69,44, N Of 5.83, N 13,50;

calc.: WITH 69,17, N 5,79, N 13,52.

Hydrochloride of 1-(2,5-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.193-194°C.

Elemental analysis for C18H18ClF2N3O:

est.: With 59,10, N 4,96, N 11,49;

calc.: WITH 58,87, N IS 4.93, N 11,48.

Hydrochloride of 1-(3,5-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.206-209°C.

Elemental analysis for C18H18ClF2N3O•0,2H2O:

est.: With 58,52, N 5,02, N 11,37;

calc.: WITH 58,46, N 5,16, N 11,19.

Hydrochloride of 1-(3,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.193-195°C.

Elemental analysis for C18H18Cl3N3O:

est.: With 54,22, N 4,55, N 10,54;

calc.: WITH 54,21, N 4,48, N 10,55.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-methoxyphenyl)propane-1-it, tpl.151-153°C.

Elemental analysis for C19H21ClFN3O2•0,5H2O:

est.: With 58,99, N 5,73, N 10,86;

calc.: WITH 58,82, N 5,61, N 10,96.

Hydrochloride of 1-(2,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.173-175°C.

Elemental analysis for C18H18Cl3N3O:

est.: With 54,22, N 4,55, N 10,54;

calc.: WITH 54,65, N 4,58, N 10,56.

3-[4-(4,5-Dihydro-1H-imidazol-2 and the amino)phenyl]-1-(6-methoxynaphthalene-2-yl)propane-1-it, tpl.147,5-156,0°C.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(naphthalene-2-yl)propane-1-it, tpl.162,7-163,8°C.

Hydrochloride of 1-(4,6-dichloro-3-forfinal)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.178-181°C.

Elemental analysis for C18H17Cl3FN3O:

est.: With 51,88, N 4,11, N 10,08;

calc.: WITH 51,84, N 4,08, N 10,16.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2,3,4-trichlorophenyl)propane-1-it, tpl.178-179°C.

Elemental analysis for C18H17Cl4N3O•0,65H2O:

est.: With 48,60, N 4,15, N 9,45;

calc.: WITH 48,57, 3,89 N, N BEING 9.61.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(naphthalene-1-yl)propane-1-it, tpl.128,4-132,8°C.

Example 3

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-he

3A) 3-(4-AMINOPHENYL)-1-(4-(morpholine-4-ylphenyl)propane-1-he

A mixture of 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-it (0.56 g, 2,32 mmole) (obtained as described in example 1B) and research (1.01 g, are 11.62 mmole) in dimethyl sulfoxide (12 ml) was heated at 100-110°C in nitrogen atmosphere for 12 hours the Reaction mixture was cooled, diluted with ethyl acetate (150 ml) and washed with cold water and salt solution. The organic layer was separated, dried and evaporated in vacuum, thus received is listed in the title compound as oil, which solidified upon storage (0.6 g, 92%), tpl.130-132°C.

Elemental analysis for C19H22NO2:

est.: With 73,52, N 7,14, N 9,03;

calc.: WITH 73,13, N 7,08, N 9,00.

3b) 3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-he

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-it, tpl.196-197,6°C, obtained by the method described in example 1B, when replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-is 3-(4-AMINOPHENYL)-1-(4-(morpholine-4-ylphenyl)propane-1-on.

Elemental analysis for C22H26N4O2:

est.: With 69,82, N 6,92, N 14,80;

calc.: WITH 69,46, N 6,90, N 14,77.

Example 4

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-morpholine-4-ylphenyl)propane-1-he

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-it, tpl.168-171°received according to the methods described in example 3, replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-she described in example 3A, 3-(4-AMINOPHENYL)-1-(2,4-differenl)propane-1-on.

Elemental analysis for C22H26ClFN4O2•0,N2O:

est.: With 56,19, N 6,21, N 12,55;

calc.: WITH $ 59.13 USD, N. 6,00, N 12,56.

Example 5

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethoxycarbonylmethyl-1-yl)phenyl]propan-1-he

5A) Ethyl) - Rev. ether 4-{4-[3-(4-AMINOPHENYL)propionyl]phenyl}piperazine-1-carboxylic acid

A mixture of 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-she (1.1 g, to 4.52 mmole) (obtained as described in example 1B), 1-ethoxycarbonylpyrimidine (2.15 g, 13,57 mmole) and Diisopropylamine (6.5 g, 4,98 mmole) in dimethyl sulfoxide (10 ml) was heated at 100-110°C for 12 h the Reaction mixture was cooled, diluted with ethyl acetate (150 ml), washed with cold water and salt solution. The organic layer was separated, dried and evaporated in vacuum. The product was purified by chromatography on silica gel (eluent: 60% ethyl acetate/hexane), was obtained is listed in the title compound, tpl.106,3-106,7°C.

Elemental analysis for C22H27N3O3:

est.: With 69,27, N 7,13, N 11,02;

calc.: WITH 69,13, N? 7.04 BABY MORTALITY, N 11,03.

5B) 3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethoxycarbonylmethyl-1-yl)phenyl]propan-1-he

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethoxycarbonylmethyl-1-yl)phenyl]propan-1-it, tpl.150-151,2°received by the method described in example 1B, when replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-she ethyl ester 4-{4-[3-(4-AMINOPHENYL)propionyl]phenyl}piperazine-1-carboxylic acid.

Elemental analysis for C25H32O3:

est.: With 66,79, N 6,95, N 15,58;

calc.: WITH 66,42, N 6,92, N 15,43.

Example 6

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-he

6A) 2,2,2-Cryptor-N-{4-[3-(4-forfinal)-3-oxopropyl]phenyl}ndimethylacetamide

A mixture of 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-it (3,34 g, 13,74 mmole) (obtained as described in example 1B) and triethylamine (4,95 g, 48,96 mmole) in dichloromethane (70 ml) was cooled in an ice bath under nitrogen atmosphere and treated by adding dropwise triperoxonane anhydride (5,14 g, 24,48 mmole). After stirring in an ice bath for 30 min the reaction was stopped by adding methanol (30 ml) and phosphate buffer solution with pH 7 (30 ml)and then was extracted with dichloromethane. The organic layer was washed with water and brine, dried and evaporated in vacuum. The product was purified by chromatography on silica gel (eluent: 20% ethyl acetate/hexane), was obtained is listed in the title compound as a solid (0.45 g, 85%), MS: 339 (M). The obtained product was used in the next stage without additional purification.

6b) tert-Butyl ether 4-(4-{3-[4-(2,2,2-triptoreline)phenyl]propionyl}phenyl)piperazine-1-carboxylic acid

Specified in the title compound was obtained in a solid beige color (64%) according to the method described in example 5, replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-it 2,2,2-Cryptor-N-{4-[3-(4-forfinal)-3-oxopropyl]phenyl}ndimethylacetamide, and 1-ethoxycarbonylpyrimidine 1-tert-butoxycarbonylmethyl described in example 5A. The floor of the obtained product was used in the next stage without additional purification.

6b) 2,2,2-Cryptor-N-{4-[3-oxo-3-(4-piperazine-1-ylphenyl)propyl]phenyl}ndimethylacetamide

A suspension of tert-butyl ester 4-(4-{3-[4-(2,2,2-triptoreline)phenyl]propionyl}phenyl)piperazine-1-carboxylic acid (2.5 g, of 4.95 mmole) in dichloromethane (10 ml) and triperoxonane acid (10 ml) was stirred at room temperature for 1 h the Reaction mixture was concentrated in vacuo and diluted with water. The obtained solid white were collected, washed with water and dried under vacuum, to receive specified in the header connection (1,93 g, 96%). The obtained product was used in the next stage without additional purification.

6 g), 2,2,2-Cryptor-N-(4-{3-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]-3-oxopropyl}phenyl)aptamil

A solution of 2,2,2-Cryptor-N-{4-[3-oxo-3-(4-piperazine-1-ylphenyl)propyl]phenyl}ndimethylacetamide (0.45 g, 1.1 mmole) was treated with methanesulfonamide (0.15 g, 1,32 mmole) and triethylamine (0.28 g, a 2.75 mmole) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred at 0°C for 15 min, diluted with ice water and was extracted with ethyl acetate. The organic extract was washed with water and brine, dried and concentrated in vacuum to receive specified in the title compound in the form of solid white (0.45 g, 85%).

6D) 3-(4-AMINOPHENYL)-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-he

A mixture of 2,2,2-trift the p-N-(4-{3-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]-3-oxopropyl}phenyl)ndimethylacetamide (0,43 g, to 0.88 mmole) and potassium carbonate solution (0,61 g, 4,39 mmole) in water (10 ml) and methanol (20 ml) was heated on the steam bath and then was stirred at room temperature for approximately 12 hours, the Reaction mixture was concentrated to one third volume, diluted with cold water and was extracted with dichloromethane. The organic extract was washed with water and brine, dried and concentrated in vacuum. The product was purified by chromatography on silica gel (eluent: 2% methanol in dichloromethane), to receive specified in the title compound in the form of solid white (0.28 g, 82%), tpl.KZT 166.5-170,0°C.

6E) 3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-he

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-it, tpl.160-163°received by the method described in example 1B, when replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-is 3-(4-AMINOPHENYL)-1-[4-(4-methanesulfonylaminoethyl-1-yl)phenyl]propan-1-it.

Elemental analysis for C23H30ClN5O3S·0,85 H2About:

est.: With 54,45, N 6,30, N 13,80;

calc.: WITH 54,49, N 6,01, N 13,80.

Example 7

The following compounds of formula Ia, where R1means substituted piperazine-4-ylphenyl, obtained similarly as described in examples 5 or 6, when replacement is 1-ethoxycarbonylpyrimidine to other piperazine derivatives or methanesulfonanilide on the other halides, respectively.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methylpiperazin-1-yl)phenyl]propan-1-it, tpl.176-178°C.

Elemental analysis for C23H29N5O:

est.: With 70,56, N 7,47, N 17,89;

calc.: WITH 70,29, N 7,38, N 17,80.

1-[4-(4-Acetylpiperidine-1-yl)phenyl]-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-it, tpl.228-230°C.

Elemental analysis for C24H29N5O2:

est.: With 68,71, N 6,97, N 16,69;

calc.: WITH 68,33, N 6,98, N 16,50.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[2-(4-ethoxycarbonylmethyl-1-yl)-4-forfinal]propane-1-it, hygroscopic foam.

Elemental analysis for C25H31ClFN5O3•0,25 H2O:

est.: With 58,84, N Of 6.26, N 13,72;

calc.: WITH 58,89, N OF 6.26, N 13,63.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-furan-2-eloxierarbeiten-1-yl)phenyl]propan-1-it, tpl.181-184°C.

Elemental analysis for C27H29N5O3•0,25 H2O:

est.: With 68,12, N 6,25, N 14,71;

calc.: WITH 68,10, N 6,18, N 14,69.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-propanesulfonate-1-yl)phenyl]propan-1-it, tpl.200-204°C.

Elemental analysis for C25H33N5O3S•0,4 H2O:

est.: With 61,18, N 6,94, N 14,27;

calc.: WITH 61,10, N OF 6.71, N 14,08.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethylenereleasing-1-yl)phenyl]propan-1-it, p is on.

Elemental analysis for C25H32N6O2•0,3 H2O:

est.: With 66,14, N 7,22, N 18,59;

calc.: WITH 66,13, N 7,22, N MT 18 : 34.

Hydrochloride 3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethoxycarbonylmethyl-1-yl)-2-forfinal]propane-1-it, tpl.213,5-214,3°C.

Elemental analysis for C25H31ClFN5O3•0,55 N2About:

est.: With 58,43, N 6,30, N 13,63;

calc.: WITH 58,44, N 6,17, N 13,49.

3-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-propoxycarbonyl-1-yl)phenyl]propan-1-it, tpl.137-139°C.

Elemental analysis for C26H33N5O3:

est.: With 67,36, N 7,18, N 15,11;

calc.: WITH 67,22, N 7,13, N 15,11.

Example 8

4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)butane-1-he

8A) 1-(4-Forfinal)-4-(4-nitrophenyl)butane-1-he

A solution of 4-(4-nitrophenyl)butyrylcholine (5,4 g, 23.7 mmole) and 4-fervently (2,6 ml, 26,2 mmole) in carbon disulfide (25 ml) was treated with portions of the aluminum chloride (4.1 g, 30,75 mmole) under nitrogen atmosphere. After adding the reagent, the reaction mixture was heated at 60-70°C for about 12 hours Then the reaction mixture was cooled in an ice bath, was treated with conc. hydrochloric acid (12 ml) and was stirred for 30 minutes the Mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with 1 N. g is droxicam sodium, water and saline solution, dried and evaporated in vacuum. The product was purified by chromatography on silica gel (eluent: 5% ethyl acetate/hexane), to receive specified in the title compound in the form of solid white (3,81 g, 56%). The product was used in the next stage.

8b) of 4-(4-AMINOPHENYL)-1-(4-forfinal)butane-1-he

A mixture of 1-(4-forfinal)-4-(4-nitrophenyl)butane-1-she (0.5 g, 1.7 mmole) and 10% palladium on coal (0.06 g) in ethyl acetate (15 ml) and tetrahydrofuran (5 ml) was first made at room temperature using a balloon with hydrogen. The catalyst was separated by filtration, the filtrate was concentrated in vacuum. The product was purified by chromatography on silica gel (eluent: 10% ethyl acetate/hexane), to receive specified in the title compound in the form of solid white (0.34 g, 78%). The product was used in the next stage.

8b) 4-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)butane-1-he

Hydrochloride 4-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)butane-1-it, tpl.171-173°received by the method described in example 1B, when replacing 3-(4-AMINOPHENYL)-1-(4-forfinal)propane-1-it 4-(4-AMINOPHENYL)-1-(4-forfinal)butane-1-on.

Elemental analysis for C19H20ClFN3O:

est.: With 63,07, N 5,85, N of 11.61;

calc.: WITH 63,21, N OF 5.89, N 11,72.

Example 9

1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(4,5-dihydro-1H-imida the ol-2-ylamino)phenoxy]alanon

9a) 1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-(4-nitrophenoxy)alanon

A mixture of 2-bromo-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)ethanone (1,03 g, 4.00 mmole), 4-NITROPHENOL (0,57 g, 4.00 mmole) and cesium carbonate (1.63 g, 5,00 mmole) in dry N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 h, the Reaction mixture was diluted with cold water. The obtained solid substance was separated by filtration, getting mentioned in the title compound (1.19 g, 94%). The product was used in the next stage without purification.

9b) 1-(4-Aminophenoxy)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)alanon

A mixture of 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-(4-nitrophenoxy)ethanone (0,63 g, 2.0 mmole) and dihydrate of tin chloride (2.25 g, 10 mmol) was stirred at room temperature for 3 days. Then the reaction mixture was added 1 n sodium hydroxide to pH 12 and was treated with methanol (75 ml) and celita. The resulting mixture was filtered, the filtrate was evaporated in vacuum. The residue was washed with water, brine and was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and solvent was removed, when it got mentioned in the title compound as brown oil (0,70 g, 25%). The product was used in the next stage without purification.

9b) 1-(2,3-Dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(4,5-dihydro-1H-imidazol-2-silts is about)phenoxy]alanon

Hydrochloride of 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenoxy]ethanone, tpl.165-168°S, MS: 354 (M+1), obtained by the method described in example 1B, when replacing 1-(4-aminophenoxy)-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)Etalon.

Elemental analysis for C19H20ClN3O4•0,6N2O:

est.: With 56,45, N 5,38, N 10,44;

calc.: WITH 56,86, N 5,09, N 9,96.

Example 10

2-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenoxy]-1-(4-methoxyphenyl)alanon

2-[4-(4,5-Dihydro-1H-imidazol-2-ylamino)phenoxy]-1-(4-methoxyphenyl)Etalon, tpl.65,5-69,0°received according to the methods described in example 9, replacing 2-bromo-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)ethanone described in example 9a, 2-bromo-1-phenylethanone.

Elemental analysis for C18H20ClN3About3•0,7N2About:

est.: With 57,74, N 5,76, N 11,22;

calc.: WITH 57,69, H 5.40, IS OF 10.93 N.

Example 11

Composition for oral administration

IngredientsWt.%
The active ingredient20,0
Lactose79,5
Magnesium stearate0,5

The ingredients were mixed and the mixture was placed in capsules of 100 mg each capsule, one capsule contains approximately the sum of the percent daily dosage.

Example 12

Composition for oral administration

IngredientsWt.%
The active ingredient20,0
Magnesium stearate0,5
Nitrocresols2,0
Lactose76,5
PVP (polyvinylpyrrolidone)1,0

The ingredients were mixed and granulated with a solvent, such as methanol. Then the composition was dried and formed into tablets (containing approximately 20 mg of active compound) using an appropriate tablet press machine.

Example 13

Composition for oral administration

IngredientsNumber
Active connection1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70%solution)is 12.85 g
Gum, Veegum K (Vanderbilt Co.)1.0 g
Flavora 0.035 ml
Dyes0.5 mg
Distilled waterq.s. to 100 ml

The ingredients were mixed, obtaining a suspension for oral administration.

Example 14

The composition for parenteral administration (intravenous)

IngredientsWt.%
The active ingredient0.25 g
Sodium chlorideq.s. before the formation of isotonic
Water for injection100 ml

The active ingredient was dissolved in a portion of water for injection was then added with stirring sodium chloride in sufficient quantity to education isotonic. The solution was brought up to the required volume of the remaining water for injection, filtered through a membrane filter with a pore size of 0.2 μm was Packed up in a sterile environment.

Example 15

The composition of the suppository

IngredientsWt.%
The active ingredient1,0
Polyethylene glycol 100074,5
Polyethylene glycol 400024,5

The ingredients were melted and mixed the and steam bath, and then poured into molds to the total mass of 2.5,

Example 16

The composition for local administration the way

IngredientsThe quantity g
Active connection0,2-2
Span 602
Twin 602
Mineral oil5
Vaseline10
Methylparaben0,15
Propylparaben0,05
Bottled hydroxyanisol (BHA)0,01
Waterq.s. to 100 ml

All the ingredients except water were mixed and heated at about 60°under stirring. Then at around 60°and under vigorous stirring was added a quantity of water sufficient to form the emulsion ingredients, then added the remaining water to approximately 100 g

Example 17

Composition for intranasal administration in the form of an aerosol

Prepared several compounds in aqueous suspensions containing from 0.025 to 0.5% of active compound, for intranasal administration in the form of an aerosol. The compositions optionally contain inactive ingredients such as microcrystalline cellulose, sodium is karboksimetilcelljuloza, dextrose and the like, the pH Value was adjusted by adding hydrochloric acid. Compositions for intranasal administration in the form of aerosol can be entered into the nasal cavity metering sprinklers that when one is triggered, usually produces 50-100 µl. A typical regimen involves 2-4 such doses every 4 to 12 hours

Example 18

Analysis of the binding of the radioactive ligand to the IP receptor of human platelets in vitro

Analysis of the binding of the radioactive ligand to the IP receptor of human platelets in vitro allows to determine the degree of binding of the investigational medicinal product with the appropriate target.

For each investigational medicinal product was determined by the concentration at which there is inhibition of binding by 50% (IC50), and the tilt angle was determined by the method of constructing an iterative curve. If you know the value of Kdradioactive ligand, for each drug the inhibition constant (Ki) was determined by the method of Cheng &Prusoff (1973). This receptor is a typical value of Kddefined in these terms, was 1E-8M. Usually lead the magnitude of the PKithat is the negative logarithm of the Ki.

The conditions of the experiment

The following buffer solutions were prepared using high-quality purified water.

The buffer is of ISIS: 10 mm Tris-HCl, 1.0 mm EDTA (di-Na), pH 7.5 at 4°C.

Buffer for analysis of: 20 mm Tris-HCl, 5.0 mm MgCl2, pH 7.4 at 25°C.

Buffer for washing: 20 mm Tris-HCl, 5.0 mm MgCl2, pH 7.4 at 4°C.

1. Obtain the membrane fraction.

The blood plasma (250 ml), platelet-rich, transferred into centrifuge tubes with a volume of 250 ml and centrifuged at 6000 g and 20°within 10 minutes the Precipitate resuspendable in the buffer for lysis and homogenized in a blender transmitter station (speed 7, the interval between pulses 1×20), the final volume was brought to 180 ml and centrifuged at 40,000 g and 4°C for 15 minutes the Precipitate resuspendable in the buffer for IP analysis, protein content was determined using BSA (Pierce firm) and before analysis were stored in vials with a volume of 2.0 ml at -80°C.

To achieve specific binding at the level of at least 80% at a competitive binding protein in each tube was 50 μg. The final concentration of radioactive ligand ranged from 1 to 3E-8M.

2. Analysis of competitive binding.

The membrane fraction was thawed at room temperature and was diluted to the appropriate concentration of the buffer solution for analysis. In a test tube for analysis were added to a buffer solution, a drug, a radioactive ligand, and then the membrane fraction. The tubes were incubated with the ri 25° C for 60 minutes the Contents of the tubes were filtered through glass fiber filter plate (GF/B), pre-treated with 0.3% solution of polyethylenimine (PEI), using the collection of cells from 96-well plates (Packard Top Count harvester). Tubes three times washed with ice-cold solution of 20 mm Tris-HCl, 5 mm MgCl2, pH 7.4 (3×0.5 ml/sample). Bound radioactivity was determined by liquid scintillation counter.

It is established that the compounds of the present invention, tested according to the described method, are antagonists of the IP receptor.

Example 19

Analysis of mechanical hyperalgesia induced carrageenan.

Anti-inflammatory/analgesic activity of the compounds of the present invention was determined by analysis of mechanical hyperalgesia induced carrageenan, the degree of suppression of paw hyperalgesia in rats induced carrageenan, using modified methods described L.O.Randall and J.J.Selitto, Archives of International Pharmacodynamics, 11, 409-419 (1957), and Vinegar, and others, Journal of Pharmacology and Experimental Therapeutics, 166, 96-103 (1969).

Male rats Sprague-Dawley (130-150 g) were weighed and statistically distributed into groups for testing (n=10). To induce mechanical hyperalgesia in rats was anestesiologi small dose of halothane gas and introduced into the bottom of the left hind paws 1% carrageenan or filler 1 (100 µl). 1 is to test rats were injected filler (10 ml/kg orally or 1 ml/kg intravenously) or compounds of the present invention (1, 3, 10, 30 and 100 mg/kg orally or 0.3, and 1.0, 3.0 and 10 mg/kg intravenously). Mechanical hyperalgesia was measured using analgesiometer (firm UGO BASILE, Biological Research Apparatus, Comerio, Italy). The rear paw of the animal treated filler or carrageenan, was placed on the upper surface of the device (sole to the plane of the device). Then on the dorsal (back) surface of the legs had increasing mechanical impact. For endpoint took impact force at which the animal draws back leg, bounces or popiskivaet.

Subjects groups were compared by the method of one-way ANOVA values, at which the animal draws back paw (RESP). Pair-wise comparison of groups receiving the drug, and the groups that received the medium was performed using a strategy LSD Fisher and methods Dunn. For each animal was calculated the percentage of suppression of mechanical hyperalgesia and average ID50using the following sigmoid model:

% inhibition = 100/(1 + exp.((ID50- dose)/N)),

where ID50means the dose of a compound required to inhibit half of the maximum response (i.e. in this model, 100%), and N denotes the parameter of the curve.

According to the analysis of compounds of the present invention have activity.

Example 20

Analysis of the mechanism is achieved hyperalgesia, induced complete adjuvant-blockers

Anti-inflammatory/analgesic activity of the compounds of the present invention can also be defined using a model of arthritic pain in rats at inducing adjuvant, where the pain is judged by the response of the animal to the compression of the inflamed paw, when used a modified method described J.Hylden etc., Pain, 37, 229-243 (1989). The modification is to assess hyperalgesia rather than changes in the activity of neurons of the spinal cord.

Brief description of the method: rats were weighed and statistically distributed on the tested group. To induce mechanical hyperalgesia in rats was anestesiologi small dose of halothane gas and introduced into the bottom of the left hind paws of 100 ál of complete adjuvant's adjuvant or saline. After 24 h and 1 h before the test rats were treated orally with water (filler) or compounds of the present invention. Mechanical hyperalgesia was measured using analgesiometer (firm UGO BASILE, Biological Research Apparatus, Comerio, Italy). The rear paw of the animal treated with saline or adjuvant's adjuvant, was placed on the upper surface of the device (sole to the plane of the device). Then on the dorsal (back) surface of the legs had increasing mechanical impact. For endpoint took effect in which the animal draws back paw, bounces or popiskivaet. Subjects groups were compared by the method of one-way ANOVA values, at which the animal draws back paw. For each animal was calculated percentage suppress hyperalgesia by the equation

100×((c/d-c/v)÷(s/v c/v)),

where c/d is the force at which the animal that received the drug, draws back paw treated with adjuvant's adjuvant, c/v means a force at which the animal received media draws back paw treated with adjuvant-blockers, and s/v means a force at which the animal received media draws back paw treated with salt solution. The reliability of the obtained data was determined using t-student test.

According to the analysis of compounds of the present invention have activity.

Example 21

Inhibition of contractions of the bladder induced isovolumetric stretching of the bladder in rats

Inhibition of contractions of the bladder was determined using a modified method described C.A.Maggi and others, J.Pharm. and.. Therapeutics, 230, 500-513 (1984).

A brief description of methods: male rats Sprague-Dawley (200-250 g) were weighed and statistically distributed into groups for testing. To induce contractions in the bladder was inserted a catheter through the urethra and poured the warm saline solution (5 ml). Rhythmic contraction was observed in approximately 30% of the animals. With the emergence of rhythmic contractions of the animals were injected intravenously, the compounds of the present invention (of 0.1, 0.3 or 1 mg/kg). Then measured the effect on rhythmic contractions.

According to the analysis of compounds of the present invention have activity.

Example 22

Inhibition of contractions of the bladder induced by changing its volume

Inhibition of contractions of the bladder was determined using a modified method of analysis described S.S.Hegde and others, Proceedings of the 26thAnnual Meeting of the International Continence Society (27-30 August 1996), abstract 126.

In female rats, Sprague-Dawley was anestesiologi urethane and installed equipment for intravenous drugs and in some cases to measure blood pressure, frequency of cardiac rhythm and pressure inside the bladder. In separate groups of animals was determined by the influence of the studied compounds on bladder contraction induced by the change in its volume. Reflex bladder contractions induced by filling the bladder with saline. The compounds were administered intravenously for funding through 10-minute intervals. As a positive control at the end of the test animals centuries the Dili atropine (0.3 mg/kg, intravenous).

According to the analysis of compounds of the present invention have activity.

Example 23

Elimination of hypotension in rats induced by endotoxin

Septic shock, sometimes called endotoxic shock caused by the presence in the bloodstream of infectious agents, especially the bacterial endotoxin, and is characterized by hypotension and organ dysfunction. Many of the symptoms of septic shock, especially hypotension, induce the rats to bacterial endotoxin. Therefore, it was expected that the connection property to inhibit the hypotension induced by endotoxin, can be used in the treatment of septic or endotoxic shock.

The activity of the compounds of the present invention in the treatment of septic or endotoxic shock was determined to eliminate hypotension in rats induced by endotoxin, using a modification of the method described .Giral and others, British Journal of Pharmacology, 118, 1223-1231 (1969).

A brief description of methods: adult rats (>200 g) was anestesiologi inhalation anesthetic, and then into the femoral artery and femoral Vienna was established catheters for sensors blood pressure and administration of drugs, respectively. Animals in a state of anesthesia was placed in a cage with latches Mawa for paws. After in the Stanovlenie from anesthesia and stabilize the heart rate and blood pressure (which usually occurs within approximately 30 min), the animals received intravenous endotoxin (50 mg/kg E. coli and 25 mg/kg Salmonella), then they recorded the change in blood pressure and heart rate. After 1 h, the animals were injected intravenously, the compounds of the present invention or the media and within the next 3 hours continuously registered cardiovascular parameters. The response of the body represented in the form of restoration of the initial blood pressure in percent. The reliability of the obtained results were evaluated using t-student test.

According to the analysis of compounds of the present invention have activity.

Although the present invention is described with reference to specific variations in its implementation, to a person skilled in the art it is evident that within the essence and scope of the invention various changes and equivalents of these options. In addition, within the essence and scope of the present invention numerous modifications are possible in accordance with a particular situation, material, composition of materials, method, stage or stages of the method. All these modifications included within the scope of paragraphs accompanying claims.

1. 2-Phenylaminopyrimidine General formula

where

R1means optionally substituted aryl, and R1not necessarily for what Eden one, two or three substituents, independently selected from the row containing alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy or optionally substituted heterocyclyl, which means a monovalent saturated carbocyclic radical containing from 3 to 7 atoms in the cycle, comprising one or two heteroatoms, independently selected from the series nitrogen, oxygen, and which optionally may be substituted by one or more substituents independently selected from the range alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkylsulfonyl, furanose;

R2means hydrogen,

And means-C(O)-(CH2)n- or-C(O)-CH2-O-,

the subscript n means an integer from 2 to 6, inclusive,

or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, in which a represents-C(O)-(CH2)n- or-C(O)-CH2-O-, and n is 2.

3. The compound according to claim 2, in which R1means aryl, optionally substituted one, two or three substituents, independently selected from the row containing alkoxy, aryl, aryloxy, aralkylated, halogen, Ethylenedioxy or optionally substituted as indicated in claim 1, heterocyclyl.

4. The compound according to claim 3 in which R1means phenyl, optionally substituted one, two or three of the Deputy is mi, independently selected from the row containing halogen, alkoxy, or optionally substituted as indicated in claim 1, heterocyclyl.

5. The compound according to claim 4, in which R1means phenyl, optionally substituted one, two or three substituents, independently selected from halogen or alkoxy.

6. The compound according to claim 5, or its pharmaceutically acceptable salt or MES, which means:

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-forfinal)propane-1-he,

1-(2,4-differenl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

1-(4-chlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

1-(2,4-dichlorophenyl)-3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(phenyl)propane-1-he /

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-methoxyphenyl)propane-1-on.

7. The compound according to claim 3 in which R1means phenyl, optionally substituted one, two or three substituents, independently selected from the row containing optionally substituted heterocyclyl as specified in claim 1, or a halogen.

8. The connection according to claim 7, in which R1means phenyl, optionally substituted one, two or three substituents, independently selected from the row containing optionally substituted morpholine-4-yl, optional for ewenny piperazine-4-yl, chlorine or fluorine.

9. The connection of claim 8, or its pharmaceutically acceptable salt or MES, which means:

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(4-(morpholine-4-ylphenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-(2-fluoro-4-morpholine-4-ylphenyl)propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-ethylenereleasing-1-yl)-phenyl]propane-1-he,

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(ethoxycarbonylmethyl-1-yl)-2-forfinal]propane-1-he /

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-methanesulfonylaminoethyl-1-yl)-phenyl]propane-1-he /

3-[4-(4,5-dihydro-1H-imidazol-2-ylamino)phenyl]-1-[4-(4-propanesulfonate-1-yl)-phenyl]propane-1-on.

10. The compound according to claim 3 in which R2means hydrogen.

11. The compound according to claim 1, in which a represents-C(O)-CH2-O-.

12. Connection by claim 11, in which R1means aryl, optionally substituted one, two or three substituents, independently selected from the row containing alkoxy, aryloxy, aralkylated, halogen, Ethylenedioxy or optionally substituted as indicated in claim 1, heterocyclyl.

13. The connection section 12, in which R1means phenyl, optionally substituted one, two or three substituents, independently selected from the row containing alkoxy, aryloxy, aralkylated, halogen, Ethylenedioxy or optionally substituted morpholine-4-yl or optionally substituted piperazine-4-yl.

14. The connection 13, in which R1means phenyl, optionally substituted one, two or three substituents independently selected from alkoxy or Ethylenedioxy.

15. The connection 14, in which R2means hydrogen.

16. The compound according to any one of claims 1 to 15 for use in the treatment or prevention of pathological conditions, symptoms alleviated in the treatment antagonist IP receptor.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of mycophenolate mofetil. Method involves the direct esterification of mycophenolic acid and 2-morpholinoethanol. The esterification reaction is carried out by boiling in ethers medium as a solvent of the general formula R3OR4 wherein R3 and R4 mean independently alkyl. Method involves using from 1.01 to 3.0 mole equivalents of 2-morpholinoethanol. The initial temperature of reaction is in the range 130-138°C and the final temperature of reaction is in the range 140-145°C, and the reaction period is from 5 to 50 h. The ratio of mycophenolic acid to solvent is in the range from 1 g/2 ml to 1 g/5 ml. Invention avoids problems associated with coloring mycophenolate mofetil, low solubility of product in higher ethers.

EFFECT: improved method of synthesis.

8 cl, 3 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivative of phenylpiperazine mesylate of the formula: possessing preferable properties as compared with form of a free base of the same compound. Also, invention describes a pharmaceutical composition and a method for inhibition of activity of dopamine D2-receptors and site of serotonin reuptake.

EFFECT: valuable pharmacological properties of derivatives.

3 cl, 1 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine that are partial agonists of D2 receptors and can be used in treatment of the central nervous system disorders, in particular, Parkinson's disease. Invention describes derivatives of benzoxazolone of the formula (1): wherein R means group of the formula (a) or (b) , and their salts. Also, invention describes a method for preparing compounds of the formula (1), pharmaceutical composition based on compounds of the formula (1), method for treatment of Parkinson's disease and method for treatment of the central nervous system disorders, such as schizophrenia, anxiety state and depression based on compounds of the formula 91). Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: improved methods for treatment, valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 1 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula: or wherein x means 1, 2, 3 or 4; m means 1 or 2; n means 1 or 2; Q represents carbon atom (C) or nitrogen atom (N); A represents oxygen atom (O) or sulfur atom (S); R1 represents lower alkyl; X represents -CH; R2 represents hydrogen (H) or halogen atom; R2a, R2b and R2c can be similar or different and they are chosen from hydrogen atom (H), alkyl, alkoxy-group or halogen atom; R3 represents aryloxycarbonyl or alkoxyaryloxycarbonyl; Y represents -CO2R4 wherein R4 represents hydrogen atom (H) or alkyl, and including all their stereoisomers, their prodrugs as esters and their pharmaceutically acceptable salts. These compounds are useful antidiabetic and hypolipidemic agents and agents used against obesity also.

EFFECT: valuable medicinal properties of compounds.

29 cl, 12 tbl, 587 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means phenyl or naphthyl comprising the following substitutes: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl (-CF3), phenyl or heteroaryl representing aromatic 5-membered ring that comprises sulfur atom; each among R2, R3, R4 and R6 and independently of one another means hydrogen atom, hydroxy-group, (lower)-alkenyl, halogen atom, (lower)-alkyl or (lower)-alkoxy-group wherein at least one radical among R2, R3, R4 and R6 doesn't mean hydrogen atom, or R3 and R4 are bound and also bound with carbon atoms to which they are bound and form ring, and R3 and R4 mean in common -CH=CH-S-, -S-CH=CH-, -CH=CH-O-, -O-CH=CH-, -CH=CH-CH=CH-, -(CH2)3-5-, -O-(CH2)2-3 or -(CH2)2-3-O- wherein R2 and R6 have above given values; R5 means (lower)-alkoxy-, (lower)-alkenyloxy-group, or ; R7 means hydrogen atom or (lower)-alkyl; R8 means (lower)-alkyl; R9 means hydrogen atom; R10 means phenyl or naphthyl that can be mono- or poly-substituted with -CF3; n means 1, 2 or 3, and wherein the bond between Ca carbon atom and Cb carbon atom represents carbon-carbon single or double bond, and to their pharmaceutically acceptable salts and esters also. Indicated compounds can be used as therapeutically active substances in treatment and/or prophylaxis of diseases mediated by agonists of PPAR-α and/or PPAR-γ receptors, for example, in treatment of diabetes.

EFFECT: valuable medicinal properties of compounds.

24 cl, 167 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 20 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

EFFECT: improved preparing method, valuable properties of compounds and pharmaceutical compositions.

15 cl, 14 tbl, 118 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology, biochemistry.

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) wherein R1 and R2 represent independently of one another hydrogen atom or methyl; R3, R4, R5 and R6 represent independently of one another hydrogen atom (H), halogen atom, formyl group, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkylenyloxycarbonyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylcarbonylamido-group, (C3-C7)-cycloalkylcarbonylamido-group, phenylcarbonylamido-group, benzyl, phenyl or naphthyl wherein benzyl, phenyl and naphthyl are substituted optionally and independently of one another with substitutes in amount up to two and chosen independently from halogen atom, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three and (C1-C4)-alkoxy-(C1-C4)-alkyl. Proposed method involves the following successive stages: (a) interaction of compound of the formula (II) wherein R3, R4, R5 and R6 are determined independently as given above with lithium-organic compound in the presence of sulfur source in medium of the first reactively inert solvent to form the reactive intermediate compound of the formula (IIa) (b) interaction of indicated reactive intermediate compound of the formula (IIa) with compound of the formula (III) to form compound of the formula (IV) (c) interaction of indicated compound of the formula (IV) with alkaline (C1-C2)-alkoxide in (C1-C2)-alkanol medium to form derivative of simple ether of the formula (V) wherein Alk represents (C1-C2)-alkyl; (d) interaction of indicated compound of the formula (V) with mineral acid to form compound of the formula (VI) and (e) oxidation of compound of the formula (VI) in the second reactively inert solvent to form compound of the formula (I). Prepared pyridazinone compounds are effective inhibitors of aldose reductase activity and can be used in prophylaxis and/or treatment of diabetes mellitus complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. Also, invention relates to new intermediate compounds of the formula (IV) used in synthesis of indicated inhibitors of aldose reductase, to a method for synthesis of compound of the formula (IV) and a method for synthesis of preferable pyridazinone compound of the formula (XI) .

EFFECT: improved preparing method, valuable medicinal properties of compounds and agents.

10 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

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

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to quinazoline derivatives of the formula (I) or their pharmaceutically acceptable salts wherein m = 0 or 1; each group R1 can be similar or different and represents halogen atom, hydroxy- and (C1-C6)-alkoxy-group, or group of the formula Q3-X1 wherein X1 represents oxygen atom (O); Q3 represents phenyl-(C1-C6)-alkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl, and wherein heteroaryl group represents aromatic 5- or 6-membered monocyclic rings with one or two nitrogen heteroatoms, and any heterocyclyl group defined as the group R1 represents non-aromatic saturated or partially saturated 3-6-membered monocyclic ring with one or two heteroatoms chosen from oxygen and nitrogen atoms, and wherein adjacent carbon atoms in any (C2-C6)-alkylene chain in the substitute R1 are separated optionally by incorporation of oxygen atom (O) in the chain, and wherein any group CH2 or CH3 in the substitute R1 comprises optionally in each of indicated groups CH2 or CH3 one or some halogen substitutes or a substitute chosen from hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkylsulfonyl or pyridyloxy-group, and wherein any heteroaryl or heterocyclyl group in the substitute R1 comprises optionally 1, 2 or 3 substitutes that can be similar or different and chosen from hydroxy-group, carbamoyl, (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]-carbamoyl, (C1-C6)-alkoxy-(C1-C6)-alkyl and cyano-(C1-C6)-alkyl, or among group of the formula -X5-Q6 wherein X5 represents a direct bond or -CO, and Q6 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that comprises optionally (C1-C6)-alkyl as a substitute wherein heterocyclyl group represents non-aromatic, fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from nitrogen and oxygen atom; R2 represents hydrogen atom; R3 represents hydrogen atom; Z represents a direct bond or oxygen atom; Q1 represents phenyl, (C3-C7)-cycloalkyl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl wherein heteroaryl group represents 5- or 6-membered aromatic monocyclic ring with I, 2 or 3 heteroatoms of nitrogen, and any heterocyclyl group represents non-aromatic fully or partially saturated 5- or 6-membered monocyclic ring with one or two heteroatoms chosen from oxygen, nitrogen or sulfur atom, or when Z represents oxygen atom (O) then Q1 can represent (C1-C6)-alkyl or (C1-C6)-alkoxy-(C1-C6)-alkyl and wherein any heterocyclyl group in the group -Q1-Z- comprises substitutes chosen from (C1-C6)-alkyl, (C1-C)-alkoxycarbonyl and pyridylmethyl, and wherein any heterocyclyl group in the group -Q1-Z- comprises optionally 1 or 2 oxo-substitutes; Q2 represents aryl group of the formula (Ia): wherein G1 represents halogen atom, trifluoromethyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C2-C6)-alkanoyl, pyrrolyl, pyrrolidinyl, piperidinyl and morpholinomethyl, and each G2, G3, G4 and G5 that can be similar or different represents hydrogen, halogen atom, cyano-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group, or G1 and G2 form in common group of formulae -CH=CH-CH=CH-, -CH=CH-O- or -O-CH=CH- being each group carries optionally halogen atom as a substitute, or G1 and G2 form in common group of formulae -O-CH2-O- or -O-CH2-CH2-O-, or -O-CH2-CH2-O-, and each among G3 and G4 represents hydrogen atom, and G5 is chosen from hydrogen and halogen atom. Proposed compounds possess anti-tumor activity and designated for preparing a medicine preparation for its using as an anti-tumor agent for suppression and/or treatment of solid tumors. Also, invention relates to a pharmaceutical composition based on abovementioned compounds.

EFFECT: valuable medicinal properties of compounds.

20 cl, 7 tbl, 57 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 4,6-dimethoxy-2-(methylsulfonyl)-1,3-pyrimidine. Method involves reaction of 4,6-dichloro-2-(methylthio)-1,3-pyrimidine with alkaline metal methoxide in inert organic solvent, transfer of prepared 4,6-dimethoxy-2-(methylthio)-1,3-pyrimidine in aqueous acid medium and the following oxidation of this compound in the presence of catalyst if necessary, preferably, with an interphase catalyst, such as tricaprylmethylammonium chloride. Then method involves carrying out the purification stage wherein pH value of the aqueous acid reaction mixture is brought about to the value from 5 to 8 with aqueous base, such as alkaline metal hydroxide, for example, sodium hydroxide at temperature 10-90°C and stirring in the presence of absence of organic solvent, for example, aromatic hydrocarbon, such as benzene, toluene or isomeric xylenes, or alcohol, such as methanol or ethanol. Also, invention relates to using the prepared compound as an intermediate substance for synthesis of herbicide, in particular, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide by reaction of 7-mercapto-3-methylphthalide of compound in preparing herbicides, for example, 7-[(4,6-dimethoxypyrimidin-2-yl)thio]-3-methylphthalide.

EFFECT: improved preparing method.

24 cl, 2 sch, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

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