2-(arylvinyl)aminoimidazole derivatives and pharmaceutical composition based on them

 

The invention relates to derivatives of 2-(arylvinyl)aminoimidazole formula I, where R1denotes a group of formula (A), (B) or (C), a R2, R3, R4, R5, R6and X are such as defined in the claims. Also described is a pharmaceutical composition based on these compounds. Technical result: received new compounds having valuable biological properties. The invention can be used in medicine as a drug. 2 C. and 18 h.p. f-crystals, 2 ill., table 4.

The present invention relates to compounds of the formula Iwhere R1denotes a group of formula (A), (B) or (C)where X in each case independently of one another denotes S, O or N;
R2and R4each independently of one another denotes
(1) hydrogen,
(2) alkoxygroup or
(3) halogen;
R3in each case, independently of one another denotes
(1) alkyl,
(2) cycloalkyl,
(Chet integer 0-3,
(7) -(CH2)mSO2NR8R9where m denotes an integer of 0-3,
(8) -(CH2)mNR7COR9where m denotes an integer of 0-3,
(9) -(CH2)mNR7SO2R9where m denotes an integer of 0-3,
(10) -(CH2)mNR7C(V)NR8R9where V represents S or O, and m denotes an integer of 0-3,
(11) -(CH2)mOY, where m denotes an integer of 0-3, a Y denotes hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl or carboxyethyl, or
(12) -O(CH2)nZ, where n denotes an integer of 1-4, a Z denotes cycloalkyl, hydroxyalkyl, cycloalkanes, heterocyclyl, alloctype, heteroaryl, -COR9, -CONR8R9, -SO2R9, -SO2NR8R9, -NR7SO2R9, unsubstituted aryl, mono-, di - or tizamidine aryl, where the substituents independently of one another selected from alkyl, halogen and alkyloxy;
R5in each case, independently of one another denotes
(1) -(CH2)mOY, where m denotes an integer of 0 to 3, and Y denotes hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, heterocyclyl or carboxyethyl, or
(2) -O(CH2)n9, -CONR8R9, -SO2R9, -SO2NR8R9, -NR7SO2R9, unsubstituted aryl, mono-, di - or tizamidine aryl, where the substituents independently of one another selected from alkyl, halogen and alkyloxy;
R6in each case, independently of one another denotes
(1) hydrogen,
(2) -COR9,
(3) -CONR8R9,
(4) -C(V)NR8R9where V denotes O or S,
(5) -SO2R9or
(6) -SO2NR8R9,
R7and R8each independently of one another denotes
(1) hydrogen,
(2) alkyl, or
(3) hydroxyalkyl;
R9in each case, independently of one another denotes
(1) alkyl,
(2) cycloalkyl,
(3) arylalkyl,
(4) hydroxyalkyl,
(5) haloalkyl,
(6) heterocyclyl,
(7) unsubstituted aryl, mono-, di - or tizamidine aryl, where the substituents independently of one another selected from alkyl, halogen and alkyloxy, or
(8) heteroaryl, or
R8and R9together with the nitrogen atom to which they are bound, form a 5 - or 6-membered monocyclic saturated or unsaturated ring, and the ring optionally substituted by exography, or
R7and Rand their pharmaceutically acceptable salts or crystalline forms.

The present invention offers a further pharmaceutical composition, containing as a component a therapeutically effective amount of the compounds of formula I, its pharmaceutically acceptable salt or crystalline form in a mixture with one or more acceptable carriers.

Further, the present invention proposes a method of treatment of painful conditions caused by various reasons, including, but not limited to, pain in inflammatory processes, pain after surgery, visceral pain, dental pain, premenstrual pain, headache, pain from burns, migraine or histamine headaches, pain in the nerve injury, neuritis, neuralgia, pain, poisoning, ischemic pain, interstitial cystitis, pain with cancer, pain associated with infection by viruses, parasites and bacteria, post-traumatic pain (including pain after fractures and sports injuries); a method of treatment of inflammation due to various reasons, including (but not limited to) the, is Peccei bladder and idiopathic inflammation of the bladder, abuse, old age, malnutrition, prostatitis, conjunctivitis, pain associated with disorders of the digestive tract, such as irritable bowel syndrome, and, in addition, a method of treatment of disorders of the work of the bladder associated with the syndrome infravesical obstruction, and incontinence (including acute incontinence, stress incontinence, and increased reactivity of the bladder); a method of treating asthma and septic shock in a mammal, comprising the introduction of a mammal in need a therapeutically effective amount of the compounds of formula I, its pharmaceutically acceptable salt or crystalline form.

Prostaglandins or prostanoids (PG) are a group of biologically active compounds isolated from membrane povoledo and get some polyunsaturated fatty acids. They belong to several main classes, denoted by letters, including D, E, F, G, H and I (prostacyclin). These main classes are further divided into subclasses, denoted by subscript numbers 1, 2 or 3, which correspond to the preceding fatty acid, for example PGEAET in response to various stimuli. They thus exhibit a variety of pharmacological properties.

The diversity of actions of prostanoids can be explained by the existence of certain receptors, which mediashout their action. Receptors for natural prostaglandin, to which they have the greatest affinity, called and separated them into five main types, denoted as DP (PGD2), FP (PG2), IP (PGI2), TP (THA2) and EP (RSU2). Additional information concerning prostaglandins and their receptors, cited in Goodman & Gillman's, The Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, new York, 1996, Chapter 26, pp. 601-616.

Prostanoids are produced by most cells in response to mechanical, thermal or chemical injury and the inflammatory process and cause sensitisation or direct activation of near sensory nerve endings. For several models of nociceptive and inflammatory processes have been reported giperalgeticheskie action (increased sensitivity to a stimulus which is normally painful sensation). Even despite the fact that PGE2widely recognized as the primary mediator of hyperalgesia, under the influence of B. the fact, when directly comparing the actions of PGE2and PGI2on the afferent neuron as giperalgeticheskie or sensitizing agents PGI2in vivo and in vitro is equally or more effective. However, until now there are no selective receptor substances-antagonists, which would definitively characterize the subtype (subtype) prostanoid receptors, mediaready sensitizing effect PGE2or PGI2.

If we take into account the characteristic instability and pharmacokinetic properties PGI2the results of most studies analgesia in vivo in rodents suggest that PGI2plays a major role in the induction of hyperalgesia. Similarly, results of in vitro studies give essentially obvious reason to believe that the IP receptors act as important modulators of sensory function of the neurons. Because the IP receptors in sensory neurons activate together as adenylylcyclase, and the phospholipase C and, therefore, camp-dependent protein kinase and protein kinase C, these receptors can exert a powerful influence on the activity of ion channels and, thus, to secrete the neuroma in pain in inflammatory processes obtained in recent studies on mice, bred vnutrivennoi mutation deprived of IP receptors (T. Murata and others, Nature 1997, 388, 678-682). In these animals caused by acetic acid or cramps caused by carrageenan swelling of the legs weakened to levels similar to those which were observed in mice of wild species when introduced into the body indomethacin. In contrast, spinal nociceptive reflexes, which were determined by kicks tail and test hot-plate, were normal. Moderate convulsions as a reaction caused by PGE2in animals, bred vnutrivennoi mutation, remained unchanged.

Based on these observations, it can be assumed that the compounds of the present invention are effective antinociceptive agents.

Besides the fact that prostanoids are mediators of hyperalgesia, they are known to be locally produced in the bladder in response to physiological stimuli such as stretch detrusor smooth muscle injuries vesicules mucous membrane and stimulation of the nerves [K. Anderson, Pharmacological Reviews, 1993, 45(3), 253-308]. PGI2is the major prostanoid allocated bladder person. Based on several lines of evidence suggest that about bladder, and activation of C-fiber afferents due to the stretching of the bladder. It has been suggested that prostanoids may participate in the pathophysiology of disorders of the work of the bladder, for example in the syndrome infravesical obstruction, and conditions associated with incontinence, such as acute incontinence, stress incontinence, and increased reactivity of the bladder. Thus, I believe that the treatment of such conditions will be useful substance-antagonists prostanoid IP receptors.

In the patent literature as examples mentioned some 2-(substituted phenyl) iminoimidazolidine connection. Thus, in particular, in European patent application EP 0017484 B1 (filed by the company Fujisawa Pharmaceutical) describes compounds that can be used to treat hypertensive, inflammatory and gastro-intestinal diseases and to alleviate pain of different nature; in U.S. patent 4287201 (issued in the name of Olson and others) described compounds, which can be applied to delay the onset of egg production in young chickens that interruption of egg production in adult chickens and for initiating artificial molt; in U.S. patent 4396617 (issued in the name Dolman and Kuipers) described fungicides, acting against inhibitors of lipoxygenase and phospholipase C and substance-receptor antagonists of platelet activating factor, which can be used for the treatment of inflammatory or allergic conditions and myocardial infarction; in U.S. patent 5326776 (issued in the name Winn and others) described compounds, which are substances-receptor antagonists angiotensin II; in the application to the United Kingdom patent GB 2038305 (filed by the company Duphar International Research) describes compounds that can be used to inhibit the growth of lateral shoots of tobacco plants or tomatoes, or inhibiting the growth of vegetation on the lawns, or for growing dwarf ornamental plants; and in the application WO 96/30350 (filed by the company Fujisawa Pharmaceutical) described compounds, which can be used as drugs for the prevention and therapeutic treatment of diseases, mediasound oxidating the synthase.

In Fig. 1 presents the x-ray crystalline form I of sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole.

In Fig. 2 presents the x-ray crystal form II sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole.

Used in this description and the claims, the following terms in all cases, unless otherwise specified, have the following values.

"Alkyl" refers to obnovlennth the native atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, etc.,

"Cycloalkyl" means a monovalent saturated carbocyclic group containing from three to fourteen carbon atoms, inclusive, such as cyclopropylmethyl, cyclopropylethyl, cyclopropyl, cyclobutyl, 3-ethylcyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl etc.

"Alkyloxy" means a radical-OR where R is alkyl, which is described above, optionally substituted by one or more alkyloxyaryl. Examples include (though are not limited to, methoxy, ethoxy, isopropoxy-, second -, butoxy, isobutoxy-, 2-ethoxy-1-(ethoxymethyl)ethoxypropan etc.

"Cycloalkylation" means a radical-OR where R denotes cycloalkyl, which is described above, for example, cyclopentyloxy, cyclohexyloxy etc.

"Hydroxyalkyl" means a linear monovalent hydrocarbon radical containing from one to four carbon atoms, or a branched monovalent hydrocarbon radical containing three or four carbon atoms, substituted by one or two hydroxyl groups, provided that if two hydroxy groups they are not associated with one and the proximately, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-hydroxybutyl, 3,4-dihydroxybutyl, 2-(hydroxymethyl)-3-hydroxypropyl, etc., preferably 2-hydroxyethyl and 1-(hydroxymethyl)-2-hydroxyethyl.

"Alkyloxyalkyl" means hydroxyalkyl in which hydrogen atom (hydrogen atoms) or one or both hydroxyl groups are replaced With1-4the alkyl, for example 2-methoxyethyl, 3-methoxybutyl, 2-methoxymethyl, 2-isopropoxyethanol, 2-ethoxy-1-(ethoxymethyl)ethyl, etc.,

"Carboxylic" means the radical-RCOOH, where R represents alkyl, which is described above, for example the balance 2-propionic acid, 3-butane acid, etc.,

"Aryl" means a monocyclic aromatic hydrocarbon radical, containing five or six ring atoms, or a 9-14 membered bicyclic or tricyclic ring system in which at least one ring, by its nature, is aromatic. Examples of aryl radicals include, but are not limited to, benzyl, phenyl, naphthyl, etc.,

"Alloctype" means a radical-OR where R represents aryl, which is described above, for example fenoxaprop etc.

"Arylalkyl" means the radical Rand

"Heteroaryl" means a monocyclic aromatic ring or 9-14 membered bicyclic ring system in which at least one ring, by its nature, is aromatic; it covers the heterocyclic compounds containing in the ring one, two or three heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl radicals include, but are not limited to, thienyl, imidazolyl, pyridinyl, pyrazinyl etc.

"Heterocyclyl" means a monovalent saturated carbocyclic radical containing five, six or seven ring atoms, of which one or two selected from nitrogen, oxygen and sulfur. Examples heterocyclyl radicals include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, [1,3] dioxane-5-yl, 5-methyl - [1,3]dioxane-5-yl, morpholine, imidazoline, piperidine, pyrrolidine, pyrrolidin-2-it, pyrrolidin-2,3-dione, etc., most preferred tetrahydropyranyl.

"Halogen" means a fluorine atom, bromine, chlorine or iodine, preferably fluorine or chlorine.

"Haloalkyl" means alkyl substituted with one to three fluorine atoms or chlorine, for example chloromethyl, trifluoromethyl, 2,2,2-triptorelin, 2,2,2-trichlorethyl etc.

"Amin is the case during some chemical reactions would be subject to transformation. Usually used aminosidine groups include those well known in the art, such as benzyloxycarbonyl (carbobenzoxy, CBS), para-methoxybenzeneboronic, trialkylsilanes, triptorelin, para-nitrobenzenesulfonyl, N-tert-butoxycarbonyl (VOS), etc. Some aminosidine group is preferable to others because of the relative ease of removal.

The terms "optional" and "optionally" means that the described event or circumstance may be or may not be, and the description includes instances when such events or circumstances occur, and when they are absent. So, for example, is not necessarily linked" means that the link may contain or be absent and that the description covers both single and double bonds.

"Inert organic solvent" or "inert solvent" mean a solvent inert to the above in the present description the terms with its use in the reaction, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform (SNS3), methylene chloride and dichloromethane (CH2Cl2), dichloroethane, diethyl ether, atwo all cases, unless otherwise stated, as solvents for carrying out the reactions according to the present invention is used inert solvents.

The term "pharmaceutically acceptable carrier" means a carrier that can be used to prepare pharmaceutical compositions, which are usually compatible with other components of the composition, has no undesirable effect on the recipient, not junk neither biologically nor otherwise and covers the media that are acceptable for veterinary use, as well as for pharmaceutical use in the treatment of humans. The term "pharmaceutically acceptable carrier" in the present description and the claims used as cover one or more than one such carrier.

The term "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological action of the parent compound. Such salts include
(1) acid additive salts obtained with the use of mineral acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or obtained from ispolzovaniya 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, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, etc., and
(2) salts formed when an acidic proton contained in the initial connection, or is replaced by a metal ion, for example an alkali metal ion, ion alkaline-earth metal or aluminum ion, or forms a coordination bond with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

The term "crystalline form" refers to R is (a) Polymorphs are crystalline structure, which may be formed during the crystallization of compounds with different crystal packings, and they all have the same elemental composition. Different polymorphs usually have different x-rays, infrared spectrum, melting point, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Specifically used for the recrystallization solvent, rate of crystallization, storage temperature, and other factors can lead to the predominance of any one crystalline form.

(b) the Solvate are in General crystalline form, which includes either stoichiometric or non-stoichiometric amount of solvent. In the process of crystallization of some compounds in the solid crystalline state often tend to capture a certain molar fraction of solvent molecules, thus forming a MES. When the solvent is water, can form hydrates.

(C) Amorphous forms are non-crystalline materials, do not have any significant ordered zone, which is usually not peculiar cha 2-[4-(4-isopropoxyphenyl)phenyl] aminoimidazole, they are marked as crystalline forms I and II. Crystalline forms I and II were obtained by the methods described in examples 1 and 22, respectively, they are described in more detail in examples 21-23. In General, the crystalline form is further described in VPP etc. in Pharmaceutical Research, 1995, vol 12(7), 945-954, and in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publisching Company, 19th ed. , Easton, pieces Pennsylvania, volume 2, Chapter 83, 1447-1462.

"Treatment" of a disease includes
(1) preventing the disease, i.e. preventing the development of clinical symptoms of a disease in a mammal that may be exposed to or to be predisposed to the disease but has not yet affected and do not show symptoms of the disease;
(2) inhibiting the disease, i.e., delay development of the disease or its clinical symptoms, or
(3) the weakening of the disease, i.e. the provision of regression of the disease or its clinical symptoms.

"Therapeutically effective amount" means that amount of compound that, when introduced into the body of a mammal for the treatment of the disease is sufficient to effect such treatment for the disease. "Therapeutically effective amount" generally varies depending on soedineniya and relative health of the patient, ways and forms of introduction into the body, the opinion of the appropriate physician and other factors.

As is well known in the art, imidazolin-2-illinoie group in compounds such as the compounds of formula I, are in tautomeric equilibrium with imidazolin-2-redenominate

For convenience, all of the compounds of formula I are represented as having imidazolin-2-illinova structure, but it must be borne in mind that the scope of the invention include both tautomeric forms.

The name and numbering of the provisions in the compounds of the present invention is illustrated below.


The side chain substituent R1numbered as shown below



Compounds according to the invention is referred to as imidazoline derivatives, and the nomenclature used in this application, is based in General on the recommendations of the IUPAC. However, because rigid adherence to these recommendations would lead to a significant change names when replacing only one alternate form of the names of compounds stores according the>
denotes a group of formula (A), R2and R4represent hydrogen atoms, and R3denotes second-butoxypropyl, called 2-[4-(4-sec-butoxyphenyl)phenyl]aminoimidazole.

In particular, the compound of formula I, in which R1denotes a group of formula (C), where X denotes S, R2and R4represent hydrogen atoms, and R5denotes a methoxy group, called 2-[4-(5-methoxytrityl-2-ylmethyl)phenyl] aminoimidazole.

For example, the compound of formula I, in which R1denotes a group of formula (C), where X denotes N, R2and R4represent hydrogen atoms, and R3denotes ethylaminomethyl, called 2-[4-(1-acylaminopenicillin-4-ylmethyl)phenyl] aminoimidazole.

In the group of the compounds of the present invention, which are presented in the summary of the invention, the preferred category includes the compounds of formula I, in which R2and R4each independently of one another in each case represents hydrogen or halogen, preferably hydrogen, fluorine or chlorine.

Within this category one preferred subgroup includes the compounds of formula I, in which R1denotes a group of formula (A), where
(1) R3about doctitle methyl, isopropyl, sec-butyl, isobutyl or tert-butyl;
(b) alkyloxyalkyl, preferably 2-ethoxy-1-(ethoxymethyl)ethyl;
(C) cycloalkyl, preferably cyclopentyl or cyclohexyl, or
(g) heterocyclyl, preferably tetrahydropyran-2-yl or tetrahydropyran-4-yl;
(2) R3denotes-O(CH2)nZ, where n denotes an integer of 1-4, a Z preferably denotes
(a) cycloalkyl, preferably cyclopentyl or cyclohexyl;
(b) heterocyclyl, preferably tetrahydropyran-2-yl or tetrahydropyran-4-yl;
(C) hydroxyalkyl, preferably 1-hydroxymethyl;
(3) R3represents -(CH2)mSO2NR8R9or -(CH2)mNR8R9where m denotes an integer of 0-3, and
(a) R8denotes hydrogen or alkyl, preferably hydrogen, methyl, ethyl or isopropyl;
(b) R9does
(I) alkyl, preferably methyl, ethyl, propyl, isopropyl, sec-butyl, n-butyl, isobutyl, sec-butyl or tert-butyl, or
(II) arylalkyl, preferably benzyl, or
(4) R3represents -(CH2)mNR7SO2R9or -(CH2)mNR7COR9where m denotes an integer of 0-3, and
(a) R7denotes hydrogen or acetyl, ethyl, propyl or isopropyl;
(II) aryl, preferably phenyl, or
(III) arylalkyl, preferably benzyl.

Within this category, another preferred subgroup includes the compounds of formula I, in which R1denotes a group of formula (V), where X denotes S, and
(1) R3represents -(CH2)mOS, preferably where m denotes an integer of 0 or 1, a Y indicates
(a) alkyl, preferably methyl, isopropyl, isobutyl, sec-butyl or tert-butyl;
(b) alkyloxyalkyl, preferably 2-ethoxy-1-(ethoxymethyl)ethyl;
(C) cycloalkyl, preferably cyclopentyl or cyclohexyl, or
(g) heterocyclyl, preferably tetrahydropyran-2-yl or tetrahydropyran-4-yl, or
(2) R3denotes-O(CH2)nZ, where n denotes an integer of 1-4, Z is a value specified for a group of formula (A).

Within this category, another preferred subgroup includes the compounds of formula I, in which R1denotes a group of formula (C), in which X denotes n

Examples of particularly preferred compounds are
2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole;
2-{4-[4-(sec-butoxy)benzyl]phenyl}aminoimidazole;
2-{4-[4-(cyclopentyloxy)benzyl]phenyl}amino) - Rev. XI)benzyl]phenyl}aminoimidazole;
2-{4-[4-(tetrahydropyran-2-ylethoxy)benzyl]phenyl}aminoimidazole;
2-{ 4-[2-fluoro-4-(tetrahydropyran-4-ylethoxy)benzyl] phenyl} aminoimidazole;
2-{4-[4-(2-ethoxy-1-(ethoxymethyl)ethoxy)benzyl]phenyl}aminoimidazole;
2-[4-(4-cyclopentylmethyl-2-ylmethyl)phenyl]aminoimidazole;
2-{4-[4-(4-methoxyphenyl)sulfonylmethane)benzyl]phenyl}aminoimidazole;
2-{4-[4-(1-hydroxyethylidene)benzyl]phenyl}aminoimidazole;
2-[4-(5-methoxytrityl-2-ylmethyl)phenyl]aminoimidazole;
2-[4-(4-buylamisilonline)phenyl]aminoimidazole;
2-[4-(4-isopropoxycarbonyl)phenyl]aminoimidazole;
2-[4-(4-sec-butoxyethanol)phenyl]aminoimidazole;
2-{4-[4-(sibutraminesolution)benzyl]phenyl}aminoimidazole
2-[4-(4-benzylaminocarbonyl)phenyl]aminoimidazole;
2-[4-(4-isopropylaminocarbonyl)phenyl]aminoimidazole;
2-[4-(4-isobutyleneisoprene)phenyl]aminoimidazole and
2-[4-(4-tert-buylamisilonline)phenyl]aminoimidazole

Compounds of the present invention can be obtained by the methods illustrated by the reaction schemes below.

Starting materials and reagents, which are used to obtain these compounds can be either p specialists in a given field of technology during the processes described in such literature as Fieser and Fieser''s Reagents for Organic Synthesis, Wiley & Sons: new York, 1991, volumes 1-15; Rodd''s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5 and supplements, and Organic Reactions, Wiley & Sons: new York, 1991, volumes 1-40. These schemes are merely illustrations of some of the methods in accordance with which can be synthesized compounds of the present invention, therefore, such schemes can be subjected to various modifications that can usually assume any expert in the art, referring to the present description. If necessary, the raw materials and intermediate products of this reaction can be extracted and cleaned in accordance with conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc., Such materials can be characterized using conventional means, including physical constants and spectrographic data.

In all cases, unless otherwise provided in this reaction is performed under atmospheric pressure in the temperature range from about -78 to about 150oS, more preferably from about 0 to about 125oS, and most preferably at PR Usually the compounds of formula I obtained by carrying out intermediate interaction Veniaminovich compounds of the formulae Ia-II with the imidazoline compound 40 in the form of an acid additive salt or free base. Schemes A-F illustrate methods of obtaining intermediate Veniaminovich compounds in which R1denotes a group of formula (A); scheme C and illustrate methods for obtaining intermediate Veniaminovich compounds in which R1denotes a group of formula (C); schema-To-M illustrate methods of obtaining intermediate Veniaminovich compounds in which R1denotes a group of formula (C). Scheme M illustrates a method of preparing compounds of formula I.

On the diagram And illustrates the method of obtaining compounds of the formula I, in which R1denotes a group of formula (A), and R3denotes-O(CH2)nZ or -(CH2)mOh, from the corresponding intermediate compounds of formula Ia.

Usually starting compound of formula 1A, 1b, 1C, 2A, 2C and 3A technically available, for example, the company Aldrich Chemical Company, or any known or can be readily synthesized by any experts in this field of technology. For example, methoxybenzonitrile 3A can be obtained by the method described in the work of Shani, Jashovam and others, published in J. Med. Chem., 1985, 28, 1504.

Method (a) illustrates obtaining the compounds of formula Ia, in which R3has the above values, in particular where m denotes 0.

Will oboznachaet leaving group, such as chlorine, in the conditions of acylation by Friedel-Crafts. This reaction is carried out in an inert atmosphere in the presence of a Lewis acid such as aluminum chloride, boron TRIFLUORIDE, etc., appropriate for conducting this reaction inert organic solvents include halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon disulfide, etc., preferably a disulfide.

In stage 2 hydroxybenzonitriles 4A is obtained by treating compound 3A a strong acid, such as a mixture of Hydrobromic acid and glacial acetic acid. The demethylation reaction proceeds with time at high temperature or at the boiling point under reflux.

At stage 3 the connection 5A receive direct alkylation of compounds 4A alkylating agent, such as alkylhalogenide, or acylation allermuir agent such as ether malodorous acid. The reaction proceeds in an inert atmosphere in the presence of iodide catalyst, such as sodium iodide or potassium, and a base such as potassium carbonate, sodium carbonate or cesium carbonate. Appropriate for conducting such reaction solvents include aprotic organic solvents such as acetone, are the Alternatively the compound 5A is produced by interaction of compound 4A with an organic phosphine, such as triphenylphosphine, in combination with dialkyldithiocarbamato, such as diethylazodicarboxylate, under the reaction conditions, Mitsunobu. Appropriate for conducting this reaction solvents include inert organic solvents, such as N,N-dimethylformamide, N-organic, ethyl acetate, tetrahydrofuran, etc., preferably tetrahydrofuran.

In stage 4 phenylamine compound of formula Ia is obtained by restoring ketogroup and nitro compounds 5A. Acceptable recovery keto and nitro group conditions include the presence of boride Nickel in acidified methanol or catalytic hydrogenation using a platinum or palladium catalyst (for example, tO2or Pd/C, preferably 10% Pd/C) in proton organic solvent, such as an acidified acidified methanol or ethanol, preferably acidified ethanol.

Method (b) illustrates another option for obtaining compounds of formula Ia, in which R3has the above values, in particular where m denotes 0.

In stage 1 substituted bramasol 2b receive processing Bromphenol 1b alkylating agent, such as alkylhalogenide. This reaction proceeds in the presence of a base, so is e to conduct this reaction solvents include aprotic solvents, such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, etc.,

In stage 2 of the ORGANOMETALLIC compound 3b, where M+Br-denotes the ORGANOMETALLIC reagent can be easily synthesized by conventional specialists in the field of technology, for example, by treatment of compounds 2b suitable metal in the conditions of the Grignard reaction. The reaction proceeds in an inert atmosphere in the environment aprotic organic solvent, such as tetrahydrofuran.

At stage 3 benzonitriles 5b is produced by interaction of compound 3b with allermuir agent such as allalone, where L denotes a leaving group such as chlorine, in the presence of a catalyst, such as tetrakis(triphenylphosphine) palladium. The reaction proceeds in an inert atmosphere in the environment aprotic organic solvent, such as tetrahydrofuran.

Further phenylamine compound of formula Ia receive in accordance with the methods described above in scheme A, method (a), stage 4.

Method (b) illustrates another option for obtaining compounds of formula Ia, in which R3has the above values, in particular where m is 1.

Benzylbromide 1d is produced by interaction of bromobenzylamine 1C with C is the field of environment aprotic solvent, such as N,N-dimethylformamide, tetrahydrofuran, acetonitrile, etc.,

Chlorobenzenamine 2d-protected amine, in which R denotes aminosidine group have interaction chlorobenzenesulfonate 2C with aminosidine reagent, such as trialkylsilyl alcohol. The reaction proceeds in an inert atmosphere in the environment aprotic solvent such as N, N-dimethylformamide, tetrahydrofuran, acetonitrile, etc.,

In stage 1 benzylphenol 3d-protected amine is obtained by reaction of a combination of compounds 1d connection 2d under the reaction conditions of Steele. This reaction proceeds, for example, in the presence of literunner compounds, such as tert-utility, compounds of tin, such as tributylphosphine, and a catalyst, such as tetrakis(triphenylphosphine)palladium. The reaction proceeds in an inert atmosphere in the environment aprotic solvent, such as hexamethylphosphoramide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, etc.,

In stage 2 phenylamine compound of formula Ia is obtained by removing aminosidine group of compounds 3d by treatment with a special chip off with a reagent such as Tetra-n-butylammonium. This reaction is carried out in an inert Atmos is sulfoxid etc.

Processes for preparing compounds of the formula I according to this method from the corresponding compounds of formula Ia are described in detail in examples 1-4. Processes for producing compounds of formula 1d and 2d are presented in detail in the examples to obtain, respectively, 1 and 2.

In scheme B illustrates another method of preparing compounds of the formula I, in which R1denotes a group of formula (A), a R3denotes alkyl, cycloalkyl, halogen, heterocyclyl or-NR8R9, from the corresponding intermediate compounds of formula Ib.

Usually the parent compound le, 2e, 1f and 2f are either commercially available, for example, are delivered by the company Aldrich Chemical Company, or known to experts in the art or can be easily synthesized. Method (a) illustrates obtaining the compounds of formula Ib, R3which is specified above, using as starting product fervently le.

In stage 1 forantimicrobial 3E is obtained by acylation of fervently le allermuir agent 2e, where L denotes a leaving group such as chlorine. Appropriate for conducting this reaction solvents include halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon disulfide, etc., preferably a disulfide.

On primary or secondary amine, such as dimethylamine, morpholine, etc., This reaction is carried out in the presence of a base, for example potassium carbonate, sodium carbonate, cesium carbonate, etc. in the environment aprotic organic solvent, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, etc., preferably in dimethyl sulfoxide.

At stage 3 phenylamine compound of formula Ib is obtained by restoring ketogroup and the nitro group of compounds of formula 6 in the reaction conditions described for scheme A, method (a), stage 4.

Method (b) illustrates another option for obtaining compounds of formula Ib, in which R3means, in particular, alkyl or cycloalkyl.

In stage 1 alkylbenzoates 6 is produced by reactions of alkyl benzene 1f with allermuir agent 2f, where L denotes a leaving group such as chlorine, in the conditions of acylation by Friedel-Crafts. This reaction is carried out in the presence of a Lewis acid such as aluminum chloride, boron TRIFLUORIDE, etc., appropriate for conducting this reaction solvents include halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon disulfide, etc., preferably a disulfide.

In stage 2 phenylamine compound of formula Ib get the and circuit And, method (a), stage 4.

The process of obtaining the compounds of formula I according to this method from the corresponding compounds of formula Ib are described in detail in example 5.

In the diagram illustrated In an alternative method of preparing compounds of formula I, R1which denotes a group of formula (A), and R3represents -(CH2)mNR7SO2R9from the corresponding intermediate compounds of formula Ic.

Method (a) illustrates obtaining the compounds of formula IC, in which R3means sulfonamidnuyu group, in particular where m is 1.

In stage 1 methylbenzonitrile 3g is obtained by acylation of methylbenzol lg allermuir agent 2g, where L denotes a leaving group such as chlorine, in the conditions of acylation by Friedel-Crafts. This reaction is carried out in an inert atmosphere in the presence of a Lewis acid such as aluminum chloride, boron TRIFLUORIDE, etc., appropriate for conducting this reaction inert organic solvents include halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon disulfide, etc., preferably a disulfide.

In stage 2 bromobenzonitrile 7 get benzylbromide the compounds of formula 3g suitable brainwashin agent, so radikalnoy polymerization, such as benzoyl peroxide, in an inert atmosphere (e.g. argon or nitrogen, preferably argon). Appropriate for conducting this reaction nonpolar solvents are chlorinated and aromatic hydrocarbons, such as carbon tetrachloride and benzene.

At stage 3 bromobenzimidazole 8 receive recovery ketogroup the compounds of formula 7 by treatment with a reducing agent selective regarding ketogroup, such as triethylsilane. This reaction proceeds in an inert atmosphere in the presence of a strong acid, such as triftoratsetata. Appropriate for conducting this reaction solvents include halogenated hydrocarbons such as dichloromethane and dichloroethane.

In stage 4 azidoaniline 9 is obtained by substitution of benzylbromide in connection 8 nucleophilic azide anion. Appropriate for conducting this reaction solvents are aprotic organic solvents, such as N,N-dimethylformamide, N-organic, tetrahydrofuran, etc.,

Stage 5 aminobenzonitriles 10 get recovery azide to the primary amine by the reactions of the compound (9) with acceptable restoring azide agent such as trio, such as diethyl ether, 1,4-dioxane, tetrahydrofuran, etc., preferably tetrahydrofuran.

On stage 6 sulfonamidophenylhydrazine 11 is produced by reactions of compound 10 with sulfonylureas agent R9SO2L, where L denotes a leaving group, particularly chlorine, in the presence of a base, such as triethylamine. Sulphonylchloride technically available or can be obtained by such methods, which are described in Langer R. F., Can. J. Chem., 1983, 61, 1583-1592; Aveta R., and others, Gazetta Chimica Italiana, 1986, 116, 649-652, and J. F. King and J. Hillhouse H., Can. J. Chem., 1976, 54, 498. Appropriate for conducting this reaction solvents are halogenated hydrocarbons such as dichloromethane, or a two-phase system comprising water and ethyl acetate (for example, the reaction by the method of the Schotten's-Bauman).

On stage 7 phenylamino connection IC is obtained by restoring the nitro group of compound (11) to the amino group. Acceptable reducing the nitro-group tools include bored Nickel in acidified methanol and a catalytic hydrogenation using a platinum or palladium catalyst (e.g., PtO2or Pd/C) in an organic solvent, such as ethanol or ethyl acetate.

In another embodiment, the method (b) the sludge is where m denotes 0.

The compound of formula IC' get the reactions of 4,4'-methylenedianiline 12 sulfonylureas agent such as sulfonylmethane, in the reaction conditions described above in the description of stage 6, and with the implementation of the acid-alkaline extraction using hydroxide and mineral acids.

The compound of formula IC can be (but not necessarily) obtained by further alkylation of the compounds of formula IC' acceptable alkylating agent in the presence of a strong base such as tert-piperonyl potassium. Suitable solvents include aprotic organic solvents, such as acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, etc., preferably dimethyl sulfoxide.

Processes for preparing compounds of the formula I according to this method from the corresponding compounds of formula IC' and IC are described in detail in examples 6-9.

Scheme G illustrates an alternative method of preparing compounds of the formula I, in which R1denotes a group of formula (A), and R3represents -(CH2)mNR7COR9from the corresponding intermediate compounds of formula Id.

Method (a) illustrates obtaining the compounds of formula Id, in which R3means carboxamido group frequent the Ana in the schema, method (a), but on stage 6 spend the interaction of aminobenzimidazole 10 allermuir agent R9COL, where L denotes a leaving group such as chlorine, getting carboxamide 13. Next phenylamine compound of formula Id is obtained by carrying out the appropriate process as described in the description of stage 7. In another embodiment, the method (b) illustrates obtaining the compounds of formula Id, R3which means sulfonamidnuyu group, in particular where m denotes 0.

In General, the compound of formula Id' get in the reaction conditions previously specified in the schema, the method (b), but spend the interaction of 4,4'-methylenedianiline 12 allermuir agent such as allalone, obtaining the compounds of formula Id'. Then you can (but not necessarily) a compound of formula Id to receive further alkylation of the compounds of formula Id' suitable alkylating agent in the presence of a strong base such as tert-piperonyl potassium. Suitable solvents include aprotic organic solvents, such as tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, etc., preferably dimethyl sulfoxide.

The process of obtaining the compounds of formula I by this method from the corresponding connection is of the formula I, in which R1denotes a group of formula (A), and R3represents -(CH2)mNR7C(V)NR8R9where V represents S or O, from the corresponding intermediate compounds of formula Ie.

Method (a) illustrates obtaining the compounds of formula I in which R3means macewindow/tiomochevinoi group, where m, in particular, refers to 1.

In General, the compound of formula Ie get under reaction conditions that were previously specified in the schema, the method (a), but on stage 6 spend the interaction of aminobenzimidazole 10 with isocyano-Tom/isothiocyanato in an aprotic organic solvent with getting motivirovalo/timesaving connection 14. Next phenylamine compound of formula I is obtained by carrying out the appropriate process as outlined in the description of stage 7.

In another embodiment, the method (b) illustrates obtaining the compounds of formula I in which R3means macewindow/tiomochevinoi group, in particular where m denotes 0.

In General, the compound of formula Ie' get in the reaction conditions previously specified in the schema, the method (b), but spend the interaction of 4,4'-methylenedianiline 12 with the isocyanate/isothiocyanato in aprotic organic races of the compounds of formula I' is not necessarily possible to obtain a compound of the formula I are suitable alkylating agent in the presence of a strong base, such as tert-piperonyl potassium. Suitable solvents include aprotic organic solvents, such as tetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, etc., preferably dimethyl sulfoxide.

In another embodiment, the method (b) illustrates obtaining the compounds of formula I in which R3means macewindow/tiomochevinoi group, in particular where m denotes 0.

In stage 1 connection 15, in which R denotes aminosidine group, get a acceptable accession aminosidine group, such as benzyl, tert-butoxycarbonyl (VOS) or carbobenzoxy (CBZ), to the connection 12 methods, which the average person skilled in the art known in the art, for example, under the reaction conditions, the Schotten's-Bauman.

In stage 2 mcevenue/tiomochevinoi compound 16 is obtained by conducting interaction connection 15 with the isocyanate/estimaciones in organic solvents, including dichloromethane, dichloroethane or tetrahydrofuran.

In stage 3, the compound of formula I is obtained by removing aminosidine group of compound 16 in the conditions of hydrogenation using a catalyst such as palladium and platinum catalysts. Appropriate for conducting this reaction is at and etc.

The process of obtaining the compounds of formula I according to this method from the corresponding compounds of formula I are described in detail in example 10.

Scheme E illustrates an alternative method of preparing compounds of formula I, R1which denotes a group of formula (A), a R3refers to a group -(CH2)mSO2NR8R9from the corresponding intermediate compounds of formula If.

Method (a) illustrates obtaining the compounds of formula If, in which R3means sulfonamidnuyu group, in particular where m denotes 0.

In stage 1 chlorosulfonylisocyanate 18 is produced by interaction of benzimidazole 17 chlorsulfuron agent such as chlorosulphonate. This reaction proceeds at temperatures from about -50 to 10oWith in an inert organic solvent such as dichloromethane or dichloroethane.

In stage 2 aminomethyltransferase 20 is produced by reactions of compound 18 with a primary or secondary amine. Appropriate for conducting this reaction solvents include inert organic solvents, such as dichloromethane, dichloroethane or tetrahydrofuran.

At stage 3 phenylamino connection It receives the restoration of the political hydrogenation using a platinum or palladium catalyst in proton organic solvent, such as methanol, ethanol or ethyl acetate.

Method (b) illustrates another option for obtaining the compounds of formula If, in which R3means sulfonamidnuyu group, in particular where m is 1.

Bromobenzimidazole 7 get a way similar to that described above in relation to scheme C.

On-going alternatively a stage 1A connection 19 is produced by interaction of the compound 7 with a salt of sulfurous acid, such as aqueous sodium sulfite or potassium sulfite. The reaction proceeds at the boiling point under reflux in water or a mixture of acetonitrile with water.

Further carried out for another test stage 1B compound 18 is obtained by treating compound 19 gloriouse agent such as pentachloride phosphorus. The reaction can be performed using only the reagents or in the presence of phosphorus oxychloride.

Next phenylamine compound of formula If receive appropriate implementation stages similar to stages 2 and 3 in the method (a) on the diagram, that is,

The process of producing compounds of the formula I by this method from the corresponding compounds of formula If is described in detail in examples 11-12.

Scheme F illustrates an alternative method of preparing compounds fo the/sup> from the corresponding intermediate compounds of formula Ig.

In stage 1 benzylbenzamide acid 22 is obtained by recovering the ketone group benzoylbenzene acid 21 with the help of a reducing agent selective in relation to the ketone group, in particular in the hydrogenation conditions using a palladium or platinum catalyst. The reaction proceeds at room temperature in the presence of a strong acid, such as Perlina acid. Appropriate for conducting this reaction solvents are proton and aprotic solvents, such as methanol, ethanol, ethyl acetate, etc.,

In stage 2 nitrobenzylamine acid 23 get to that described in the chemical literature, for example in the work of Coon and others in J. Org. Chem. , 1973, 38, 4243. In General, the connection 22 nitrous obtaining nitronium salts in this way, as the interaction with triftormetilfullerenov acid and nitric acid. Appropriate for conducting this reaction solvents include inert organic solvents, such as halogenated hydrocarbons, for example dichloromethane or dichloroethane.

At stage 3 nitrobenzenesulfonic 24 is produced by treating compound 23 gloriouse agent such as phosgene and Ayer). Appropriate for conducting this reaction solvents include inert organic solvents, such as halogenated hydrocarbons such as dichloromethane and dichloroethane.

In stage 4 aminocarbonylmethyl 25 is produced by reactions of compound 24 with a primary or secondary amine. The reaction proceeds in the presence of a base, such as pyridine, in an inert organic solvent, such as dichloromethane, dichloroethane and tetrahydrofuran.

Stage 5 phenylamino connection Ig receive recovery nitro compounds 25 to amino groups. Acceptable for nitrogroup reduction conditions include hydrogenation using a platinum or palladium catalyst in an alcohol solvent such as methanol and ethanol.

The process of producing compounds of the formula I by this method from the corresponding compounds of formula Ig are described in detail in example 13.

Figure 3 illustrates an alternative method of preparing compounds of the formula I, in which R1denotes a group of formula (V), where X denotes S, and R5indicates or-O(CH2)nZ, or -(CH2)mThe OS, in particular where m denotes 0, corresponding promezhutochnym anion, for example the anion of sodium methoxide, in the presence of copper salts, such as iodide monovalent copper. The reaction proceeds in an inert atmosphere at an acceptable aprotic organic solvent such as N,N-dimethylformamide, N-organic, tetrahydrofuran, etc.,

In stage 2 ortho-chlorinated teenlove connection 28 can be obtained by the methods described in the chemical literature, for example in the work Stanetty, etc. in Monatshefte Chemie, 1989, 120, 65. In General, compound 27b in an inert atmosphere process palodiruyut agent such as chloride Sulfuryl. Appropriate for conducting this reaction solvents include hexane, dichloromethane and dichloroethane.

At stage 3 titelverzeichnis 29 is produced by treating compound 28 strong base, such as n-utility, and then benzaldehyde. The reaction is carried out with cooling in an inert atmosphere. Appropriate for conducting this reaction solvents include aprotic organic solvents, such as tetrahydrofuran, diethyl ether, etc., preferably tetrahydrofuran.

In stage 4 tamilmidiringtonesdoje connection 30 receive recovery hydroxymethylene group connection 29 alkilirovanny galoisienne, therefore, ka is the first reaction solvents include aprotic solvents, for example acetonitrile, N,N-dimethylformamide, etc.,

Stage 5 phenylamine compound of formula Ih receive recovery nitro compounds 30 to amino groups. Acceptable for nitrogroup reduction conditions include the presence of boride Nickel in acidified methanol, chloride tin(II) in ethanol or catalytic hydrogenation using a platinum or palladium catalyst (for example, tO2or Pd/C) in an organic solvent, such as ethanol, isopropanol and ethyl acetate.

The process of producing compounds of the formula I by this method from the corresponding compounds of formula Ih is described in detail in example 14.

On the diagram, And illustrates an alternative method of preparing compounds of the formula I, in which R1denotes a group of formula (V), where X denotes S, and R5indicates or-O(CH2)nZ, or -(CH2)mThe OS, in particular where m denotes 0, from the corresponding intermediate compounds of formula Ii.

In stage 1 teenlove connection 27b can be obtained according to the method described in the chemical literature, for example in the work of M. A. Keeystra and others in Tetrahedron, 1992, 48, 3633. In General Bratanova connection 26b process alkoxide anion, for example by anion methoxyphenol temperature in an inert atmosphere, followed by the addition of salts of copper, such as bromide monovalent copper or iodide monovalent copper. Appropriate for conducting this reaction solvents include inert organic solvents, such as methanol, ethanol, dioxane and tetrahydrofuran.

In stage 2 Eskilstuna 31 receive stanimirova the compounds of formula 27b, the processing haloalkylthio, such as chloride (tri-n-butyl)tin in the presence of laisteridge reagent, for example n-utillity. The reaction proceeds in an inert atmosphere in the environment aprotic organic solvent, such as tetrahydrofuran or diethyl ether.

At stage 3 R-secured connection 32, where P denotes aminosidine group, get the reactions of compound 31 with benzylchloride reagent with a protected amino group, in particular trimethylsilylimidazole group. The reaction proceeds in the presence of a suitable catalyst, such as platinum or palladium catalyst, for example tetrakis(triphenylphosphine)palladium, in the co-solvent, such as hexamethylphosphoramide.

In stage 4 phenylamine compound of formula Ii is obtained by removing from the connection 32 aminosidine group by processing the NUS is the first solvent, such as dioxane, tetrahydrofuran, diethyl ether, etc.,

In another embodiment, other phenylamino the compounds of formula Ii can be obtained by replacing the group-O(CH2)nZ or -(CH2)mShelter in the compounds of formula Ii where Y or Z represents alkyl or cycloalkyl, other alkyl groups in the presence of acid such as p-toluensulfonate. This reaction proceeds in an inert atmosphere while boiling under reflux. Acceptable for the reaction solvents include alcohol solvents such as methanol, ethanol and isopropanol.

The process of producing compounds of the formula I by this method from the corresponding compounds of formula Ii are described in detail in examples 15-17.

In the diagram It is illustrated an alternative method of preparing compounds of the formula I, in which R1denotes a group of formula (C), where X denotes N, and R6denotes the group-C(V)NR8R9where V denotes O or S, from the corresponding intermediate compounds of formula Ij.

In stage 1 getprocessimagefilenamew 34 receive the recovery of aromatic and nitro group of heteroaromatisations 33 in conditions
catalytic hydrogenation, for example using platinum is logical solvent, such as an acidified acidified methanol or ethanol, preferably acidified ethanol. The reaction proceeds at a temperature of from about 20 to 100oWith the pressure of 20-100 psi.

In stage 2 phenylamine compound of formula Ij is obtained by conducting interaction connection 34 with the isocyanate/thioisocyanate in an inert organic solvent, such as dichloromethane, diethylamine or tetrahydrofuran. The reaction proceeds in an inert atmosphere at a temperature of from about -10 to 30oC.

The process of obtaining the compounds of formula I by this method from the corresponding compounds of formula Ij is described in detail in example 18.

In scheme L illustrates an alternative method of preparing compounds of formula I, R1which denotes a group of formula (C), where X denotes N, a R6refers to a group-COR9or-SO2R9, from the corresponding intermediate compounds of formula Ik.

Getprocessimagefilenamew 34 receives the same way as shown above in scheme K.

In stage 1, R1-secure connection 35, where R1means aminosidine group have a connection to the connection 34 acceptable aminosidine groups, such as triptorelin ordinary skilled in the art. In General, the connection 34 is treated with di-tert-BUTYLCARBAMATE in an aprotic organic solvent such as tetrahydrofuran.

In stage 2, R1and R2-secure connection 36, where R2also indicates aminosidine group, obtained by joining the corresponding aminosidine group such as TRIFLUOROACETYL, benzyl, tert-butoxycarbonyl (VOS) or carbobenzoxy (CBZ), preferably TRIFLUOROACETYL, phenylaminopropyl connection 35 methods known to the person skilled in the art. In General, the connection handle 35 triperoxonane anhydride in the presence of a base such as triethylamine. The reaction proceeds in an inert atmosphere in an inert organic solvent, such as dichloromethane, dichloroethane, tetrahydrofuran, etc.,

In stage 3, R2-secure connection 37 is obtained by removing aminosidine R1group in connection 36 his handling strong organic acid, such as triperoxonane acid, in an inert organic solvent, such as new halogen hydrocarbons, for example dichloromethane or dichloroethane.

In stage 4, the connection 38 receive as a result of interaction of compound 37 with sulfurous againinto atmosphere in the presence of a base, such as triethylamine, in a halogenated organic solvent such as dichloromethane or dichloroethane.

Stage 5 phenylamine compound of formula Ik is obtained by removing aminosidine R2-group connections 38 processing base, such as lithium hydroxide. Appropriate for conducting this reaction solvents include alcohol and proton solvents, such as methanol, ethanol and water.

The process of obtaining the compounds of formula I by this method from the corresponding compounds of formula Ik is described in detail in example 19.

In scheme M illustrates an alternative method of preparing compounds of the formula I, in which R1denotes a group of formula (C), where X denotes N, and R6refers to a group-CONR8R9or-SO2NR8R9from the corresponding intermediate compounds of formula Il.

R2-secure connection 37 to receive the same, as illustrated in the diagram above L.

The connection 39 to receive the result of the interaction of compound 37 with carbamoylation or sulfamoylanthranilic. The reaction proceeds in an inert atmosphere in the presence of a base such as triethylamine, in a halogenated organic RA is ly Il is obtained by removing the protecting P2-group connection 39 the processing base, such as lithium hydroxide. Appropriate for conducting this reaction solvents include alcohol and proton solvents, such as methanol, ethanol and water.

The process of obtaining the compounds of formula I by this method from the corresponding compounds of formula Il are described in detail in example 20.

Scheme N in General illustrates the formation of compounds of formula I, where the values of R1and R2specified in the summary of the invention, from the corresponding intermediate compounds of formula Ia-II.

2-Imidazoline compounds of formula 40 are known or they can be easily synthesized by conventional specialists in this field of technology. For example, the synthesis of the sulfate salt of formula 40, where L denotes chlorine, described A. Trani, and E. Bellasio, J. Het. Chem., 1974, 11, 257.

In General, the imidazoline compounds of formula I can be obtained by interaction of the corresponding intermediate compounds of formula Ia-II with 2-imidazoline compound 40 in the form of an acid additive salt or free base. The reaction proceeds by boiling under reflux, typically in an inert atmosphere. Acceptable for carrying out this reaction, a solvent alleuropean, dioxane, etc., the Choice of solvent usually depends on the purpose of application of the acid additive salt or free base.

General indications for use
Substance-receptor antagonists IP, such as proposed by the present invention exhibit both anti-inflammatory and analgesic properties in vivo. Thus, these compounds can be used as anti-inflammatory and painkillers for mammals, especially for humans. They are used when dealing with pain caused by various reasons, including, but not limited to, pain in inflammatory processes, pain after surgery, visceral pain, dental pain, premenstrual pain, headache, pain from burns, migraine or histamine headaches, pain in the nerve injury, neuritis, neuralgia, pain, poisoning, ischemic pain, pain in interstitial cystitis, pain with cancer, pain associated with infection by viruses, parasites and bacteria, post-traumatic pain (including pain after fractures and sports injuries) and the pain associated with disorders of the digestive tract, such as the syndrome section is svannah various reasons, including, but not limited to, bacterial, fungal and viral infection, rheumatoid arthritis, osteoarthritis, surgery, bladder infection and idiopathic inflammation of the bladder, abuse, old age, malnutrition, prostatitis, conjunctivitis.

Such compounds are also used in the treatment of disorders of the work of the bladder associated with the syndrome infravesical obstruction, and incontinence of urine, such as spontaneous urination, urinary stress incontinence and increased reactivity of the bladder.

In addition, these compounds find application in the treatment of respiratory diseases such as asthma, in which C-fibers in the lungs are hypersensitive to a number of surrounding stimuli, including cold air, dust, pollen and other antigens. Since these C-fibers Express prostanoid IP receptors, activation of these receptors by PGI2and the subsequent allocation of neurokinin can reduce tissue of smooth muscles of the lungs, edema and mucus secretion. Thus, the compounds of the present invention, used either systemically or in the form of aeroso which are also used in the treatment of septic shock.

Test
Anti-inflammatory/analgesic activity of the compounds of the present invention can be evaluated by conducting in vivo tests, such as score from induced in rats by carrageenan mechanical hyperalgesia paws and assessment of symptom Freund caused by adjuvant mechanical hyperalgesia in rats, which are described in more detail in examples 30 and 31. The efficiency of inhibition of contractions can be evaluated by conducting in vitro tests, such as the inhibition of contractions of the bladder caused by the test isovolumetric stretching of the bladder, which is described in more detail in examples 32 and 33. The efficiency of inhibition of septic shock can be assessed in vivo tests, such as tests with elimination in rats caused by the action of endotoxins hypotension, which is described in more detail in example 34.

Methods of administration and pharmaceutical composition
According to the invention features a pharmaceutical composition comprising the compound of the present invention, its pharmaceutically acceptable salt or crystalline form together with one or more pharmaceutically acceptable carriers and optionally other therapeutic is therapeutically effective amount of any acceptable by administering drugs, which serve such purpose. Depending on a number of factors, such as severity of the disease that must be cured, the age and relative health of the patient, the activity used in the connection path and the form of the introduction into the organism, the indication, in respect of which includes the introduction, the choice and experience of the attending physician, acceptable intervals doses are 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily. A therapeutically effective amount of the compounds of the present invention in the case of specific diseases in the state to install an ordinary specialist in the field of treatment of such diseases without holding excessive number of experiments based on our own knowledge and based on the description to this application.

Compounds of the present invention is usually administered in the form of pharmaceutical compositions, including compositions suitable for oral use (including transbukkalno and sublingual methods), rectal, intranasal, locally, through the lungs, vaginal and parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous methods), or in preparative form, p is capacity, to use a convenient scheme daily intake of medicines, you can make adjustments in accordance with the seriousness of the disease.

The compounds according to the invention together with conventional adjuvants, carriers or diluents can be shaped in the form of pharmaceutical compositions and single doses. Pharmaceutical compositions and single-use dosage forms may include conventional components in the usual proportions together with additional active compounds or active basis or without them, and in a one-time dosage form can contain any acceptable effective amount of the current component corresponding to the intended range of daily input doses. Such pharmaceutical composition can be used in the form of solid preparations such as tablets and filled capsules, semi-solid preparations, powders, drugs emitting at a constant concentration or liquids such as solutions, suspensions, emulsions, elixirs, or filled their capsules, for oral administration in the form of suppositories for rectal or vaginal injection or in the form of sterile injectable solutions for parenteral rst and, containing 1 mg of active ingredient or, more broadly, from 0.01 to 100 mg per pill.

On the basis of the compounds of the present invention can be prepared in a variety of dosage forms for oral administration. The active component of the pharmaceutical compositions and dosage forms may include compounds according to the invention, their pharmaceutically acceptable salts and crystalline forms. Pharmaceutically acceptable carriers can be either solid or liquid form. Solid preparative forms include powders, tablets, pills, capsules, starch wafers, suppositories, and dispersible granules. A solid carrier can include one or more substances which may also act as diluents, flavoring and aromatic additives, solubilization, lubricity additives, suspendida substances, binders, preservatives, additives that mechanical destruction of the tablets, or encapsulating material. In powders, the carrier is in the form of finely ground solids, which is a mixture with finely ground active ingredient. In tablets, the active component is mixed with the carrier having the measure. Preferred powders and tablets contain from one to about seventy percent of the active substance. Acceptable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc., the Term "drug" includes a combination of active ingredient with encapsulating material as a carrier, forming a capsule in which the active component, together with carriers or without them, is surrounded by media, associated, therefore, with him. Similarly, this term covers starch wafers and cakes. Tablets, powders, capsules, pills, starch wafers and cakes can be in solid form, acceptable for oral administration.

Other forms acceptable for oral administration include drugs in liquid form, which include emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, and drugs in solid form, which are intended to be translated in the form of liquid preparations shortly before use. Emulsions can be prepared as solutions in water propilenglikolem solutions or can contain emulgatorului component in water and adding an acceptable dyes, aromatic and flavor additives, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing finely ground active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose and other well-known suspendresume agents. The liquid forms include solutions, suspensions and emulsions, they may include, in addition to the active component, colorants, perfumes and flavorings, stabilizers, buffer additives, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.,

Using the compounds of the present invention can be prepared in preparations for parenteral administration (e.g. by injection, in particular for injection loading dose of the substance or continuous infusion), they can be contained in a medicinal product in doses at one time in the form of ampoules, pre-filled syringes, containers, small volume infusion containers or for multiple doses, with added preservative. The compositions can be shaped in such forms as suspensions, solutions or emulsions in oily or aqueous fill, is rastvoritelei or excipients include propylene glycol, polyethylene glycol, vegetable oils (e.g. olive oil) and organic esters for injection (for example, etiloleat) they can be used for dispensing additives, such as preservatives, wetting agents, emulsifiers, suspendresume agents, stabilizers and/or dispersants. Alternatively the active ingredient may be in powder form, obtained by selection in aseptic conditions with sterile solid or by lyophilization from solution, and before using it combined with acceptable excipient such as sterile pyrogen-free water.

For the local introduction of the epidermis on the basis of the compounds of the present invention can be prepared ointments, creams and lotions or patches for insertion through the skin. Ointments and creams can be prepared, for example, using aqueous or oily base with the addition of acceptable thickening and/or gelatinizing additives. Lotions can be prepared using an aqueous or oily base, they usually contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida additives, thickening vasectomies substances in aroma and flavor additive in the base, usually sucrose and Arabian gum or tragana, lozenges, containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum, and liquid mouth rinse containing the active substance in an acceptable liquid carrier.

Using the compounds according to the present invention it is possible to prepare drugs for administration in the form of suppositories. Low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, is first melted, then the active component of the homogeneous dispersed, for example, by stirring. The molten homogeneous mixture is poured into forms to normal size, allow to cool and thus solidify.

Using the compounds of the present invention can be prepared in preparations for vaginal administration. Acceptable can be considered as vaginal suppositories, tampons, creams, gels, pastes, sponge or sprays containing in addition to the active ingredient, such carriers which are known in the art.

Using the compounds of the present invention can be prepared preparations for intranasal administration. Solutions and suspensions are injected directly into the nasal cavity by conventional means, the gas or multiple dosage forms. In this latter case, when there is a dropper or pipette, this can be achieved by the introduction of the patient corresponding predetermined volume of solution or suspension. In the case of a spray, this can be accomplished, for example, using atomization atomizer with a metering pump.

Using the compounds of the present invention can be prepared drugs for aerosol administration, particularly to the introduction into the respiratory tract and including intranasal administration. When this substance is usually characterized by small particle size, in particular of about 5 microns or less. Such particle sizes can be achieved by means known in the art, for example by treatment in micron colloidal mill. The active substance is in the package under pressure acceptable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other acceptable gas. Aerosol drug usually can also include a surfactant, such as lecithin. The dose of the drug can be controlled using a metering valve. In another embodiment, using existing vasectomise basis, such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). Powdered media in the nasal cavity usually forms a gel. The powdered composition can be prepared in the form of the drug in doses at one time, for example, capsules or wafers, in particular gelatin and bubble packing, of which the powders can be entered using the inhaler.

If necessary, medication can be provided with a coating of the small intestine is adapted for permanent or variable selection in the body of the current component.

In a preferred embodiment, the pharmaceutical composition is prepared in the form of the drug in doses at once. In such form the preparation is divided into uniform doses containing appropriate quantities of the active component. Uniform dosage form can be a packaged preparation, the package contains a separate quantity of the drug, in particular packaged tablets, capsules, and powders in vials or ampoules. Drug doses at one time can be a capsule, tablet, starch wafer or cake or on the bearers and cooked with their use of the drugs described in Remington: The Science and Practice of Pharmacy, 1995, edited by E. W. Martin, Mack Publishing Company, 19th ed., Easton, pieces Pennsylvania. Typical pharmaceutical compositions containing the compounds of the present invention, described in examples 24-29.

The following composition, and examples are intended to give an opportunity to those in the art to more clearly understand the present invention and its practical implementation. They should not be considered as limiting the scope of invention, but as examples only an illustrative purpose.

EXAMPLE OBTAIN 1
1-Bromo-4-isopropoxyethanol.

0.96 g of sodium hydride (24 mmole 60% in mineral oil at 0-5oC in an atmosphere of argon was added into the solution to 7.59 ml (36 mmol) of ISO-propanol in 30 ml of dry N, N-dimethylformamide. After stirring the mixture for about 25 min was added 4-bromobenzylamine and the mixture was stirred at 20oC for another 1 h, the Solution was distributed between 50 ml of saturated solution of ammonium chloride and 50 ml of diethyl ether. The aqueous phase was extracted with 3 portions of 20 ml of diethyl ether, and the combined organic layers were washed with water, dried over Na2SO4) and was evaporated in vacuum. The crude product was filtered through silica gel to obtain telelevelocity ether 4-chloromethylisothiazolinone acid
In a mixture of 1.07 g (6.4 mmol) of 4-chloromethylpyridine in 22 ml of tetrahydrofuran at 20-25oWith in a stream of argon was added of 0.91 ml (6.4 mmol) of 2-trimethylsilylethynyl. The mixture was stirred for 4 h at 20-25oC. the Solvent is evaporated in vacuum. Was added a saturated solution of sodium bicarbonate and the product was extracted with ethyl acetate. The extract was washed with water, brine, dried over Na2SO4) and concentrated to dryness. After treatment, the Express by chromatography on silica and elution with hexane/ethyl acetate as a white crystalline solid substance obtained 1.24 g (68% yield) 2-trimethylsilylacetamide ether 4-chloromethylisothiazolinone acid with tPL55-56oC.

1H-NMR: 7,38 (d, J=8,6, 2H), 7,32 (d, J=8,6, 2H), 6,60 (bs, 1H), 4,55 (s, 2H), 4.26 deaths (m, 2H), of 1.05 (m, 2H), by 0.06 (s, 9H).

EXAMPLE 1.

2-[4-(4-Isopropoxyphenyl)phenyl]aminoimidazole.

Following receipt of the compounds of formula I from the corresponding compound of formula Ia, in which R1denotes a group of formula (A), R2and R4each represents hydrogen, Y represents isopropyl, and m is 0.

Stage 1.

The compound of formula 3A was obtained in accordance with the method of Shani J., and others, J. Med. Chem., 1985, 28, 1504. So, for example, a mixture of 90 g (0,48 my flask, equipped with a device for supplying nitrogen, a refrigerator and a mechanical stirrer, and the flask was cooled in an ice bath. Separate portions were added 84,0 g (to 0.63 mole) of aluminum chloride and stirring was continued at the temperature of the ice bath for 30 min and then at room temperature for a further 1 h the Reaction mixture was cooled, and treated with 150 ml of concentrated hydrochloric acid and diluted with 250 ml of cold water. The product was collected, filtered, washed, dried and was led from ethyl acetate to obtain as not quite white solid 4-(4-methoxybenzoyl)nitrobenzene with tPL120-122oC. elemental analysis Data for C14H11NO4calculated: From 65.3, N Or 4.31, N 5,44; found: 65.22 Per, N 4,16, N 5,69.

Stage 2.

A solution of 150 g (of 0.58 mol) of 4-(4-methoxybenzoyl)nitrobenzene, 500 ml of glacial acetic acid and 400 ml of Hydrobromic acid concentration of 48 wt. % boiled under reflux for 16 hours, the Reaction mixture was cooled to room temperature and poured into crushed ice. The crude product was filtered, repeatedly washed with water and dried in high vacuum at approximately the 50oC. In the crystallization from ethyl acetate/is and13H9NO4calculated: 64,20, N Of 3.73, N USD 5.76; found: 63,95, N 3,65, N 5,85. MS m/e (%): 243 (M+; 45).

Stage 3.

The reaction mixture contained 48,63 g (0.2 mol) of 4-(4-hydroxybenzoyl)nitrobenzene, to 98.4 g (0,8 mol) of 2-bromopropane, 1.5 g of sodium iodide and 27.6 g (0.2 mole) of anhydrous potassium carbonate in 200 ml of N,N-dimethylformamide, kept at about 60-70oWith in a stream of nitrogen for 18 hours the Reaction mixture was concentrated, and the residue was stirred with water and filtered. The crude product is repeatedly washed with water and dried with receipt of 54.8 g (96%) are painted in cream color of the product, which then was led from ethyl acetate to obtain 4-(4-isopropoxybenzoic)nitrobenzene with tPL138oC. elemental analysis Data for C16H18NO4: calculated: 67,36, N. And 5.30, N 4,91; found: 67,39, N 5,28, N 5,07.

Stage 4.

A mixture of 14.0 g (49,09 mmole) of 4-(4-isopropoxybenzoic)nitrobenzene with 2.0 g of 10% palladium on coal in a solution of 250 ml of ethanol and 30 ml of concentrated hydrochloric acid under a pressure of 50 psig for 16 h was first made in the apparatus Parra. The catalyst was removed by filtration through a pad of celite (brownmillerite), and the filtrate was concentrated in vacuum. The residue was diluted with chilled lencheski extracts were washed with water and brine and dried over Na2SO4). After removal of solvent received a thick oil, which was subjected to crystallization from ethyl acetate/hexane to obtain a white solid product 10.4 g (87%) of 4-(4-isopropoxyphenyl)phenylamine with tPL92-93oC; elemental analysis data for C16H19NO calculated: 79,63, N 7,94, N 5,80; found: 79,51, N 7,92, N 5,96. MS m/e (%): 241 (M+; 83).

The final stage.

2-Chloro-2-imidazolinone received in accordance with the methods described in A. Trani, and E. Bellasio in J. Het. Chem., 1974, 11, 257.

The mixture 24,36 g (120 mmol) sulphate 2-chloro-2-imidazoline from 24.1 g (100 mmol) of 4-(4-isopropoxyphenyl)phenylamine in 300 ml isopropanol within 1-2 h was heated under reflux in an inert atmosphere. The reaction mixture was concentrated in vacuo and the residue was diluted with ice water. The mixture was podslushivaet 10% sodium hydroxide and carefully was extracted with dichloromethane. The combined organic extracts were washed with cold water and brine, dried (on the K2CO3) and concentrated. As a result of crystallization from diethyl ether/hexane as not quite white solid substance was obtained 9,94 g(96%) 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole with tPL103-S 73,51, N 7,42, N 13,57. MS m/e (%): 309 (M+; 100).

In a mixture of 0.5 g of 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole with 14 ml of acetone was added a solution of 0.08 g of sulfuric acid in 1 ml of acetone. The mixture was heated, stirred for 15 min and filtered, obtaining in the form of a white solid substance of 0.56 g of 2-[4-(4-isopropoxyphenyl)phenyl]iminoimidazolidine with tPL215-216oC. elemental analysis Data for C38H48N6O6S calculated: 63,66, N Is 6.75, N 11,72; found: 63,50, N 6,64, N 11,72.

In the process similar to stage 1 in example 1, and the process directly to stage 4 and final stage in example 1 was obtained 2-[4-(4-methoxybenzyl)phenyl]aminoimidazole with tPL114-116oC.

In the process similar to stage 1 in example 1, but replacing 4-nitrobenzaldehyde 3-methoxy-4-nitrobenzofurazan, and the process directly to stage 4 and final stage in example 1 was obtained 2-[4-(4-methoxybenzyl)-3-methoxyphenyl] aminoimidazole with tPL127-128oC.

In the process similar to stage 3 in example 1, but replacing 2-bromopropane ethyl-2-bromopropionate, and then respectively similar to the subsequent stages in example 1, the data of elemental analysis for C19H21N3About3: calculated: 67,24, N 6,24, N 12,38; found: 66,90, N 6,23, N 12,31.

In the process similar to stage 3 in example 1, but replacing 2-bromopropane other alkylhalogenide, and then respectively similar to the subsequent stages in example 1 were obtained the following compounds of formula I:
2-[4-(4-ethoxybenzyl)phenyl]aminoimidazole with tPL152-153o;
hydrochloride 2-{4-[4-(2,2,2-triptoreline)benzyl]phenyl}aminoimidazole with tPL75-78o;
oxalate 2-[4-(4-propoxyphenyl)phenyl]aminoimidazole with tPL146-147o;
hydrochloride of 2-[4-(4-butoxybenzoyl)phenyl]aminoimidazolePL97-100o;
oxalate 2-[4-(4-butoxybenzoyl)phenyl]aminoimidazole with tPL172-174oC;
hydrochloride of 2-[4-(4-salutogenesis)phenyl]aminoimidazole with tPL127-129o;
oxalate 2-[4-(4-interoceanic)phenyl]aminoimidazole with tPL163-166o;
2-{4-[4-(1-methylbutoxy)benzyl]phenyl}aminoimidazole with tPL99-112oC;
hydrochloride 2-{4-[4-(4-hydroxypropoxy)benzyl]phenyl}aminoimidazolePL129-133o;
maleate 2-{ 4-[4-(3-hydroxy-2-hydroxymethylpropane)benzyl]phenyl}aminoimidazole with tPL70-75o;
hydrochloride of 2-[schiano: 70,13, N 6,14, N 10,67; found: 69,79, N 6,10, N a 10.74;
hydrochloride of 2-[4-(4-cyclopentylacetyl)phenyl] aminoimidazole with tPL116-119o;
hydrochloride of 2-[4-(4-cyclohexadienyl)phenyl] aminoimidazole with tPL108-110o;
hydrochloride of 2-[4-(4-cyclohexylmethoxy)phenyl] aminoimidazole with tPL95-100o;
oxalate 2-[4-(4-tetrahydropyran-2-eloxiertes)phenyl]aminoimidazole with tPL168-170o;
2-{ 4-[2-(4-methoxyphenyl)ethoxybenzyl] phenyl}aminoimidazole with tPL122-124o;
hydrochloride of 2-[4-(4-benzoylmethylene)phenyl]aminoimidazole; the data of elemental analysis for C24H24N3O2CL calculated: 67,28, N 5,86, 9,81 N; found: 67,27, N 5,76, N 9,62;
hydrochloride of 2-{ 4-[4-(cyclopentanecarbonyl)methoxybenzyl]phenyl}aminoimidazole with tPL78-81o;
hydrochloride 2-[4-[4-(1-piperidinylcarbonyl)methoxybenzyl] phenyl]aminoimidazole with tPL65-67o;
hydrochloride of 2-{ 4-[4-(phenylenecarbonyl)methoxybenzyl] phenyl}aminoimidazole with tPL186-187o;
hydrochloride of 2-{ 4-[4-(diisopropylaminoethyl)methoxybenzyl]phenyl}aminoimidazole with tPL62-65o;
hydrochloride of 2-{ 4-[4-(diethylaminomethyl)methoxybenzyl]phenyl}aminopyrazine: 60,91, N? 7.04 baby mortality, N 12,95;
hydrochloride of 2-[4-[4-(isopropylaminocarbonyl)methoxybenzyl]phenyl}aminoimidazole with tPL66-78o;
hydrochloride of 2-{4-[4-(N-isopropyl-N-methylaminomethyl)methoxybenzyl]phenyl}aminoimidazole with tPL77-81o;
hydrochloride 2-{ 4-[4-(4-methoxyphenyl)aminocarbonylmethyl] phenyl} aminoimidazole; the data of elemental analysis for C25H27N4O3C1 calculated: 63,33, N 5,91, N 11,82; found: 63,34, N 5,78, N 11,67;
oxalate 2-[4-(2-fluoro-4-propoxyphenyl)phenyl] aminoimidazole with tPL130-133o;
oxalate 2-[4-(3-fluoro-4-isopropoxyphenyl)phenyl] aminoimidazole with tPL120-121oC;
maleate 2-[4-(2-fluoro-4-tetrahydropyran-2-elecoxiban)phenyl] aminoimidazole with tPL138-141o;
hydrochloride of 2-[4-(3-chloro-4-isopropoxyphenyl)phenyl] aminoimidazole with tPL118-120o;
hydrochloride of 2-[4-(2-chloro-4-methoxybenzyl)phenyl] aminoimidazole with tPL126-129oC;
hydrochloride of 2-[4-(3-fluoro-4-methoxybenzyl)phenyl] aminoimidazole with tPL138-140oC;
hydrochloride of 2-[4-(4-fluoro-2-methoxybenzyl)phenyl] aminoimidazole with tPL230-233o;
hydrochloride of 2-[4-(2,4-dimethoxybenzyl)phenyl] aminoimidazole with tPL137-143o;
GI-4-methoxybenzyl)phenyl] aminoimidazole with tPL169-172oC.

EXAMPLE 2
2-[4-(4-Tetrahydropyran-4-eloxiertes)phenyl]aminoimidazole

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compound of formula Ia, in which R1denotes a group of formula (A), R2and R4each represents hydrogen, Z represents 4-tetrahydropyran-4-yl, and n denotes 0.

2-[4-(4-Tetrahydropyran-4-eloxiertes)phenyl] aminoimidazole was obtained by carrying out the process similar to the stages 1 and 2 in example 1, and then the implementation of the alternative stage 3.

1.47 g (8.4 mmole) of diethylazodicarboxylate slowly dropwise added in an inert atmosphere with simultaneous stirring at room temperature into a solution of 1.7 g (7 mmol) of 4-(4-hydroxybenzoyl) nitrobenzene (obtained as described in example 1, stages), 0,78 g (7.7 mmole) 4-hydroxymitragynine and 2.2 g (8.4 mmole) of triphenylphosphine in 20 ml of dry tetrahydrofuran. The reaction mixture was stirred for one hour and then the reaction was stopped by adding 1 ml of water and the mass was concentrated in a vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2 the Sana'a) and was led from hexanol obtaining in the form of a white solid 1.4 g (61%) of 4-(4-tetrahydropyran-4-roxylenol)nitrobenzene with tPL105-106oWith; the data of elemental analysis for C18H17NO5calculated: 66,05, N 5,23, N to 4.28; found: 65,95, N 5,14, N of 4.38. MS m/e (%): 283 (M+; 100).

In the process similar to stage 4 and final stage in example 1, but replacing 4-(4-isopropoxybenzoic)nitrobenzene 4-(4-tetrahydropyran-4-roxylenol)nitrobenzene was obtained 2-[4-(4-tetrahydropyran-4-eloxiertes)phenyl]aminoimidazole with tPL169-170oC.

In the process similar to example 2, but replacing 4-hydroxymitragynine other hydroxidealuminum received the following compounds of formula I:
2-{4-[4-(1-ethylpropoxy)benzyl]phenyl}aminoimidazole; the data of elemental analysis for C21H27N3O calculated: 74,74, N Of 8.06, N 12,45; detected %, With 74,62, N Of 7.90, N of 12.33;
hydrochloride of 2-{ 4-[4-(sec-butoxy)benzyl] phenyl}aminoimidazole with tPL118-119oC;
maleate (R)-2-{ 4-[4-(Deut-butoxy)benzyl] phenyl} aminoimidazole with tPL163-164o;
maleate (S)-2-{ 4-[4-(Deut-butoxy)benzyl] phenyl} aminoimidazole with tPL163o;
hydrochloride (S)-2-{4-[4-(2-methylbutoxy)benzyl]phenyl}aminoimidazolePL119-122oC;
oxalate 2-[4-(4-hexyloxybenzoyl)phenyl]aminoimidazo ;
2-[4-(4-hydroxybenzyl)phenyl]aminoimidazole with tPL170-177oC;
2-{4-[4-(2-hydroxyethoxy)benzyl]phenyl}aminoimidazole with tPL164-165o;
hydrochloride 2-{ 4-[4-(3-ethoxypropane)benzyl] phenyl}aminoimidazole with tPL91-92o;
2-{ 4-[4-(chloroethoxy)benzyl] phenyl} aminoimidazole; the data of elemental analysis for C20H24N30OCl calculated: 67,12, N 6,76, N 11,74; found: 66,84, N 6,79, N 11,80;
hydrochloride 2-{ 4-[4-(2-methoxy-1-methylethoxy)benzyl] phenyl} aminoimidazole with tPL71-74oC;
hydrochloride 2-{ 4-[4-(3-methoxyphenoxy)benzyl] phenyl]aminoimidazole with tPL71-76oC;
hydrochloride 2-{ 4-[4-(1-hydroxyethylidene)benzyl] phenyl}aminoimidazole, m/s 326 (M+1);
hydrochloride 2-{4-[4-(2-hydroxy-1-hydroxyethyloxy)benzyl]phenyl}aminoimidazole with tPL50-55o;
hydrochloride 2-{4-[4-(2-ethoxy-1-ethoxymethyl)ethoxybenzyl]phenyl}aminoimidazole, retinoid weight;
hydrochloride 2-{ 4-[4-(2,3-dihydroxypropane)benzyl]phenyl}aminoimidazole with tPL55-60o;
hydrochloride 2-{4-[4-(2-phenylethane)benzyl]phenyl}aminoimidazole; the data of elemental analysis for C24H26N3OCl calculated: 70,66, N 6.42 Per, N 10,30; found: 70,42, N 6,37, N 10,42;
hydrochlorate)benzyl]phenyl}aminoimidazole c tPL101-104oC;
hydrochloride of 2-[4-(4-cyclopropylmethoxy)phenyl] aminoimidazole with tPL121-122o;
2-[4-(4-cyclobutanecarbonyl)phenyl]aminoimidazole; the data of elemental analysis for C21H25N3O calculated: 75,19, N 7,51, N 12,53; found: 74,69, N 7,32, N 11,96;
oxalate 2-{4-[4-(2-cyclopentyloxy)benzyl]phenyl}aminoimidazole c tPL152-153o;
maleate 2-{4-[4-(2-cyclohexylmethoxy)benzyl]phenyl}aminoimidazole with tPL144-147oC;
oxalate 2-{4-[4-(2-cyclohexylmethoxy)benzyl]phenyl}aminoimidazole with tPL120-127o;
hydrochloride 2-{4-[4-(2-isopropoxyphenoxy)benzyl]phenyl}aminoimidazole with tPL76-80o;
hydrochloride 2-{ 4-[4-(2-(2-oxopyrrolidin-1-yl)ethoxy)benzyl]phenyl}aminoimidazole with tPL143-145o;
hydrochloride 2-{ 4-[4-(2-(2-Oxymetazoline-1-yl)ethoxy)benzyl]phenyl}aminoimidazole with tPL85-88o;
2-[4-(4-tetrahydropyran-4-elecoxiban)phenyl] aminoimidazole with tPL159-160oC;
2-[4-(4-(tetrahydrofuran-3-elecoxiban)phenyl] aminoimidazole with tPL147-149oC;
2-[4-(4-(tetrahydrofuran-3-eloxiertes)phenyl] aminoimidazole with tPL149-150o;
2-{ 4-[4-(4-methylcyclohexylamine)benzyl]aminoimidazole with tPL85-90oC;
hydrochloride 2-{4-[4-(3-chloro-2-hydroxymethyl-2-methylpropoxy) benzyl]phenyl}aminoimidazole with tPL65-70o;
hydrochloride 2-{ 4-[4-(2-Tien-2-ylethoxy)benzyl] phenyl}aminoimidazole; the data of elemental analysis for C22H24N3ClS calculated: 63,83, N Of 5.84, N 10,15; found: 63,85, N 5,80, N 10,14;
hydrochloride 2-{ 4-[4-(2-Tien-3-ylethoxy)benzyl] phenyl}aminoimidazole; the data of elemental analysis for C22H24ClS calculated: 63,14, N 5,90, N 10,04; found: 63,30, N Of 5.81, N 10,11;
hydrochloride 2-{ 4-[4-(2-methansulfonate)benzyl]phenyl}aminoimidazole with tPL172-175oC;
hydrochloride 2-{ 4-[4-(4-methoxyphenyl)sulfonylureatolerant] phenyl} aminoimidazole; the data of elemental analysis for C26H31N4O6lS calculated: 58,08, N 5,95, N 10,41; found: 57,97, N 9,94, N of 10.58;
oxalate 2-[4-(3-fluoro-4-salutogenesis)phenyl] aminoimidazole with tPL134-135o;
hydrochloride of 2-[4-(2-fluoro-4-salutogenesis)phenyl]aminoimidazole c tPL134-135oC;
hydrochloride of 2-{ 4-[3-fluoro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}aminoimidazole with tPL149-151o;
2-{ 4-[2-fluoro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}aminoimidazole with tPL169-170o-4-(tetrahydropyran-4-ylethoxy)benzyl]phenyl}aminoimidazole with tPL154-155o;
maleate 2-{4-[2-fluoro-(4-tetrahydropyran-4-ylethoxy)benzyl]phenyl}aminoimidazole with tPL134-135o;
hydrochloride of 2-[4-(2-fluoro-4-interoceanic)phenyl] aminoimidazole, melts with puckering at 72o;
oxalate 2-{4-[4-(2-isopropoxyphenoxy)benzyl]phenyl}aminoimidazole c tPL134-137oC;
2-[4-(3-chloro-4-salutogenesis)phenyl]aminoimidazole with tPL126-128oAnd
hydrochloride of 2-{ 4-[3-chloro-4-(tetrahydropyran-4-yloxy)benzyl]phenyl}aminoimidazole with tPL128-130oC.

EXAMPLE 3.

2-[4-(4-Isopropoxyphenyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compound of formula Ia, in which R1denotes a group of formula (A), R2and R4each denotes hydrogen, Y denotes isopropoxide, a m denotes 0.

Stage 1.

A mixture of 30.0 g (173 mmole) of 4-bromophenol, 26,3 g (190 mmol) of potassium carbonate, 0,60 g (4 mmole) of sodium iodide, 85,1 g (0,692 mmole) of 2-bromopropane and 173 ml of N, N-dimethylformamide was kept at 60oC for 17 hours, the Solution was cooled to room temperature and was added 300 ml of water. The solution was extracted with diethyl ether. The extract is washed with aqueous hydroxide which was purified by vacuum distillation to obtain a colourless liquid with 25.3 g (118 mmol) of 4-bromotetradecane.

Stage 2.

A mixture of 0.534 g (22,0 mmole) of magnesium and 20 ml of tetrahydrofuran in a stream of nitrogen brought to the boil under reflux. To the solution was slowly added 3,10 g (14.4 mmol) of 4-bromotetradecane and to ensure initiation of the reaction 0.74 g (3,93 mmole) of 1,2-dibromethane. After completion of the reaction of the Grignard solution was cooled to room temperature and was added to 14.5 ml (7.3 mmol) of 0.5 M solution of zinc chloride in tetrahydrofuran. The solution was kept at the boiling point under reflux for 30 min, and then cooled to room temperature.

Stage 3.

A mixture of 1.47 g (7,92 mmole) of 4-nitrobenzylamine, and 0.46 g (0.40 mmol) of tetrakis(triphenylphosphine)palladium and 10 ml of tetrahydrofuran in a stream of nitrogen was cooled in a bath of ice water. To the solution was added to a portion (3.5 mmole) solution diarizing. The solution was stirred for 1 h in a bath of ice water, and then over night at room temperature. The solution was diluted with 15 ml of water and concentrated. The concentrate was extracted with dichloromethane. The extract was dried over MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel, receiving 1.0 g (3.5 mmole) of 4-isopropoxybenzoic-4-nitrobenzene with tPL135,6-136,9oC.

the preliminary stage of example 1, as a product identical to that obtained in example 1 was formed 2-[4-(4-isopropoxyphenyl)phenyl] aminoimidazole.

EXAMPLE 4.

2-[4-(4-Isopropoxycarbonyl)phenyl] aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compound of formula Ia, in which R1denotes a group of formula (A), R2and R4each denotes hydrogen, Y denotes an isopropyl, a m is 1.

Stage 1.

In a mixed solution of 300 mg (13.1 mmol) of 1-bromo-4-isopropoxyethanol (obtained analogously to example obtain 1) in 1.4 ml of dry tetrahydrofuran at -78oC in an atmosphere of argon was added dropwise of 1.62 ml (2.75 mmol) of 1.7 M tert-utility in pentane. After stirring the mixture for about 20 min was added 0.35 ml (1,31 mmole) chloride tri-n-butyanova. The mixture was allowed to warm to 0-5oC and was stirred for about 1 h At 0-5oWith the added mixture of 374 mg (13.1 mmol) of 2-trimethylsilylacetamide ether (4-chloromethylene)carbamino acid (obtained as described in example obtaining 2), 4,4 ml hexamethylphosphoramide and 29.3 mg (0,025 mmol) tetrakis(triphenylphosphine)palladium(0) and then kept at 65oFor the 2nd and the combined organic solutions were washed with water and brine, dried over Na2SO4) and evaporated in vacuo. The residue was dissolved in acetonitrile, washed with 2 portions of 20 ml of hexane, dried over Na2SO4), concentrated in vacuo and purified Express chromatography to produce in the form of a clear oil 204 mg (26%) of pure 2-trimethylsilylacetamide ester 4-(4-isopropoxyphenyl)phenylcarbinol acid.

Stage 2.

In the solution 734 mg (1.84 mmol) of 2-trimethylsilylacetamide ester 4-(4-isopropoxyphenyl)phenylcarbinol acid in dry dimethyl sulfoxide at 20oC in an atmosphere of argon was added 5,52 ml (5,52 mmole) of fluoride, Tetra-n-butylamine in tetrahydrofuran. After stirring the mixture for 1 h, the solution was distributed between 50 ml water and 50 ml of diethyl ether. The aqueous phase was extracted with 2 portions of 20 ml of diethyl ether and the combined organic layers were washed with water and brine, dried over MgSO4) and evaporated in vacuo. The crude product was purified Express chromatography, receiving in the form of a clear oil 405 mg (86%) of pure 4-(4-isopropoxyphenyl)phenylamine.

The final stage.

In a solution of 400 mg (1.57 mmol) of 4-(4-isopropoxyphenyl) phenylamine in 4.8 ml of isopropanol at 20oC in an atmosphere of argon deballasting evaporated in vacuum, added water and 10% sodium hydroxide to achieve a pH of 11-12. The basic aqueous phase was extracted with 3 portions of 20 ml of dichloromethane and the combined organic layers were washed with water, dried over Na2SO4) and evaporated in vacuo. The crude product was purified Express chromatography, washed of 0.07 M potassium carbonate and concentrated to produce in the form of a clear oil 463 mg (91%) of pure 2-[4-(4-isopropoxycarbonyl)phenyl]imidazoline.

To 2-[4-(4-isopropoxycarbonyl)phenyl] imidazoline added 129 mg (1,43 mmole) of oxalic acid and recrystallization from acetone as a white crystalline solid was obtained 507 mg of oxalate 2-[4-(4-isopropoxycarbonyl)phenyl]imidazoline with tPL156,3-156,7oWith; the data of elemental analysis for C20H25N3AboutWith2H2O4calculated: 63,91, N To 6.58, N 10,16; found: 63,98, N 6,53, N 10,24.

During the process the same way as is specified in the description of stage 1 of example 4, but replacing 1-bromo-4-isopropoxyethanol 1-bromo-4-second-butoxyethanol, and then in accordance with the subsequent stages received oxalate 2-[4-(4-sec-butoxyethanol)phenyl] imidazoline with tPL145,0-145,34calculated: 64,62, N 6,84, N 9,83; found: 64,81, N 6,82, N 9,98.

EXAMPLE 5.

2-[4-(4-Morpholinomethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula Ib, in which R1denotes a group of formula (A), R2and R4each represents hydrogen, and R3means morpholine.

Stage 1.

26,0 g (195 mmol) of aluminium chloride in individual portions was added to a solution of 27.8 g (150 ml) of 4-nitrobenzotrifluoride and 15.8 g (165 mmol) of 4-fervently in 100 ml of carbon disulphide. After 1 h, the resulting yellow mixture was carefully treated with 60 ml of concentrated hydrochloric acid and was stirred for 30 minutes the mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with diluted sodium hydroxide solution, water and brine, dried over MgSO4) and in vacuum solvent was removed. As a result of crystallization from diethyl ether/hexanol in the form of a white solid substance was obtained 10.6 g (82%) of 4-(4-perbenzoic) nitrobenzene with tPL87-88oWith; the data of elemental analysis for C13H8NO3F calculated: 63,69, N 3,26, N 5,71; found: 63,89, N 3,28, N 5,78.

Stage 2.

The mixture, containing a 1.96 g (8 mm is foxed, kept at 100-110oC for 12 h, the Reaction mixture was cooled to room temperature, diluted with cold water and filtered. The crude product is repeatedly washed with water and dried, obtaining 2.28 g (91%) of 4-(4-morpholinomethyl)nitrobenzene with tPL173-175oWith that used in the subsequent stage without further purification.

Stage 3.

1.0 g of 4-(4-morpholinomethyl)nitrobenzene was first made at a pressure of 50 psi using 10% palladium on coal in ethanol and a mineral acid, as indicated in the above description stage 5 in example 1. 0.66 g (77%) of 4-(4-morpholinomethyl)phenylamine obtained in this way as a product used in the subsequent stage without further purification.

The final stage.

During the process similar to the final stage in example 1, but replacing 4-(4-isopropoxyphenyl)phenylamine and 4-(4-morpholinomethyl)phenylamine (0,63 g) was obtained 0.51 g(63%) 2-[4-(4-morpholinomethyl)phenyl] aminoimidazole with tPL177-179oWith; the data of elemental analysis for C20H24N4O calculated: 71,44, N 7,14, N 16,66; found: 71,62, N 7,24, N 16,41.

During the process similar to stage 1 in example 5, and then respectively sub>110-112oC.

During the process similar to stage 2 of example 5, but replacing the research of N,N-(2-hydroxyethyl)amine, and then respectively similar to the subsequent stages in example 5 was obtained 2- { 4- [4-(N,N-(2-hydroxyethyl)amino)benzyl]phenyl}aminoimidazole with tPL150-152oC.

During the process similar to stage 1 in example 5, but replacing 4-fervently 2,4-differentlal, and then respectively similar to stage 3 and the final stage in example 5 was obtained the hydrochloride of 2- [4-(2,4-diferensial)phenyl] aminoimidazole with tPL150-152oC.

During the process similar to stage 1 in example 5, but replacing 4-fervently alkylated benzenes, and then respectively similar to the subsequent stages in example 5 were obtained the following compounds of formula I:
hydrochloride of 2-[4-(4-active compounds)phenyl]aminoimidazole with tPL72-74o;
fumarate 2-[4-(4-isopropylbenzyl)phenyl]aminoimidazole; the data of elemental analysis for C19H23N3About0,754H4About2calculated: 62,60, N 6,28, N 9,78; found: 62,61, N 6,44, N 10,00;
fumarate 2-[4-(4-isobutylphenyl)phenyl] aminoimidazole with tPL182-184o;
hydrochloride 2-{4-[4-(3-Eastern Europe and Caucasus: From 69,94, N to $ 7.91, N 7,76; found: 69,84, N 11,65, N 11,75;
hydrochloride of 2-[4-(4-propylbenzyl)phenyl] aminoimidazole; the data of elemental analysis for C19H24N3O calculated: 68,07, N 7,39, N 12,53; found: 68,05, N 7,21, N 12,70;
fumarate 2-{ 4-[4-(cyclopentyl)benzyl] phenyl} aminoimidazole; the data of elemental analysis for C25H29N3O4calculated: 62,20, N Is 6.19, N 8,43; found: 62,42, N 6,23, N 8,63, and
fumarate 2-{ 4-[4-(cyclohexyl)benzyl] phenyl} aminoimidazole; the data of elemental analysis for C22H28N3CL calculated: 68,43, N 7,78, N 10,88; found: 68,36, N 7,45, N 11,23.

EXAMPLE 6.

2-{4-[4-(4-methoxyphenyl)sulfonylmethane]phenyl}aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula IC, in which R1denotes a group of formula (A), R2, R4and R7each denotes hydrogen, R9represents 4-methoxyphenyl, a m is 1.

Stage 1.

9.3 g of aluminium chloride in one portion was injected into a mixture of 10 g of 4-nitrobenzylamine and 6.3 ml of toluene, dissolved in 35 ml of carbon disulfide. The mixture was heated from room temperature to the boiling point and boiled under reflux for 3 h M ivali in water and 3 times was extracted with dichloromethane. The extract was washed with diluted ammonium hydroxide and water, dried over Na2SO4) and evaporated. By recrystallization from ethyl acetate as pale yellow solid was obtained 10.6 g (82%) of 4-(4-methylbenzoyl)nitrobenzene with tPL122,4-123,1oC.

Stage 2.

In a mixture of 1.20 g of 4-(4-methylbenzoyl) nitrobenzene and 0,89 g of N-bromosuccinimide, suspended in 63 ml of carbon tetrachloride was added 0,012 g benzoyl peroxide. The reaction mixture was heated in a stream of argon under reflux for 4 h, at the same time irradiating lamp. The mixture was filtered, and the yellow solution containing the crude product, evaporated and chromatographically on silica gel, elwira hexane/ethyl acetate, to produce in the form of a white solid 1,79 g (81%) of 4-(4-bromomethylphenyl)nitrobenzene withPL112,7-113,1oC.

Stage 3.

500 mg of 4-(4-bromomethylphenyl)nitrobenzene was dissolved in 5 ml dichloromethane and stirred in a stream of argon. Was added dropwise a solution of 0.27 ml triftoratsetata in 2 ml of dichloromethane, and then a solution of 0.37 ml of triethylsilane in 2 ml of dichloromethane. After 5 min was added to the second portion of triftoratsetata and triethylsilane (in the same proportions). The reaction mixture was perineuronal dichloromethane. The solution containing the crude product, evaporated, chromatographically on silica gel, elwira product with hexane/ethyl acetate, and evaporated to dryness, obtaining 270 mg (56%) of 4-(4-bromomethylphenyl)nitrobenzene.

Stage 4.

210 mg (1.15 EQ.) of sodium azide was introduced into a solution of 901 mg of 4-(4-bromomethylphenyl)nitrobenzene in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 2 h, poured into water and 3 times was extracted with diethyl ether. The organic phase is 3 times washed with water, dried over MgSO4) and evaporated to dryness. Chromatography on silica gel, elwira hexane/ethyl acetate, in the form of a yellow oil was obtained 492 mg (62%) of 4-(4-azidomethyl)nitrobenzene.

Stage 5.

The solution 5,835 g of 4-(4-azidomethyl)nitrobenzene in 175 ml of tetrahydrofuran was treated of 0.43 ml of water and 6,45 g (1.1 EQ.) triphenylphosphine. The mixture was stirred at room temperature for 18 h and the solvent evaporated. The residue is suspended in water, the suspension was acidified by adding dropwise hydrochloric acid up to pH values of approximately 1, and then 3 times was extracted with diethyl ether. The aqueous phase was podslushivaet 50% aqueous sodium hydroxide and 3 times was extracted with dichloromethane to produce in the form of max ammonium, in the form of a yellow solid was obtained 3,91 g (79%) of 4-(4-aminomethylbenzoic)nitrobenzene.

Stage 6.

500 mg of 4-(4-aminomethylbenzoic)nitrobenzene was dissolved in 7 ml of dichloromethane and heated with 426 mg of 4-methoxybenzenesulfonamide and 0.3 ml of triethylamine. The mixture was stirred at room temperature for 15 h, then poured into dilute aqueous solution of hydrochloric acid and 3 times was extracted with dichloromethane. The solvent is evaporated, resulting in a yellow solid product 851 mg(~100%) 4-[4-(4-methoxyphenyl)sulfonylmethane] nitrobenzene, which without further purification was used at a later stage.

Stage 7.

791 mg of 4-[4-(4-methoxyphenyl)sulfonylmethane] nitrobenzene was dissolved in 15 ml ethyl acetate and was first made at room temperature over 5% palladium on coal. The reaction was carried out for 6 h, the mixture was filtered and evaporated to dryness. Thus obtained crude product was chromatographically in a short column with silica, elwira hexane/ethyl acetate 1: 1 ratio to produce in the form of a yellow solid 645 mg(87%) 4-[4-(4-methoxyphenyl)sulfonylmethane]phenylamine.

The final stage.

During the process similarly afflicted methylbenzyl]phenylamine by concentration by evaporation of the solvent and chromatography on silica gel, elwira dichloromethane/methanol/ammonium hydroxide in the ratio of 60:10:1, and recrystallization from acetone with 134 mg (1 EQ.) oxalic acid in the form of a white solid substance was obtained 685 mg (75%) of the oxalate 2-{4-[4-(4-methoxyphenyl)sulfonylmethane] phenyl} aminoimidazole with tPL167,0-167,5oWith; the data of elemental analysis for C26H28N4About7S calculated: 57,89, N 5,11, N of 10.47; found: 57,77, N 5,22, N 10,36.

During the process similar to the stage 6 of example 6, but replacing 4-methoxybenzenesulfonamide other sulphonylchloride, and then respectively similar to the subsequent stages in example 6 were obtained the following compounds of formula I:
hydrochloride of 2-[4-(4-benzensulfonamidelor)phenyl]aminoimidazole with tPLto 228.2-229,2o;
oxalate 2-{4-[4-(4-forfinal)sulfonylmethane]phenyl}aminoimidazole with tPL170,0 of 171.2o;
oxalate 2-{4-[4-(2-forfinal)sulfonylmethane]phenyl}aminoimidazole with tPL94,4-95,6o;
oxalate 2-[4-(4-isopropylaminomethyl)phenyl]aminoimidazole with tPL128,5-129,5oC and
oxalate 2-[4-(4-propelcolumntypes)phenyl]aminoimidazole with tPL122,8-123,5oC.

1denotes a group of formula (A), R2and R4each denotes hydrogen, R9denotes ethyl, a m denotes 0.

Stage 1.

1.1 ml (10 mmol) of acanaloniidae in the form of one portion was injected into a solution of 1.98 g (10 mmol) of 4,4'-methylenedianiline in 25 ml of dichloromethane. The reaction mixture was stirred for 1 h and evaporated to obtain solid, which was dissolved in 50 ml of dichloromethane and poured into a mixture of diethyl ether/2% aqueous potassium carbonate solution in a 1:1 ratio. After extraction of the aqueous layer was removed and discarded. The organic layer was extracted with 2 portions of 100 ml of 1% aqueous solution of potassium hydroxide, the aqueous layer was treated with excess amount of carbon dioxide and was extracted with 3 portions of 25 ml dichloromethane. The dichloromethane layer was diluted with 125 ml of diethyl ether and was extracted with 2 portions of 100 ml of 1% aqueous solution of hydrochloric acid. The layers were again separated, the aqueous phase was extracted with 50 ml diethyl ether and the organic phases were dumped in the waste. The aqueous phase, which contained the product was neutralized with solid potassium carbonate, was extracted with 4 portions of 20 ml of dichloromethane and evaporated to dryness. By recrystallization from acetone/is PL
108-109oC.

The final stage.

During the process similar to the final stage in example 1, but replacing 4-(4-isopropoxyphenyl)phenylamine 290 mg (1 mmol) 4-[4-(econsultancy)aminobenzyl]phenylamine and crystallization from etelaat received 319 mg(89%) 2-[4-(4-ethanolamines)phenyl]aminoimidazole.

The hydrochloride was obtained by suspendirovanie free base in 10 ml of methanol and the addition of ethanolic hydrochloric acid solution to achieve a sour reaction. The solvents are evaporated and the product was boiled under reflux with stirring in 5 ml of ethyl acetate. Filtration and drying of the hydrochloride of 2-[4-(4-ethanolamines)phenyl] aminoimidazole received the product with tPL178-178,5oWith; the data of elemental analysis for C18H23ClN4O2S, calculated %: 54,74, N By 5.87, N 14,19; found %: 54,65, N 5,79, N 14,21.

During the process similar to stage 1 in example 7, but replacing acanaloniidae other sulphonylchloride, and then respectively similar to the subsequent stages in example 7 were obtained the following compounds of formula I:
hydrochloride of 2-[4-(4-benzosulfimide)phenyl] aminoimidazole; elemental analysis data for�-{ 4-[4-(4-were)sulfanilamides]phenyl}aminoimidazole; the data of elemental analysis for C23H25lN4About2S calculated: 59,40, N 5,61, N 12,07; found: 59,59, N 5,64, N 11,66;
hydrochloride of 2-[4-(4-isopropylaminomethyl)phenyl]aminoimidazole with tPLto 206.6-207o;
hemoccult 2-[4-(4-methanesulfonylaminoethyl)phenyl] aminoimidazole with tPL254,2-254,5oC;
hydrochloride of 2-[4-(4-benzylmethylamine)phenyl] aminoimidazole; the data of elemental analysis for C23H25ClN4O2S calculated: 60,45, N 5,51, of 12.26 N; found: 60,33, N 5,67, N KZT 12.39;
hydrochloride 2-{4-[4-(2,2,2-triptorelin)sulfanilamides] phenyl}aminoimidazole; the data of elemental analysis for C18H201F3N4O2S calculated: 48,16, N 4,49, N 12,48; found: 47,89, N 4,47, N of 12.33;
hydrochloride of 2-[4-(4-propylsulfonyl)phenyl] aminoimidazole; the data of elemental analysis for C19H25ClN4O2S calculated: 55,56, N 6,18, N 13,64; found: 55,34, N 6,17, N 13,44;
hydrochloride of 2-[4-(4-butylsulfonyl)phenyl] aminoimidazole with tPL157-160o;
hydrochloride 2-{4-[4-(4-methoxyphenyl)sulfanilamides]phenyl}aminoimidazole; the data of elemental analysis for C23H25lN4About3S, the calculated is isoimidazole with tPL109,5-110oAnd
hydrochloride of 2-[4-(4-dimethylaminocarbonylmethyl)phenyl] aminoimidazole with tPL198,5-201oC.

During the process similar to stage 1 in example 7, but replacing acanaloniidae carbonylchloride, and then respectively similar to the subsequent stages in example 7 from the corresponding compounds of formula Id is received, the following compounds of formula I:
2-{ 4-[4-(tetrahydropyran-4-ylcarbonyl)aminobenzyl]phenyl}aminoimidazole with tPL225-227oAnd
chloride 2-{ 4-[4-(isopropylcarbonate)aminobenzyl] phenyl}aminoimidazole, retinoid mass.

EXAMPLE 8.

2-{4-[4-(Econsultancy)methylaminomethyl]phenyl}aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula IC, in which R1denotes a group of formula (A), R2and R4each denotes hydrogen, R7denotes methyl, R9denotes ethyl, a m denotes 0.

113 mg (1 mmol) of solid tert-butoxide potassium was introduced into a solution of 290 mg of 4-(4-ethanolamines)phenylamine (obtained in the foregoing example 7) in 2 ml of dimethylsulfoxide. The mixture was stirred and added 0.1 ml (1.5 mmole) methyliodide the phase is dried over potassium carbonate, evaporated and chromatographically on silica gel, elwira dichloromethane/acetone, to produce in the form of a yellow solid product 200 mg(66%) 4-[4-(econsultancy)methylaminomethyl]phenylamine.

During the process similar to the final stage in example 1, but replacing 4-(4-isopropoxyphenyl)phenylamine 300 mg (0.99 mmol) of 4-[4-(econsultancy)methylaminomethyl] phenylamine, boiling the reaction mixture under reflux in isopropanol for 16 h and crystallization from ethyl acetate/hexane received 318 mg(89%) 2-{4-[4-(econsultancy)methylaminomethyl]phenyl}aminoimidazole. This free amine was converted into cleaners containing hydrochloride salt with tPL178-178,5oWith; the data of elemental analysis for C19H23ClN4O2S calculated: 53,68, N 6.35mm, N of 13.18; found: 53,72, N 6,01, N to 13.09.

During the process as in example 8, but with replacement under the conditions other alkylidene and then correspondingly as in example 8, were obtained the following compounds of formula I:
hydrochloride of 2-{4-[4-(methanesulfonyl)benzylamines]phenyl}aminoimidazole; the data of elemental analysis for C24H2ClN4O2S calculated: 58,08, N 5,95, N 10,41; found: 57,97, N 5,94, N of 10.58;
hydrochloride of 2-{4-[4-(isopr4About2S calculated: 55,15, N 6,57, N 12,86; found: 55,11, N 6,39, N 12,76;
hydrochloride of 2-{4-[4-(propylsulfonyl)methylaminomethyl]phenyl}aminoimidazole; the data of elemental analysis for C20H2ClN4O2S calculated: 56,31, N 6,47, N 13,13; found: 56,10, N 6,34, N 13,04;
hydrochloride of 2-{4-[4-(econsultancy)ethylaminomethyl]phenyl)aminoimidazole; the data of elemental analysis for C21H29lN4About2S calculated: 56,55, N Is 6.78, N 12,56; found: 56,51, N Is 6.61, N 12,51, and
hydrochloride of 2-{4-[4-(econsultancy)propylaminoethyl]phenyl}aminoimidazole; the data of elemental analysis for C22H31ClN4O2S calculated: 54,47, N 6,62, N 12,70; found: 54,40, N 6,44, N 12,59.

EXAMPLE 9.

2-{4-[4-(1,1-Dioxothiazolidine-1-yl)benzyl]phenyl}aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula IC, in which R1denotes a group of formula (A), R2and R4each represents hydrogen, and R3denotes 1,1-dioxothiazolidine-1-yl.

1.40 g (3.9 mmol) of 4-[4-(3-chlorpropyl)sulfanilamides]phenylamine (obtained analogously to example 7) were mixed in solution in 25 ml of tetrahydrofuran containing 180 mg hydride who was agarawala dichloromethane. Evaporation and recrystallization in the form of not quite white solid product was obtained 1,09 g(86%) 4-[4-(1,1-dioxothiazolidine)benzyl]phenylamine with tPL134,5-135,5oC.

During the process similar to the final stage in example 1, but replacing 4-(4-isopropoxyphenyl)phenylamine 4-[4-(1,1-dioxothiazolidine-1-yl)benzyl] - phenylamine, received 2-{4-[4-(1,1-dioxothiazolidine-1-yl)benzyl] phenyl} aminoimidazole with tPL197,2-198,5oWith; the data of elemental analysis for C21H24N4O6S calculated: 54,74, N 5,25, N 12,17; found: 54,63, N 5,28, N 12,11.

EXAMPLE 10.

2-{4-[4-(3-Phenylurea)benzyl]phenyl}aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of the formula Ia, in which R1denotes a group of formula (A), R2, R4, R7and R8each denotes hydrogen, R9denotes phenyl, V represents Oh, a m denotes 0.

Stage 1.

A mixture of 19.8 g of 4,4'-methylenedianiline with 20 g of potassium carbonate in 300 ml of ethyl acetate and 200 ml of water was stirred in an ice bath. To the mixture was slowly added to 15 ml of benzylchloride. The resulting mixture was stirred for 1 h, then separated the organic layer and the aqueous layer is nd and brine, dried over Na2SO4) and in vacuum solvent was removed. By column chromatography with silica gel were isolated crude mixture elwira a mixture of 30% ethyl acetate/hexane, to produce in the form of a solid substance benzyl ester 4-(4-aminobenzyl)phenylcarbinol acid.

Stage 2.

0,997 g (3 mmole) of benzyl ester of 4-(4-aminobenzyl)phenylcarbinol acid was introduced into the solution 0,393 g (3.3 mmole) of phenylisocyanate in 20 ml of dichloromethane. The reaction mixture was stirred for 1 h at room temperature in a stream of nitrogen. Then the reaction in the reaction mixture was stopped by mixing with water and the mixture was concentrated in vacuum. The residue is suspended in water, filtered, washed with water and dried to obtain a white solid product of 1.38 g of benzyl ester {4-[4-(3-phenylurea)benzyl]phenyl}carbamino acid.

Stage 3.

A mixture of 1.3 g of benzyl ester {4-[4-(3-phenylurea)benzyl]phenyl}carbamino acid and 0.35 g of 10% palladium on coal in 150 ml of ethanol was first made at a pressure of 50 pounds per square inch in a Parr apparatus for 12 hours, the Reaction mixture was filtered through a pad of celite (brownmillerite) to remove the catalyst. When the concentration of the filtrate in the form of a white solid substance was obtained from 0.76 g of 4-[4-(3-f is niamina with 0,673 g (3.32 mmole) of 2-chloro-2-imidazolinone in 20 ml of 2-propanol was heated under reflux for 1 h The reaction mixture was concentrated, diluted with dichloromethane and was podslushivaet 10% sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with additional dichloromethane. The combined organic extracts were washed with water and brine, dried (on the K2CO3) and in vacuum solvent was removed. The residue was chromatographically on aluminum oxide (neutral, activity I, 15% methanol/dichloromethane) to give a white solid 2-{4-[4-(3-phenylurea)benzyl] phenyl}aminoimidazole with tPL167-170oWith; the data of elemental analysis for C23H23N5O calculated: 71,70, N 5,97, N 18,18; found: 71,34, N 5,98, N 17,91.

During the process the same way as is specified in the description of stage 6 in example 6, but replacing 4-methoxybenzenesulfonamide phenylisocyanate, and then correspondingly as in example 6 was obtained fumarate 2-{ 4-[4-(3-phenylurea)methylbenzyl]phenyl}aminoimidazole with tPL207-208,5oC.

EXAMPLE 11.

2-[4-(4-Dimethylaminocarbonylmethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula If, in which R1putting the Diya 1.

A solution of 4.26 deaths g (70 mmol) of 4-benzisothiazole in 25 ml dichloromethane at -30oWith dropwise introduced into a solution of 6 ml of chlorosulfonic acid in 25 ml of dichloromethane. The mixture was stirred for 10 min at 0oWith, and then poured into ice and shake. The organic phase was separated and evaporated solvents. The residue was recrystallized from dichloromethane/hexane to obtain in the form dichlormethane hemisulfate crystals 5,52 g (78%) of 4-(4-chlorosulfonylphenyl)nitrobenzene.

Stage 2.

354 mg (1 mmol) of dichloromethane hemisulfate 4-(4-chlorosulfonylphenyl) nitrobenzene dissolved in 5 ml of tetrahydrofuran, was added a 2 M solution (excess) of dimethylamine in tetrahydrofuran. The mixture was stirred for 1 h, were extracted with a solution of diethyl ether and diluted with potassium carbonate. The organic layer was separated and evaporated solvents. The residue was recrystallized from acetone/hexane to obtain 311 mg (98%) of 4-(4-dimethylaminocarbonylmethyl)nitrobenzene.

Stage 3.

311 mg of 4-(4-dimethylaminocarbonylmethyl)nitrobenzene was dissolved in ethyl acetate and was first made under the pressure of 40 psi using 10% palladium on coal as a catalyst for 2 hours the Mixture Phi is halilbasic)phenylamine.

The final stage.

A mixture of 288 mg of 4-(4-dimethylaminocarbonylmethyl)phenylamine and 110 mg sulfate 2-Chloromycetin in 2-propanol was heated under reflux for 16 hours In this mixture is quickly poured into a dilute solution of potassium carbonate and was extracted with 4 portions of 15 ml of dichloromethane. The solvent is evaporated, resulting in a solid 320 mg of 2-[4-(4-dimethylaminocarbonylmethyl)phenyl]aminoimidazole.

The product was dissolved in ethyl acetate and treated with excess methanolic solution of hydrogen chloride to obtain the crude product. The solvents are evaporated, and the residue was recrystallized from 2-propanol/ethyl acetate to produce in the form of a white solid substance 292 mg (76%) of the hydrochloride of 2-[4-(4-dimethylaminocarbonylmethyl)phenyl] aminoimidazole with tPL194,1-195,3oWith; the data of elemental analysis for C18H23ClN4About2S calculated: From 54.99, N By 5.87, N 14,19; found: 54,74, N By 5.87, N 13,96.

During the process similar to stage 2 of example 11, but replacing dimethylamine other amines, and then respectively similar to the subsequent stages in example 11, were obtained with other compounds of formula I:
hydrochloride of 2-[4-(4-benzylaminocarbonyl)phenyl] b>ClN4O2S0,7 H2O, calculated %: 59,04, N Of 5.45, N of $ 11.97; found %: 59,05, N 5,42, N 11,90;
hydrochloride of 2-[4-(4-sibutraminesometimes)phenyl]aminoimidazole, plavuchiye like glassy mass; the data of elemental analysis for C20H27ClN4O2S0,7 H2O, calculated %: 55,36, N 6,34, N 12,91; found %: 55,38, N 6,21, N 12,66;
hydrochloride of 2-[4-(4-pyrrolidin-1-ylsulphonyl)phenyl] aminoimidazole with tPL190,0-191,2oWith; the data of elemental analysis for C20H25ClN4O2S, calculated %: 57,06, N 5, 99, N 13,31; found %: 56,97, N 5,93, N 13,15;
oxalate 2-[4-(4-isopropylaminocarbonyl)phenyl] aminoimidazole with tPL138,0-to 140.5oWith; the data of elemental analysis for C21H26N4O6S calculated: 54,53, N 5,67, N 12,11; found: 54,39, N 5,58, N 12,02;
hydrochloride of 2-[4-(4-diisopropylaminoethanol)phenyl]aminoimidazole, plavuchiye like glassy mass; the data of elemental analysis for C22H31ClN4O2S0.5 H2O calculated: 57,57, N For 6.81, N 12,20; found: 57,67, N 6,85, N 11,81;
oxalate 2-[4-(4-tert-buylamisilonline)phenyl] aminoimidazole, PL is g src="https://img.russianpatents.com/chr/8226.gif">H2O calculated: 53,43, N 6,11, N 11,33; found: 53,67, N 6,30, N 11,03, and
oxalate 2-[4-(4-buylamisilonline)phenyl] aminoimidazole with tPL153,6-154,4oWith; the data of elemental analysis for C22H28N4O6S calculated: 55,45, N Of 5.92, N 11,76; found: 55,23, N 5,80, N 11,67.

EXAMPLE 12.

2-[4-(4-Benzylaminocarbonyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula If, in which R1denotes a group of formula (A), R2, R4and R8each denotes hydrogen, R9denotes benzyl, and m is 1.

Alternative stage 1A.

A solution of 0.73 g (7 mmol) of sodium sulfite in 10 ml of water was added to a solution of 1.41 g (5.6 mmol) of 4-(4-bromomethylphenyl) nitrobenzene in 10 ml of acetonitrile. The mixture was stirred and boiled under reflux for 2 hours Evaporated the solvent and dried to obtain a white powder to 2.29 g of sodium salt of 4-(4-nitrobenzyl)phenylmethanesulfonyl.

Alternative stage 1B.

to 2.29 g of sodium salt of 4-(4-nitrobenzyl)phenylmethanesulfonyl combined with 1.45 g of pentachloride phosphorus. The mixture was stirred at 90oC for 5 min, poured in the th yellow solid was 0.63 g of 4-(4-chlorosulfonylphenyl)nitrobenzene. This product was used directly in the subsequent stage.

Stage 2.

0.3 ml of benzylamine was added to a solution of 100 mg 4-(4-chlorosulfonylphenyl)nitrobenzene in 4 ml of tetrahydrofuran. The mixture was stirred for 2 h, poured into diluted aqueous solution of potassium carbonate and was extracted with 3 portions of 15 ml of dichloromethane. Evaporated the solvent and the residue was chromatographically on silica gel, elwira 2% solution of acetone in dichloromethane, to produce in the form of solids 44 mg of 4-(4-benzylaminocarbonyl)nitrobenzene.

Stage 3.

A solution of 44 mg of 4-(4-benzylaminocarbonyl)nitrobenzene was dissolved in ethyl acetate and was first made under the pressure of 40 psi with 10% palladium on coal as a catalyst for 2 hours the Mixture was filtered and the solvent evaporated to produce in the form of not quite white solid product 39 mg of 4-(4-benzylaminocarbonyl)phenylamine.

The final stage.

A mixture of 39 mg of 4-(4-benzylaminocarbonyl)phenylamine with 1 EQ. 2-chloronicotinamide base in 2-propanol was heated under reflux for 16 hours the mixture was added a dilute solution of potassium carbonate and was extracted with 4 portions of 15 ml determental)phenyl] aminoimidazole with tPL115-118oWith; the data of elemental analysis for C24H25lN4O2SH2O calculated: 58,94, N 5,98, N 11,46; found: 59,01, N 5,91, N 11,30.

During the process the same way as is specified in the description of stage 2 of example 12, but replacing benzylamine other amines, and then respectively similar to the subsequent stages in example 12 were obtained with other compounds of formula I:
hydrochloride of 2-[4-(4-sibutramineangiotensin)phenyl]aminoimidazole (51,5 mg solids) with tPLof 113.2-114,6oWith; the data of elemental analysis for C21H29ClN4O2S0.5 H2O calculated: 56,55, N Is 6.78, N 12,56; found: 56,68, 6,67 N, N 12,40.

oxalate 2-[4-(4-dimethylaminocarbonylmethyl)phenyl]aminoimidazole (73 mg, 58%) with tPL154,4-154,8oWith; the data of elemental analysis for C23H28N4O6S calculated: 56,54, N 5,78, N 11,42; found: 56,56, N 5,67, N 11,46, and
oxalate 2-[4-(4-pyrrolidin-1-isalphanumeric)phenyl] aminoimidazole (105 mg, 63%) with tPL160-161oWith; the data of elemental analysis for C21H26N4O6S calculated: 54,53, N 5,67, N 12,11; found: 54,48, N 5,58, N 12,13.

Princessa obtain the compounds of formula I from the corresponding compounds of formula Ig, in which R1denotes a group of formula (A), R2and R4each denotes hydrogen, R8and R9taken together with the nitrogen atom to which they are bound, form pyrrolidin, a m denotes 0.

Stage 1.

0.5 g of 10% palladium on coal was added to the solution to 11.31 g (50 mmol) 4-benzoylbenzene acid in 250 ml of ethanol and 10 ml of 70% perchloro acid. The suspension was first made at room temperature under a pressure of 40 pounds per square inch for 8 hours was removed by Filtration of the catalyst and the filtrate was neutralized with an aqueous solution of sodium bicarbonate. Evaporated the solvent and the residue was distributed between ethyl acetate and dilute aqueous potassium hydroxide solution. The aqueous phase was acidified with hydrochloric acid. Falling precipitated acid was filtered, washed and dried to obtain a 10.74 g (~100%) 4-benzylbenzoate acid.

Stage 2.

4-(4-Nitrobenzyl)benzoic acid was obtained in accordance with the methods described in Coon, etc. in J. Org. Chem., 1973, 38, 4243.

and 3.16 ml of 70% nitric acid was added dropwise to the suspension 9,34 ml (105,6 mmol) triftoratsetata in 250 ml of dichloromethane. This suspension was cooled in a bath of dry ice with acetone and was added dropwise a solution 10,19 g (48 mmol) 4-Ben is omnitele 2 h at room temperature. The reaction mixture was poured into crushed ice. Selected organic layer 2 times washed with dichloromethane and the combined organic layers were dried over Na2SO4) and evaporated the solvent. By recrystallization of the crude product from methanol/ethyl acetate as a yellow solid product was obtained 9,27 g (58%) of 4-(4-nitrobenzyl)benzoic acid.

Stage 3.

1,03 g (4 mmole) of 4-(4-nitrobenzyl)benzoic acid was dissolved in 40 ml of dichloromethane. To the mixture was added at 0.42 ml (1.2 EQ.) oxalicacid, and then 1 drop of N, N-dimethylformamide. The mixture was stirred for 1 h at room temperature and evaporated the solvent to produce in the form of a pale yellow solid product 1.10 g of 4-(4-chlorocarbonyl)nitrobenzene.

Stage 4.

4-(4-Chlorocarbonyl)nitrobenzene was dissolved in 40 ml dichloromethane was added a solution of 64 mg (1 EQ.) pyrrolidine in 0.2 ml of pyridine. The mixture was stirred for 2 h at room temperature, washed with dilute potassium hydroxide solution and evaporated the solvent to obtain a residue as a yellow oil. The residue was chromatographically on silica gel, elwira dichloromethane/methanol, obtaining 299 mg (99%) 4-(4-pyrrolidin-1-ylcarbonyl)nitrobenzene.

Stage 5.

CME which was first made under the pressure of 40 psi for 16 hours The mixture was filtered through a pad of celite (brownmillerite) and the solvent evaporated to obtain a white solid product 187 mg(99%) 4-[4-(1-pyrrolidinecarbonyl)benzyl]phenylamine.

The final stage.

A mixture of 182 mg (of 0.64 mmole) 4-[4-(1-pyrrolidinecarbonyl)benzyl]phenylamine with 131 mg (1 EQ.) bisulfate 2-chloro-2-imidazoline in 30 ml of 2-propanol was stirred at 60oWith over 60 hours Evaporated the solvent and the residue is suspended in a dilute solution of potassium hydroxide. The suspension was extracted with dichloromethane and was chromatographically on silica gel, elwira methanol/ammonium hydroxide, to obtain 205 mg of a white solid. This white solid was extracted with ethyl acetate, washed with dilute potassium hydroxide and treated with excess amount of hydrochloric acid in diethyl ether to obtain 193 mg (77%) of the hydrochloride 2-{4-[4-(1-pyrrolidinecarbonyl)benzyl] phenyl} aminoimidazole that when 46oWith wrinkled; the data of elemental analysis for C21H25ClN4O0,7 H2O calculated: 63,71, N 6,69, N 14,09; found: 63,44, N 6,38, N 13,81.

During the process the same way as is specified in the description of stage 4 in example 13, but with Samanosuke the compounds of formula I:
oxalate 2-[4-(4-isobutyleneisoprene)phenyl]aminoimidazole with tPL100-144oWith; the data of elemental analysis for C23H28N4O5calculated: 62,71, N 6,41, N 12,72; found: 62,44, N 6,36, N 12,72, and
oxalate 2-[4-(4-benzylaminocarbonyl)phenyl] aminoimidazole with tPL188,5-195,0oWith; the data of elemental analysis for C24H24N4O0,85 C2H2O4calculated: 66,95, N 5,62, N 12,15; found: 67,05, N Of 5.55, N of 12.26.

EXAMPLE 14.

2-[4-(4-Cyclopentyloxy-2-ylmethyl)phenyl]aminoimidazole.

Following receipt of the compounds of formula I from the corresponding compounds of formula Ih, in which R1denotes a group of formula (V), where X denotes S, R2denotes hydrogen, Y denotes cyclopentyl, a m denotes 0.

Stage 1.

In a solution of 8.75 ml (95.8 mmol) Cyclopentanol in 250 ml of N,N-dimethylformamide at 0-5oWith in a stream of nitrogen in the form of a 60% dispersion in mineral oil was introduced of 3.84 g (95.8 mmol) of sodium hydride. After 10 min the mixture was allowed to reach room temperature and was stirred for 40 minutes was Added 3,59 ml (38,3 mmole) 3-bromothiophene, and then 14,63 g (76,8 mmole) iodide monovalent copper. The mixture was stirred at 120oC 25 mole) of sodium cyanide in 200 ml of water. The mixture was stirred for 10 min, and then filtered. The filtrate was extracted with hexane. The extract was washed with water, dried over Na2SO4) and concentrated to dryness. By distillation (100oWith a residual pressure of 8 mm RT.CT.) as a slightly pale yellow oil was obtained to 4.52 g (70%) 3-cyclopentanedione.

1H-NMR (300 MHz, CDCl3,): to 7.15 (dd, J=5,2, 3.1 Hz, 1H), 6,72 (dd, J= 5,2, 15 Hz, 1H), to 6.19 (dd, J=3.1 and 1.5 Hz, 1H) and 4.65 (quintet, J=4,2 Hz, 1H), 1,55-of 1.95 (m, 8H).

MC m/e (%): 168 (M+; 17).

Stage 2.

2-Chloro-3-cyclopentyloxy received in accordance with the methods described P. Stanetty, and E. Puschautz in Monatsheefte Chemie, 1989, 120, 65. For example, in a solution of 3.98 g (23.7 mmole) 3-cyclopentanedione in 35 ml of dichloromethane and 15oWith in a stream of argon was introduced 2 ml (24,9 mmole) of sulfurylchloride. The mixture was stirred for 1 h, and then concentrated to dryness. After treatment, the Express by chromatography (silica, 100% hexane) as a pale yellow oil was obtained 2,75 g (59%) of 2-chloro-3-cyclopentanedione.

1H-NMR (300 MHz, CDCl3,): of 6.99 (d, J=6.0 Hz, 1H), 6.75 in (d, J=6.0 Hz, 1H), 4,69-4,74 (m, 1H), 1,7-of 1.93 (m, 6H), of 1.5-1.7 (m, 2H).

MC m/e (%): 202 (M+; 6).

Stage 3.

In a solution of 2.15 g (10.6 mmole) of 2-chloro-3-cyclopentyloxy hexane. The mixture was allowed to reach 20-25oC and was stirred for 4 h After re-cooling to -78oWith was added dropwise a solution of 1.56 g (10.3 mmole) of p-nitrobenzaldehyde in tetrahydrofuran. The mixture was stirred at -78oC for 1 h At -78oWith added saturated ammonium chloride and the mixture was allowed to reach approximately 10oC. the ethyl Acetate was extracted crude product was washed with water and brine, dried over Na2SO4) and concentrated to dryness to obtain 3.6 g of 4-(5-chloro-4-cyclopentyloxy-2-yl)-(4-nitrophenyl)methanol, which was used directly in the subsequent stage.

Stage 4.

4-(4-Cyclopentyloxy-2-ylmethyl)nitrobenzene can be obtained according to the methods described by E. J. Stoner and others in Tetrahedron, 1995, 51, 11043. For example, in the suspension 6,64 g (44,3 mmole) of sodium iodide in 10 ml of acetonitrile in a stream of argon at 20-25oWith introduced 5.6 ml (44,3 mmole) of tributyltinchloride. After stirring for 15 min at 20-25oThe mixture was cooled to 0-5oC and slowly added 3.6 g of 4-(5-chloro-4-cyclopentyloxy-2-yl)-(4-nitrophenyl)methanol in 10 ml of acetonitrile. Added 11.5 ml of 10% aqueous sodium hydroxide solution, and then an excessive amount of water. Product b>SO4) and concentrated to dryness. After treatment, the Express by chromatography (silica, hexane/ethyl acetate in the ratio of 98.5:1.5) are in the form of pale yellow oil was obtained 1.25 g (40%) of 4-(4-cyclopentyloxy-2-ylmethyl) nitrobenzene.

1H-NMR (300 MHz, CDCl3,): of $ 11.97 (d, J=8,8 Hz, 2H), 7,40 (d, J=8,8 Hz, 2H), 6,45 (m, 1H), 6,03 (d, J=1.7 Hz, 1H), 4,60 (quintet, J=4.3 Hz, 1H), 4,13 (s, 2H), 1,5-1,89 (m, 8H).

MS m/e (%): 303 (M+; 15).

Stage 5.

To a solution of 1.28 g (4.2 mmole) of 4-(4-cyclopentyloxy-2-ylmethyl)nitrobenzene in 34 ml of absolute ethanol in a stream of nitrogen at 20-25oWith the added value of 4.76 g (of 21.2 mmole) of hydrate of tin dichloride. The mixture was stirred at 75oC for 2.5 h and was cooled to 0-5oC. To achieve pH 8 was added a saturated solution of sodium bicarbonate. Added ethyl acetate and the mixture was filtered. Was the separation, the aqueous phase was extracted with additional ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4) and concentrated to dryness. After treatment, the Express by chromatography (silica, hexane/ethyl acetate) as a pale yellow oil was obtained of 0.47 g (41%) of 4-(4-cyclopentyloxy-2-ylmethyl)phenylamine.

1H-NMR (300 MHz, CDCl3(bs, 2H), 1,67-of 1.88 (m, 6H), 1,46-to 1.67 (m, 2H).

The final stage.

In a solution of 463 mg (1,69 mmole) of 4-(4-cyclopentyloxy-2-ylmethyl)phenylamine in 7 ml of isopropyl alcohol was introduced a solution of 293 mg (2.8 mmole) of 2-chloro-2-imidazoline in 7 ml of isopropyl alcohol. The mixture was heated under reflux overnight and vacuum was removed with isopropyl alcohol. Was added 10% aqueous sodium hydroxide and the product was extracted with dichloromethane. The extract was washed with water, dried (over PA2SO4) and concentrated to dryness to obtain the crude product.

578 mg of this crude product was dissolved in 20 ml of toluene and then adding 4 ml of Cyclopentanol and 674 mg hydrate p-toluenesulfonic acid. The mixture was stirred at 100-110oC for 2 h and cooled to room temperature. Was added 10% aqueous sodium hydroxide solution. The final product 3 times was extracted with dichloromethane, washed with water, dried over Na2SO4) and concentrated to dryness. In the purification preparative thin-layer chromatography with elution by ethyl acetate/methyl alcohol/isopropylamino in the form of pale yellow oil was obtained 290 mg(50%) 2-[4-(4-cyclopentyloxy-2-ylmethyl)phenyl]aminoimidazole

1H-NMR (300 MHz, CDCl3,

Oxalate 2-[4-(4-cyclopentyloxy-2-ylmethyl)phenyl] aminoimidazole has tPL142,4-br143.3oC.

During the process similar to stage 1 in example 14, but replacing Cyclopentanol with isopropanol, and then respectively similar to the subsequent stages in example 14 was obtained oxalate 2-[4-(4-isopropoxide-2-ylmethyl)phenyl]aminoimidazolePL151, 3mm-to 151.8oC.

EXAMPLE 15.

2-[4-(5-Meliksetian-2-ylmethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula Ii in which R1denotes a group of formula (V), where X denotes S, R2represents hydrogen, Y represents methyl, and m is 0.

Stage 1.

2-Methoxythiophene received in accordance with the methods described N. A. Keeystra and others in Tetrahedron, 1992, 48, 3633. So, for example, a solution of sodium methoxide in methanol was prepared by adding 2,12 g (92,2 mmole) of sodium in 14 ml of methanol. Supporting boiling under reflux, was added 10 g (61,3 mmole) of 2-bromothiophene. Introduced 0,88 g (6.1 mmole) of bromide monovalent copper, supporting boiling the mixture under reflux for 5.5 hours Under vigorous stirring at 20-25oWith dastic, were extracted with hexane, dried over Na2SO4) and concentrated to dryness. In the distillation (90oWith under a residual pressure of 80 mm RT.CT.) in the form of a colorless oil was obtained 5.35 g (76%) of 2-methoxythiophene.

Stage 2.

5-Meliksetian-2-yl(tri-n-butyl)stannane was obtained by adding in a stream of argon at -78oWith 3,81 ml 1,98 M (7,54 mmole) n-utility in hexane into a solution of 860 mg (7,54 mmole) of 2-methoxythiophene 4.3 ml of tetrahydrofuran. The mixture was allowed to reach 0 to 5oC and was stirred for 2 h, re-cooled to -78oWith and added 2,05 ml (7,54 mmole) chloride presence of TBT. The mixture was allowed to reach 0 to 5oC and was stirred for 1 h, the Product, 5-Meliksetian-2-yl(tri-n-butyl)stannane, used directly in the subsequent stage.

Stage 3.

In 2.15 g (7,54 mmole) 2-trimethylsilylacetamide ether 4-chloromethylisothiazolinone acid (described in example obtaining 2) at 20-25oWith added 5-Meliksetian-2-yl(tri-n-butyl)stannane, and then 11 ml hexamethylphosphoramide and 174,2 mg (0,146 mmole) tetrakis(triphenylphosphine) palladium. The mixture was stirred at 65oWith over 4.5 hours was Added water and the product was extracted with diethyl ether. The extract was washed with water, dried over Na2SO4and koncentrirebuli to dryness and purified Express chromatography on silica, then, elwira hexane/ethyl acetate, in the form of a yellow liquid was obtained 690 mg (25%) 2-trimethylsilylacetamide ester [4-(5-Meliksetian-2-ylmethyl)phenyl]carbamino acid.

1H-NMR (300 MHz, CDCl3,): of 7.25 (d, J=8.5 Hz, 2H), 7,16 (d, J=8.5 Hz, 2H), of 6.49 (bs, 1H), 6,37 (dt, J=3,7, 1.0 Hz, 1H), 5,98 (d, J=3,7 Hz, 1H), 4,25 (m, 2H), 3,94 (bs, 2H), 3,82 (s, 3H), 1.04 million (m, 2H), by 0.06 (s, 9H).

Stage 4.

In the solution 684 mg (of 1.88 mmole) 2-trimethylsilylacetamide ester [4-(5-Meliksetian-2-ylmethyl)phenyl] carbamino acid in 24 ml of dimethylsulfoxide at 20-25oWith in a stream of argon was added 5.6 ml of 1 M solution of Tetra-n-butylammonium in tetrahydrofuran. The mixture was stirred for 1 h was Added diethyl ether and the solution was washed with water and brine, dried over Na2SO4) and concentrated to dryness. Cleaning Express chromatography on silica, elwira hexane/ethyl acetate, in the form of a thick yellow oil was obtained 372 mg (90%) of 4-(5-Meliksetian-2-ylmethyl)phenylamine.

1H-NMR (300 MHz, CDCl3,): 7,02 (d, J=8.5 Hz, 2H), 6,63 (d, J=8.5 Hz, 2H), 6,36 (dt, J=3,7, 1.1 Hz, 1H), 5,97 (d, J=3,7 Hz, 1H), a 3.87 (bs, 2H), 3,81 (s, 3H), 3,4-3,7 (broad s, 1H).

MC m/e (%): 219 (M+; 100).

The final stage.

To a solution of 145 mg (0,BB mmole) of 4-(5-Meliksetian-2-ylmethyl)phenylamine in 10 Sa the suspension is kept at 80oC for 1.5 h the Mixture was diluted with dichloromethane and washed with 10% sodium hydroxide solution and water, dried over Na2SO4) and concentrated to dryness. In the purification preparative thin-layer chromatography with elution by ethyl acetate/methyl alcohol/isopropylamino in the form of a yellow oil was obtained 132 mg(70%) 2-[4-(5-Meliksetian-2-ylmethyl)phenyl]aminoimidazole.

1H-NMR (300 MHz, CDCl3,): for 7.12 (d, J=8,4 Hz, 2H), 6,93 (d, J=8,4 Hz, 2H), 6,39 (dt, J=3,7, 1.1 Hz, 1H), 5,98 (d, J=3,7 Hz, 1H), 3,92 (bs, 2H), 3,82 (s, 3H), 3,52 (s, 4H), 3,15-to 3.35 (broad s, 2H).

Oxalate 2-[4-(5-Meliksetian-2-ylmethyl)phenyl] aminoimidazole has tPLthe level of 121.8-122,8oC.

EXAMPLE 16.

2-[4-(5-Cyclopentyloxy-2-ylmethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula Ii in which R1denotes a group of formula (V), where X denotes S, R2denotes hydrogen, Y denotes cyclopentyl, and m denotes 0.

In a mixture of 51.1 ml high (0.56 mole) of Cyclopentanone with 50 ml of dioxane at 0-5oWith in a stream of argon was injected 60% sodium hydride (4,91 g, 0.12 moles) in mineral oil. The mixture was stirred at 80oTo the formation of homogeneous solution. When 80ivali at 120oC for 6 hours After cooling to 20-25oWith added 30 g (0,61 mole) of sodium cyanide in 200 ml of water. The mixture was intensively stirred for 20 min, filtered and extracted with hexane. Hexane extract was washed with water, dried over Na2SO4) and concentrated to dryness. Filtration through a column with silica (elution with 100% hexane) as a colorless oil was obtained 2.6 g (25,2%) 2-cyclopentylacetyl.

1H-NMR (300 MHz, CDCl3,): 6,7 (dd, J=5,7, and 3.7 Hz, 1H), is 6.54 (dd, J= 5,7, 1.5 Hz, 1H), 6,18 (dd, J=3,7, 1.5 Hz, 1H), 4,66 (septet, J=2.7 Hz, 1H), 1.5 to 2.0 (m, 8H).

During the process similar to stage 2 of example 15, but replacing 2-methoxythiophene 2-cyclopentylacetyl, and then respectively similar to the subsequent stages in example 14 was obtained oxalate 2-[4-(5-cyclopentyloxy-2-ylmethyl)phenyl]aminoimidazole with tPL71,2-75,5oC.

EXAMPLE 17.

2-[4-(5-Isopropoxide-2-ylmethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compounds of formula Ii in which R1denotes a group of formula (V), where X denotes S, R2represents hydrogen, Y represents isopropyl, and m is 0.

In RA is 0 mg (2.4 mmole) of hydrate p-toluenesulfonic acid. The mixture was boiled under reflux for 24 h and was cooled to 20-25oC. was Added 5% aqueous sodium hydroxide solution and the product was extracted with dichloromethane. The extract was dried over Na2SO4) and concentrated to dryness. In the purification preparative thin-layer chromatography with elution with hexane/ethyl acetate as pale yellow oil received 135 mg (57%) of 4-(5-isopropoxide-2-ylmethyl)phenylamine.

1H-NMR (300 MHz, CDCl3,): 7,02 (d, J=8.5 Hz, 2H), 6,63 (d, J=8.5 Hz, 2H), 6,34 (dt, J=3,7, 1.1 Hz, 1H), 6,01 (d, J=3,7 Hz, 1H), 4.26 deaths (quintet, J= 6,1 Hz, 1H), 3,88 (bs, 2H), 1,31 (d, J=6,1 Hz, 6N).

MS m/e (%): 247 (M+; 58).

The final stage.

To a solution of 131 mg (of 0.53 mmole) of 4-(5-isopropoxide-2-ylmethyl)phenylamine in 8 ml of acetonitrile at 20-25oWith in a stream of argon was added 121 mg (0,59 mmole) sulphate 2-chloro-2-imidazoline. The mixture was stirred at 80oC for 1.5 h the Mixture was diluted with dichloromethane and washed with sodium hydroxide and water, dried over Na2SO4) and concentrated to dryness. In the purification preparative thin-layer chromatography with elution by ethyl acetate/methyl alcohol/isopropylamino in the form of a thick yellow oil was obtained 150 mg(90%) 2-[4-(5-isopropoxide-ylmethyl) is, N), 6,37 (dt, J=3,7, 1.0 Hz, 1H), 6,02 (d, J=3,7 Hz, 1H), 4,28 (quintet, J= 6.2 Hz, 1H), 3,93 (bs, 2H), 3,52 (s, 4H), 3,24-3,5 (broad s, 2H), 1,32 (d, J=6.2 Hz, 6N).

MS m/e (%): 316 (M+; 100%).

Oxalate 2-[4-(5-isopropoxide-2-ylmethyl)phenyl] aminoimidazole has tPLRUR 134.4-135oC.

EXAMPLE 18.

2-[4-(1-Isopropylaminocarbonyl-4-ylmethyl)phenyl]aminoimidazole.

The following describes the process for obtaining the compounds of formula I from the corresponding compounds of the formula Ij, in which R1denotes a group of formula (C), where X denotes N, R2, R4and R8each denotes hydrogen, R9denotes isopropyl, V represents Oh, a m denotes 0.

Stage 1.

The mixture is 12.85 g (60 mmol) of 4-(4-nitrobenzyl)pyridine with 1.0 g of platinum oxide (IV), 5 ml (60 mmol) of 12 N. hydrochloric acid and 5 ml of water and 200 ml of ethanol was first made under the pressure of 40 pounds per square inch in a Parr apparatus for 12 hours the Reaction mixture was concentrated in vacuo, the residue was diluted with cold water and podslushivaet 10% sodium hydroxide solution. The formed mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over Na2SO4) and concentrated in vacuum. As a result of crystallization of the residue from ethyl acetate/hexane as oC.

Stage 2.

A solution of 0.57 g (3 mmole) of 4-(piperidine-4-ylmethyl)phenylamine in 20 ml of dichloromethane under nitrogen atmosphere was cooled in an ice bath. Dropwise to the solution was added 0.28 g (3.3 mmole) isopropylmalate and stirred at the temperature of the ice bath for 30 minutes the Reaction in the reaction mixture was stopped by mixing with water and the mixture was extracted with dichloromethane. The combined organic extracts were washed with water and brine, dried and vacuum removal of solvent. The crude product was chromatographically on silica gel, elwira system 2% methanol/dichloromethane containing 0.01% ammonium hydroxide, to produce in the form of a resinous product 0.66 g (80%) of 4-(1-isopropylaminocarbonyl-4-ylmethyl)phenylamine.

The final stage.

A mixture of 0.64 g (2,31 mmole) of 4-(1-isopropylaminocarbonyl-4-ylmethyl)phenylamine with 0.70 g (3,47 mmol) sulphate 2-chloro-2-imidazoline in 20 ml of 2-propanol was heated under reflux for 30 minutes, the Reaction mixture was concentrated in vacuum. The residue was diluted with water, podslushivaet 10% sodium hydroxide solution and was extracted with dichloromethane. The organic layer was washed with water and brine, dried (over PA2SO4) and concentrated in vacuum. Raw prodovol of ethyl acetate, containing some amount of ethanol to obtain a white solid product of 0.47 g(59%) 2- [4-(1-isopropylaminocarbonyl-4-ylmethyl)phenyl]aminoimidazole with tPL191-192oC.

During the process similar to stage 1 in example 18 and during the process immediately before the final stage in the form of a foam was obtained the hydrochloride of 2-[4-(piperidine-4-ylmethyl)phenyl]aminoimidazole.

During the process the same way as is specified in the description of stage 2 of example 18, but with the replacement isopropylmalate other isocyanates, and then respectively similar to the final stage in example 15 were obtained with other compounds of formula I:
hydrochloride of 2-[4-(1-phenylaminopyrimidine-4-ylmethyl)phenyl]aminoimidazole that when 99oWith wrinkled (vysokochastotnyi)22H28N5Cl, and
hydrochloride of 2-[4-(1-acylaminopenicillin-4-ylmethyl)phenyl] aminoimidazole that if 97oWith wrinkled (very hygroscopic), C18N28N5OCl.

EXAMPLE 19.

2-[4-(1-Benzosulfimide-4-ylmethyl)phenyl]aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compound is achet hydrogen, R9denotes benzene.

Stage 1.

A solution of 7.5 g (39,44 mmol) of 4-(piperidine-4-ylmethyl)phenylamine in 200 ml of dry tetrahydrofuran under nitrogen atmosphere was cooled in an ice bath. In this solution the individual portions were added 9,76 g of di-tert-BUTYLCARBAMATE and was stirred for 30 minutes the Reaction in the mixture formed was stopped by mixing with water, the mixture was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and vacuum removal of solvent. The crude product was chromatographically in a short column with silica gel, elwira system 30% ethyl acetate/hexane, received in the form of oil, which was hardened, 9,25 g(81%) 4-[1-(N-tert-butoxycarbonyl)piperidine-4-ylmethyl]phenylamine with tPL91-92oC.

Stage 2.

A solution of 3.55 g (12,24 mmole) 4-[1-(N-tert-butoxycarbonyl)piperidine-4-ylmethyl] phenylamine and 10.2 ml (73,4 mmole) of triethylamine in 70 ml of dichloromethane was cooled in nitrogen atmosphere in an ice bath. Dropwise into the solution was introduced with 5.2 ml (36.7 mmol) triperoxonane anhydride. The resulting mixture was stirred for 30 min, the reaction was stopped by mixing with 100 ml of phosphate buffer (pH 7.0) and 150 ml of methanol and stirred at room temperature for 15 minutes Reacts altnoy water and brine, dried in vacuo removal of solvent. The crude product was chromatographically on silica gel, elwira system 30% ethyl acetate/hexane, was obtained as solid product 4,43 g (94%) of 2,2,2-Cryptor-N-{4-[1-(N-tert-butoxycarbonyl)piperidine-4-ylmethyl] phenyl}ndimethylacetamide with tPL145-146oWith; the data of elemental analysis for C19H25N2About3F3calculated: 59,06, N Of 6.52, N of 7.25; found: 59,40, N Is 6.54, N 7,42.

Stage 3.

A mixture of 3.3 g of 2,2,2-Cryptor-N-{4-[1-(N-tert-butoxycarbonyl)piperidine-4-ylmethyl] phenyl}ndimethylacetamide with 5 ml triperoxonane acid in 30 ml dichloromethane was stirred at room temperature for 2 hours, the Reaction mixture was diluted with dichloromethane and cold water and neutralized with sodium bicarbonate solution. The organic layer was separated, washed with water and brine, dried and vacuum was removed the solvent to produce in the form of foam 1.5 g of 2,2,2-Cryptor-N-[4-(piperidine-4-ylmethyl)phenyl]ndimethylacetamide.

Stage 4.

0.5 g (1.75 mmol) of 2,2,2-Cryptor-N-[4-(piperidine-4-ylmethyl)phenyl]ndimethylacetamide and 0.23 g (2.1 mmole) of triethylamine in 10 ml of dichloromethane under nitrogen atmosphere was cooled in an ice bath. In this mixture at her stirring was added a solution of 0.37 g (2.1 mmole) of benzosulfimide in 1 ml dichloromethane. After 2 h the reaction is SOLOM, dried in vacuo removal of solvent. The residue was led from ethyl acetate/hexane to obtain 0,43 g (57%) of 2,2,2-Cryptor-N-[4-(1-benzosulfimide-4-ylmethyl)phenyl] ndimethylacetamide with tPL194-195oWith; the data of elemental analysis for C20H21N2O3SF3calculated: 56,32, N 4,96, N to 6.57; found: 56,54, N 4,99, N 6,68.

Stage 5.

A mixture of 0.45 g of 2,2,2-Cryptor-N-[4-(1-benzosulfimide-4-ylmethyl)phenyl] ndimethylacetamide from 0.23 g of lithium hydroxide in 10 ml of methanol and 1 ml of water was stirred for approximately 48 hours, the Reaction mixture was concentrated in vacuum, diluted with cold water and was extracted with dichloromethane. The organic layer was washed with cold water and brine, dried and vacuum removal of solvent. The residue was led from ethyl acetate/hexane to obtain 0,29 g (83%) of 4-(1-benzosulfimide-4-ylmethyl)phenylamine with tPL158oWith; the data of elemental analysis for C18H22N2O2S calculated: 65,43, N Of 6.71, N 8,48; found: 65,59, N Is 6.61, N 8,66.

The final stage.

A mixture of 0.28 g (0,83 mmole) of 4-(1-benzosulfimide-4-ylmethyl)phenylamine with 0.25 g (1.25 mmol) sulphate 2-chloro-2-imidazoline in 20 ml of 2-propanol was heated under reflux in the atmosphere is sodium hydroxide and was extracted with dichloromethane. The organic layer was washed with cold water and brine, dried and vacuum removal of solvent. The residue was chromatographically on neutral alumina, elwira 1% methanol/dichloromethane, to produce in the form of foam 0.29 grams(89%) 2-[4-(1-benzosulfimide-4-ylmethyl)phenyl] aminoimidazole. The data of elemental analysis for C21H26N4O2S5H2O calculated: 61,89, N Of 6.68, N of 13.75; found: 62,00, N Of 6.52, N 13,85.

During the process the same way as is specified in the description of stage 4 in example 19, but replacing benzosulfimide other sulphonylchloride or carbonylchloride, and then respectively similar to the subsequent stages in the example 19 was received by other compounds of formula I:
hydrochloride of 2-[4-(1-methanesulfonamido-4-ylmethyl)phenyl]aminoimidazole; the data of elemental analysis for C16H25N4O2ClS;
2-[4-(1-isopropylpiperazine-4-ylmethyl)phenyl] aminoimidazole with tPL193-194oWith; the data of elemental analysis for C18H28N4O2S4H2O calculated: 58,16, N 7,81, N 15,07; found: 58,26, N 7,52, N 14,96;
2-[4-(1-isopropylcarbodiimide-4-ylmethyl)phenyl]amino: 69,41, N 8,59, N 16,95;
2-[4-(1-isobutylbarbituric-4-ylmethyl)phenyl] aminoimidazole with tPL122-125oC; MS m/z 343 (M+1), and
hydrochloride 2-{4-[1-(3-methylbutanoyl)piperidine-4-ylmethyl]phenyl}aminoimidazole with tPL155-157oWith; the data of elemental analysis for C21H33N4Ol calculated: 64,19, N 8,46, N 14,26; found: 64,05, N 8,39, N 14,27.

EXAMPLE 20.

2-{4-[1-(1-Piperidinylmethyl)piperidine-4-ylmethyl]phenyl}aminoimidazole.

The following describes another variant of the process for obtaining compounds of formula I from the corresponding compound of formula Il in which R1denotes a group of formula (C), where X denotes N, R2and R4each denotes hydrogen, R8and R9together with the nitrogen atom to which they are attached, form a piperidine.

Stage 4.

A solution of 0.5 g (1.75 mmol) of 2,2,2-Cryptor-N-[4-(piperidine-4-ylmethyl)phenyl]ndimethylacetamide (obtained as described in the above description of the stages 1-3 in example 19) and triethylamine in 10 ml of dichloromethane under nitrogen atmosphere was cooled in an ice bath. The mixture is then treated with a solution of 0.39 g (2.09 mmol) of 1-piperidinecarbonitrile in 1 ml dichloromethane. The reaction mixture was stirred for 1.5 h at 0-5oC and the reaction was stopped by mixing with water. Igomyway water and brine, dried in vacuo removal of solvent. The residue was chromatographically on silica gel, elwira system 30% ethyl acetate/hexane, to produce in the form of a white solid product of 0.48 g of 2,2,2-Cryptor-N-[4-(1-piperidinecarbonitrile-4-ylmethyl)phenyl] ndimethylacetamide with tPL156-157oWith; the data of elemental analysis for C19H26N3About3SF3calculated: 52,64, N 6,05, N RS 9.69; found: From 52.84; H 6,00, N 9,79.

Stage 5.

A mixture of 0.48 g (1.11 mmol) of 2,2,2-Cryptor-N-[4-(1-piperidinecarbonitrile-4-ylmethyl)phenyl]ndimethylacetamide from 0.23 g (5,54 mmol) of lithium hydroxide in 10 ml of methanol and 1 ml of water kept at 60oC for about 2 hours, the Reaction mixture was concentrated in vacuum, diluted with water and was extracted with dichloromethane. The organic extracts were washed with water and brine and dried over Na2SO4). The residue was led from ethyl acetate/hexane to obtain a white solid of 0.30 g of 4-(1-piperidinecarbonitrile-4-ylmethyl)phenylamine with tPL144-145oC; elemental analysis data for C17H27N3About2S calculated: Of 60.50, H Of 8.06, N 12,45; found: 60,76, N 8,07, N 12,56.

The final stage
During the process the same way as is specified in wiseppe-4-ylmethyl)phenyl]aminoimidazole. The data of elemental analysis for C20H31N5O2S calculated: 59,23, N Of 7.70, N 17,27; found: $ 59.13 USD, N. 7,56, N 17,13.

During the process similar to stage 4 in example 20, but replacing 1-piperidinecarbonitrile 1-pyrrolidinecarboxamido and, accordingly, similarly, subsequent stages in example 20 in the form of a foam was obtained 2-[4-(1-pyrrolidineacetonitrile-4-ylmethyl)phenyl] aminoimidazole; the data of elemental analysis for C19H29N5O2S calculated: 57,23, N 7,53, N 17,56; found: 57,27, N 7,24, N 17,40.

EXAMPLE 21.

X-ray crystal form I.

Crystalline form I of sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole prepared by the methods described above in example 1. The radiograph shown in Fig. 1, were obtained using a diffractometer for powder x-ray diffraction Scintag X1, equipped with copper radiation source K1. The numbers shown in Fig.2 in the upper and lower parts of the x-axis, indicate respectively the constant "d" 2, and the right and left sides of the axis of ordinate respectively indicate the relative intensity in % and the number of pulses per second (PPS./C).

Below dannieaddison is the wavelength of x-ray radiation, which was used for calculations was 1,5406710-10cm (see table. 1).

EXAMPLE 22.

Obtaining crystalline form II.

194 mg of sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole was dissolved at 60oWith 1 ml of water, transparent top layer was transferred into a tube Craig and cooled in a bath of ice water. Centrifugation was collected crystals were dried in vacuum at room temperature to obtain 138 mg of crystalline form II sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole with tPL217-218oC.

In another embodiment, 38 g of sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole was dissolved in 80oWith 500 ml of water. After hot filtration, the solution was cooled to room temperature and kept at 4oC for 5 hours was collected by Filtration the crystals were dried at room temperature to obtain a 33.6 g of crystalline form II sulfate 2-[4-(4-isopropoxyphenyl)phenyl]aminoimidazole with tPL216-217oC.

EXAMPLE 23.

X-ray crystal form II.

X-ray crystal form II is shown in Fig.2, were obtained using a diffractometer for powder x-ray diffraction Scintag X1, equipped with copper radiation source Kand with the right and left sides of the axis of ordinate respectively indicate the relative intensity (in %) and the number of pulses per second (PPS./C).

Following x-ray powder data are presented in units of constant d and the relative intensity (RI) of over 3%. The weighted average wavelength of x-ray radiation, which was used for calculations was 1,540610-10cm (see table.2).

EXAMPLE 24.

Composition for oral administration, wt.%:
Active substance - 20,0
Lactose - 79,5
Magnesium stearate - 0,5
Both components are mixed and dispensed into capsules, each containing 100 mg of product; one capsule a total of approximately corresponds to a single daily dose.

EXAMPLE 25.

Composition for oral administration, wt.%:
Active substance - 20,0
Magnesium stearate - 0,5
Nitrocresols - 2,0
Lactose - 76,5
PVP (polyvinylpyrrolidone) - 1,0
The above components are mixed and granularit using methanol as solvent. Next, the composition is dried and using the appropriate teletrauma machine is formed with reception of tablets, each containing 20 mg acting /> Sodium chloride In an amount necessary for isotonic
Water for injection, ml - 100
The active substance is dissolved in parts of water for injection. Next, with stirring, sodium chloride in an amount necessary to obtain an isotonic solution. The remaining water for injection mass of the solution is brought to the necessary, filtered through the 0.2-micrometer membrane filter and filled into sterile conditions.

EXAMPLE 27.

Composition for suppositories, wt.%:
Active substance - 1,0
Polyethylene glycol 1000 - 74,5
Polyethylene glycol 4000 is 24.5
The components of the alloy between them, mixed in a steam bath and poured into molds containing in total over 2.5 g of product.

EXAMPLE 28.

Composition for topical application, g:
The active substance is 0.2 - 2
Span 60 - 2
Twin 60 - 2
Mineral oil - 5
Vaseline - 10
Methylparaben - 0,15
Propylparaben - 0,05
Bottled hydroxyanisol (BHA) - 0,01
Water Up to 100
All of the above components, except water, are mixed and heated with stirring to 60oC. Next, with vigorous stirring, add water, heated to 60oWith, in sufficient quantity to emulsify the components and nasal spray.

As compositions for intranasal spray are also several water suspensions containing 0.025 to 0.5% active ingredient. These compositions optionally include inert components, such as microcrystalline cellulose, sodium carboxymethyl cellulose, dextrose, etc., To regulate the pH, you can add hydrochloric acid. Composition intranasal spray can to dose using dosing pump for intranasal spray, as a rule, the feed per cycle 50-100 ál of the drug. In a typical dosing regimen provided by 2-4 cycles of pulverizate every 4-12 hours

EXAMPLE 30.

Evaluation of mechanical hyperalgesia caused by carrageenan.

Anti-inflammatory/analgesic activity of the compounds of the present invention was determined by evaluation caused by carrageenan mechanical hyperalgesia, establishing the degree of inhibition induced by carrageenan in rats of hyperalgesia paws using a modified method described by L. O. Randall and J. J. Selitto in the Archives of International Pharmacodynamics, 1957, 11, 409-419, and Vinegar, and others in the Journal of Pharmacology and Experimental Therapeutics, 1969, 166, 96-103.

Male rats Sprague-Dawley (130-150 g) were weighed and randomly distributed in groups (number 10) in experimental animals. what you left hind paw was injected 1% carrageenan or filler (100 μl). An hour before testing, the rats were injected filler (10 ml/kg orally or 1 ml/kg intravenously) or compounds of the present invention (at a dose of 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 determined using analgesiometer (UGO BASILE firms Biological Research Apparatus, Comerio, Italy). The treated filler or carrageenan hind paw was placed on the arch of the device so that the surface of the sole facing down. Next on the dorsal surface of the paw was affected by a constantly increasing force. For endpoint took the force at which the animal was pulling back his paw, started or made a noise.

Experimental groups were compared to the results of one-way analysis based on the distinction efforts, causing OTDELENIE feet (PEAK). Pairwise comparisons of animals treated with drugs groups of animals group, which was treated filler, using the methodology NSR (least significant difference) Fisher and method Danna. For each animal was calculated degree of inhibition mechanical hyperalgesia in percent, and the average value of EID50was calculated using the following sigmoid modelimpl for the inhibition of the half-maximum response (i.e., 100% in this model), and refers To the curve parameter.

In this test, compounds of the present invention showed activity.

EXAMPLE 31.

Score from symptom Freund mechanical hyperalgesia caused by the adjuvant.

Anti-inflammatory/analgesic activity of the compounds of the present invention can also be defined using the model caused by the adjuvant in rats pain of arthritis when pain is estimated by the reaction of animals to the compression of the inflamed foot in accordance with a variant of the technique described by J. Hylden and others in Pain, 1989, 37, 229-243. This option includes evaluating hyperalgesia and not change the activity of neurons of the spinal cord.

In General, animals were weighed and randomly distributed in groups of experimental animals. To cause mechanical hyperalgesia animals were exposed to the light anaesthesia with halothane gas and through the skin of the sole of the left hind paw was injected with 100 μl of adjuvant for symptom Freund or saline. Twenty-four hours later the rats one hour before the start of the oral tests were injected water (filler) or compounds of the present invention. Mechanical hyperalgesia was determined using analgesiometer (UGO BASILE firms Biological Research Apparat way to the surface of the sole facing down. Next on the dorsal surface of the paw was affected by ever-increasing effort and for the final point took the force at which the animal was pulling back his paw, started or made a noise. Experimental groups were compared to the results of one-way analysis based on the distinction efforts, causing OTDELENIE paws. For each animal, the degree of inhibition percentage was calculated in the form
100 x [(K/l - K/n)(s/n - K/n)],
where K/l denotes the force at which the animal, which was injected drug was withdrawn treated with carrageenan paw; K/n denotes the force at which the animal, which was introduced filler, drawing-treated carrageenan paw; and s/n denotes the force at which the animal, which was introduced filler, drawing the treated saline paw. Significance was determined using student's criterion.

In this test, compounds of the present invention showed activity.

EXAMPLE 32.

Inhibition in rats contractions of the bladder caused isovolumetric stretching of the bladder.

The degree of inhibition of contractions mosheim. and.. Therapeutics, 1984, 230, 500-513.

In General, male rats Sprague-Dawley (200-250 g) were weighed and randomly distributed in groups of experimental animals. To cause contraction of the bladder through the urethra into the bladder was injected, the catheter was performed by injecting 5 ml of warm saline. About 30% of the animals it caused rhythmic contractions. At the beginning of the regular rhythmic contractions intravenously injected compounds according to the invention (of 0.1, 0.3 or 1 mg/kg). Then determined the effect on rhythmic contractions.

In this test, compounds of the present invention showed activity.

EXAMPLE 33.

The inhibition due to the number of contractions in rats.

The degree of inhibition of contractions of the bladder was determined by test in accordance with a variant of the method described by S. S. Hegde and others in Proceedings of the 26th Annual Meeting of the International Continence Society, 27-30 August 1996, abstract 126.

Male rats Sprague-Dawley were anesthetized with urethane and connected devices for intravenous drugs, and in some cases to measure blood pressure, heart rate and pressure inside the bladder. On a separate group of animals was determined the influence of isbytearray bladder caused by filling the bladder with saline. The test compounds were administered intravenously in cumulative mode in 10-minute intervals. Upon completion of the research for positive control effect of intravenously injected with 0.3 mg/kg of atropine.

In this test, compounds of the present invention showed activity.

EXAMPLE 34.

Elimination in rats hypotension, caused by the action of endotoxins.

Septic shock, sometimes referred to as endotoxin bacterial toxic shock, induced by the presence of currents in the blood of infectious agents, in particular of bacterial endotoxins, and is characterized by hypotension and organ dysfunction. Many of the symptoms of septic shock, including hypotension, cause in rats by introduction of bacterial endotoxins. Thus, the ability of compounds to inhibit caused by endotoxins hypotension is an indicator of the usefulness of the compounds in the treatment of septic or bacterial endotoxin-toxic shock.

The action of the compounds according to the invention in the treatment of septic or bacterial endotoxin-toxic shock was evaluated by determining the extent of eliminating induced in rats with endotoxin hypotension in accordance with a variant of the method described by M. Giral and the AI usual means and input sensors blood pressure and placement of lines administering drugs were Coulibaly respectively femoral artery and vein. While the animals were under the influence of the usual means, they were placed in the fixture Mayo for fixation of the limbs. After the termination of anesthesia and stabilize the heart rate and blood pressure (which usually required about 30 min) was intravenously injected endotoxin (50 mg/kg E. coli and 25 mg/kg Salmonella). Follow changes in blood pressure and heart rate. After one hour also intravenously injected compounds of the present invention or the filler and in the next three hours constantly watched for cardiovascular indicators. The reaction was estimated percentage of return to the initial diastolic blood pressure. Significance was determined using student's criterion.

In this test, compounds of the present invention showed activity.

Although the present invention is described with reference to specific ways of its implementation, specialists in the art it should be borne in mind that they can make various changes and be replaced by equivalents without changing the true essence and without leaving the scope of the invention. In addition, to achieve compliance with the specific situation is asego of the invention may be resorted to many modifications. All these modifications should be considered as falling under the scope of the attached claims.

2. Activity.

Affinity to the IP receptor is expressed as PKiwhose value is in the range of 8.00-9,06 for compounds of the present invention.

The values of the PKi(PKi=-ODCi) was determined according to the following formula:

despite the fact that the values of the IC50are the concentrations of the tested compounds in PM, which is replaced 50% of the ligands that bind to receptors. [L] is the ligand concentration, and the value of KDis the dissociation constant of the ligand. These tables show that the compounds of the present invention possess the desired activity.

The root problem underlying the present invention is to provide new compounds that are antagonists of IP receptors, and which therefore could be used to treat conditions such as pain or septic shock, inflammatory diseases, urinary incontinence, asthma.

From the above table.4 can be seen that the compounds in which the phenyl ring is attached to the amino group in the 4 position, ocasla substituted in position 2.

Moreover, the connection with the connecting bridge, described in EP 017484 (preferably A= -O - or-S -) are less active part of the IP receptor in comparison with the compounds described in this invention. The degree of affinity measured in terms of the values of the PKiwhich is a logarithmic value, respectively, a single value increases (or increases) of 10 in terms of affinity. In General, the higher the value of the PKiindicates a higher affinity of binding between the potential drug and its target.


Claims

1. 2-(Arylvinyl)aminoimidazole General formula I

where R1denotes a group of formula (A), (B) or (C)



where X is independently in each case denotes S or N;
R2and R4each independently of one another in each case represents (1) hydrogen, (2) alkoxygroup or (3) halogen;
R3independently in each case refers to (1) alkyl, (2) cycloalkyl, (3) halogen, (4) morpholinyl, 1,1-dioxothiazolidine-1-yl, (5) -NR8R9, (6) -(CH2)mCONR8R9, DG> where m= 0, (9) -(CH2)mNR7SO2R9where m= 0-3, integer (10) -(CH2)mNR7C(V)NR8R9where V denotes O, a m= 0-3, integer (11) -(CH2)mOh, where m= 0-3, integer, Y is hydrogen, alkyl, alkyloxyalkyl, cycloalkyl, haloalkyl, hydroxyalkyl, tetrahydropyranyl, tetrahydrofuryl, 5-methyl-[1,3] -dioxane-5-yl or carboxyethyl, or (12) -O(CH2)nZ, where n= 1-4, an integer, a Z - cycloalkyl, hydroxyalkyl, cycloalkylation, tetrahydropyranyl, tetrahydrofuryl, fenoxaprop, thienyl, -COR9, -CONR8R9, -SO2R9, -NR7SO2R9, unsubstituted phenyl;
R5independently in each case represents -(CH2)mOh, where m= 0, and Y is hydrogen, alkyl, cycloalkyl;
R6independently in each case denotes: (1) hydrogen, (2) -OR9, (3) -CONR8R9, (4) -C(V)NR8R9where V denotes O, 2 (5) -SO2R9or (6) -SO2NR8R9, R7and R8each independently of one another in each case represents (1) hydrogen, (2) alkyl or (3) hydroxyalkyl;
R9independently in each case refers to (1) alkyl, (2) cycloalkyl, (3) benzyl, (4) hydroxyalkyl, (5) haloalkyl, (6) piperidinyl, tetrahydropyranyl, pyrrole is a, halogen free and alkyloxy, or (8) thienyl; or
R8and R9together with the nitrogen atom to which they are bound, form a 5 - or 6-membered monocyclic saturated ring,
as well as its pharmaceutically acceptable salt or crystalline form.

2. Connection on p. 1, in which R1denotes a group of formula (A).

3. Connection on p. 2, in which R2and R4each independently from each other hydrogen, fluorine or chlorine.

4. Connection on p. 2, in which R3represents -(CH2)mOh, where m = 0-3, an integer, a Y is methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 2-ethoxy-1-(ethoxymethyl)ethyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl or tetrahydropyran-2-yl.

5. Connection on p. 2, in which R2and R4each is hydrogen, Y is isopropyl, and m= 0.

6. Connection on p. 2, in which R denotes-O(CH2)nZ, a n= 1-4, an integer.

7. Connection on p. 6, in which the Z - cyclopentyl, cyclohexyl, tetrahydropyran-4-yl, tetrahydropyran-2-yl or 1-hydroxymethyl.

8. Connection on p. 2, in which R3represents -(CH2)mCONR8R9where m= 0, or -(CH2)mSO2NR8R9where m= 0-3, integer.

9. Connection on p. 2, in which R9is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

11. Connection on p. 2, in which R3represents -(CH2)mNR7SO2R9where m= 0-3, integer, or -(CH2)mNR7COR9where m= 0.

12. Connection on p. 11, in which R7is hydrogen, methyl, ethyl or propyl, and R9is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl or benzyl.

13. Connection on p. 1, in which R1is a group of formula (B).

14. Connection on p. 13, in which X represents S, R3-(CH2)mOY, a m = 0-3, integer .

15. Connection on p. 14, in which Y is methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 2-ethoxy-1-(ethoxymethyl)ethyl, cyclopentyl, cyclohexyl, tetrahydropyran-4-yl or tetrahydropyran-2-yl.

16. Connection on p. 13, in which X represents S, R3-O(CH2)nZ, a n = 1-4, an integer.

17. Connection on p. 1, in which R1is a group of formula (C).

18. Connection on p. 17, in which X denotes n

19. Connection on p. 1, selected from the group including
2-[4-(4-isopropoxyphenyl)phenyl] aminoimidazole;
2-[4-[4-(sec-butoxy)benzyl] phenyl} aminoimidazole;
2-{ 4-[4-(cyclopentyloxy tetrahydropyran-4-ylethoxy)benzyl] phenyl} aminoimidazole;
2-{ 4-[2-fluoro-4-(tetrahydropyran-4-ylethoxy)benzyl] phenyl)-aminoimidazole;
2-{ 4-[4-(2-ethoxy-1-(ethoxymethyl)ethoxy)benzyl] phenyl} aminoimidazole;
2-[4-(4-cyclopentylmethyl-2-ylmethyl)phenyl] aminoimidazole;
2-{ 4-[4-(1-hydroxyethylidene)benzyl] phenyl} aminoimidazole;
2-[4-(5-Meliksetian-2-ylmethyl)phenyl] aminoimidazole;
2-[4-(4-buylamisilonline)phenyl] aminoimidazole;
2-[4-(4-isopropoxycarbonyl)phenyl] aminoimidazole;
2-[4-(4-sec-butoxyethanol)phenyl] aminoimidazole;
2-{ 4-[4-(sibutraminesolution)benzyl] phenyl] aminoimidazole;
2-[4-(4-benzylaminocarbonyl) phenyl] aminoimidazole;
2-[4-(4-isopropylaminocarbonyl)phenyl] aminoimidazole;
2-[4-(4-isobutyleneisoprene)phenyl] aminoimidazole
2-[4-(4-tert-buylamisilonline)phenyl] aminoimidazole.

20. The pharmaceutical composition intended for the introduction of mammals that are in a morbid condition, which is eliminated by the treatment of substance-receptor antagonist IP, and this composition as a component comprises a therapeutically effective amount of the compounds according to paragraphs. 1-19, its pharmaceutically acceptable salt or crystalline form in a mixture with men who 1,4-12 and 14-19;
04.09.1977 on PP. 2,3,13 and 20.

 

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< / BR>
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< / BR>
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The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups

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

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

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)
The invention relates to a new process for the preparation of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent

The invention relates to new derivatives of amides and urea of the formula I

R1-(CH2)n(Y)q-(Z)r-CO-NH-R2(I)

in which R1- 3-indolyl, unsubstituted or monosubstituted, AO, Hal, CN;2represents a

< / BR>
< / BR>
or

< / BR>
m = 1 or 2; n = 0, 1, 2, 3 or 4; Y is 2,4-cyclohexylamine, 1,3 - pyrrolidinone, 1,4-piperazinone or 1,4-piperidinylidene ring, which may also be partially digidrirovanny; Z - (CH2)nNH-, q = 0 or 1; r = 0 or 1; R3- A; R4- AO; Hal Is F, Cl, Br, J; A - unbranched or branched C1-C6alkyl, provided that q and r are not simultaneously equal to 0, and their physiologically acceptable salts

The invention relates to new Amida acids of the formula I

< / BR>
where R1- C1-C6alkanoyl,1-C6alkoxycarbonyl, benzoyl, benzoyl substituted halogen (C1-C6)-alkoxy, C1-C6alkylsulfonyl, phenylsulfonyl, phenylsulfonyl, substituted with halogen, or cyclo (C3-C6) alkylsulphonyl, R2- phenyl, phenyloxy or phenylamino, where each phenyl may be substituted with halogen; pyridyl or pyridylamino, a represents a single bond, E is ethylene, X represents CH, Y is-NR5where R5is hydrogen, Q is-C(O)- or-SO2-, R3and R4together form ethylene, or their pharmaceutically acceptable salts

The invention relates to new indole derivative of the formula I

< / BR>
where R1- H, halogen, CN; R2and R3the same or different is H, C1-C4alkyl, halogen; R4- H, C1-C4alkyl; And means cyanoaniline, aminosulphonylphenyl, aminopyridine, aminopyrimidine, halogenopyrimidines or cianciarulo group, provided that if all R1, R2and R3- N, when both R2and R3- N or when ring A - aminosulphonylphenyl group and both R1and R2the halogen atoms is excluded; and, in addition, when the ring a represents cyanophenyl group, 2-amino-5-pyridyloxy group or 2-halogen-5-pyridyloxy group, and R1represents a cyano or halogen group, at least one of R2and R3must not be a hydrogen atom

The invention relates to new cyclic diamine compounds of the formula I, where

< / BR>
represents an optionally substituted divalent residue of benzene, where the substituents are selected from unsubstituted lower alkyl groups, unsubstituted lower alkoxygroup, unsubstituted lower acyl group, a lower allylthiourea, lower alkylsulfonyl group, halogen atom, etc. or unsubstituted pyridine; Ar represents a phenyl group which may be substituted by one to four groups selected from unsubstituted lower alkyl group, the unsubstituted alkoxygroup, low allylthiourea, lower alkylsulfonyl group, and so on, optional substituted amino group, alkylenedioxy; X is-NH-, oxygen atom or sulfur atom; Y is a sulfur atom, sulfoxide or sulfon; Z represents a single bond or-NR2-; R2- the atom of hydrogen or unsubstituted lower alkyl group; l = 2 or 3; m = 2 or 3; n = 1, 2, or 3, or their salts, or their solvate

The invention relates to a form of omeprazole, which is effective as an inhibitor of the secretion of gastric acid and is useful as an antiulcer agent

The invention relates to N-oxides of heterocyclic compounds of the formula (I), where R1is CH3CH2F, CHF2, CF3; R2is CH3, CF3; R3represents F, Cl, Br, CH3; R4represents H, F, Cl, Br, CH3

The invention relates to the use of 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic to modulate the activity of metabotropic glutamate receptors (mGluR) and to the treatment of mGluR5 mediated diseases, to pharmaceutical compositions intended for use in such therapy, as well as to new 2-arylalkyl-, 2-heteroaromatic-, 2-arylalkyl-, 2-heteroarylboronic-, 2-arylazo - and 2-heteroarylboronic

The invention relates to substituted 3-cyanohydrins formula (1), where R1, R2, R3, R4, Y and X are such as defined in the claims

The invention relates to medicine, namely to drugs with immunomodulatory, anti-inflammatory, antitumor and antioxidant effect
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