Pharmaceutical composition (options), derivatives of 3,5 - diphenyl-1,2,4-triazoles in her inbox

 

(57) Abstract:

Describes a pharmaceutical composition for the treatment of diseases which cause an excess of iron in the human or animal, or which is due to them containing at least one compound of formula I, where R1and R5at the same time or independently of one another denote hydrogen, halogen, hydroxyl, C1-C4alkyl, Gialos1-C4alkyl, C1-C4alkoxy, Gialos1-C4alkoxy, carboxyl, carbarnoyl, N-, C1-C4allylcarbamate, N,N-di-C1-C4allylcarbamate or nitrile, R2and R4at the same time or independently of one another denote hydrogen, C1-C4alkanoyl, benzoyl, toluene, naphtol or para-methoxybenzoyl or a radical that can be removed in a physiological environment, R3denotes hydrogen, C1-C4alkyl, hydroxys1-C4alkyl, Gialos1-C4alkyl, carboxy1-C4alkyl, C1-C4alkoxycarbonyl1-C4alkyl, R6R7N-C(O)-C1-C4alkyl, phenyl, unsubstituted or substituted by carboxyla, nitrogroup, halogen, C1-C4alkoxygroup,1-C4acylaminoalkyl, para-cyanobenzyl, para-pyrrolidinones or pyridyl, unsubstituted or linked via C1-C4alkylenes group, R6and R7at the same time or independently of one another denote hydrogen, C1-C4alkyl, hydroxys1-C4alkyl, alkoxyl1-C4alkyl, hydroxyalkoxy1-C4alkyl, amino1-C4alkyl, N-C1-C4alkylamino1-C4alkyl, N, N-di-C1-C4alkylamino1-C4alkyl, N-(hydraxis1-C4alkyl)amino1-C4alkyl,

N,N-di-(hydraxis1-C4alkyl)amino1-C4alkyl, benzyl, 4-morpholinylmethyl, (4-methyl-1-piperazinil)ethyl or together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine, R8and R9together with the nitrogen atom to which they are attached, form morpholino or 4 methylpiperazine, or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier; novel compounds falling under the General formula I and a pharmaceutical composition containing the new compounds. 4 C. and 3 h.p. f-crystals.

Various disorders in warm-blooded animals are associated with an excess in body tissues of metals, in particular trivalent metals, for example with an excess of aluminum in dialysis with encephalopathy and osteomalacia, as well as in Alzheimer's disease. In other diseases, in particular, a person in various tissues formed by excess iron. Such a violation is called iron overload (formerly known as hemosiderosis). This occurs, for example, after parenteral administration of iron (especially when repeated blood transfusions), or as a result of increased absorption of iron from the gastrointestinal tract. Repeated transfusions necessary for severe anemia, especially in large thalassemia, severe form of thalassemia, as well as other anemias. Increased absorption of iron from the gastrointestinal tract or is primary, for example, due to genetic defect (so-called hemochromatosis), or secondary, for example, anemia requiring blood transfusion, for example, after a moderate thalassemia-thalassemia moderate form.

Iron overload in the absence of treatment can cause serious damage. Compounds which form chelate complexes with iron, can mobilize and remove pending in the bodies of the iron and thereby reduce associated with excess iron morbidity and mortality.

The decrease in the concentration of iron (III) is also of interest for the treatment of disorders associated with dependent iron (III) microorganisms and parasites, which play a key role not only in human diseases, such as, in particular malaria, but also in the veterinary diseases. The formation of complexes with other metals, in particular with trivalent metals, can also be used for their excretion from the body. Numerous other applications are also described in the literature, for example, in G. Kontoghiorghes, Toxicology Lett., 80, 1-18 (1995).

For these purposes for a long period of time is known and is used in therapy desferrioxamine In (N. Bickel, H. Keberle and E. Vischer, Helv. Chem. Acta, 46, 1385-1389 [1963]). The disadvantage of this drug, however, is that desferrioxamine and its salts have only a small, inadequate activity in oral introduction, and in their application in all the above cases, the required form of parenteral administration. For them, for example, is recommended as about the, the fact, however, requires the use of a portable mechanical device, such as a syringe for infusion, driven by an electric drive. In addition to their discomfort, these solutions contribute to the current high cost of treatment, which seriously restricts their use, in particular, it is impossible to treat thalassemia in the Mediterranean countries, the Middle East, India and Southeast Asia, malaria worldwide and sickle cell anemia in Africa. Widespread disease, thus representing a serious public health problem in these countries, which makes it extremely necessary in this area to develop a simple and cheaper method of treatment, preferably using drugs, active in oral introduction.

Various 3,5-diphenyl-1,2,4-triazole known for a long period of time, and their application are described as herbicides, for example, in EP 0185401, as antagonists of angiotensin II receptor in ER 0480659 or in very General form as intermediates and starting compounds for the pure chemical compounds, for example, in JP 06345728.

Currently, it was found that certain C the treatment of disorders caused by an excess of metal in a human or animal or caused this, first of all a proven ability to communicate with ions of trivalent metals, in particular iron (A. E. Martell and R. J. Motekaitis, "Determination and Use of Stability Constants", VCH Publishers, New York, 1992). Among other things they have the ability to inhibit the deposition of pigments containing iron, and in the case of the presence in the body iron depot to cause excretion, for example, in animal models when using iron overloaded rats after choledochotomy (R. J. Bergeron and others, J. Med. Chem., 34, 2072-2078 (1991)) or overloaded iron monkey (R. J. Bergeron and others, Blood, 81, 2166-2173 (1993)), in doses of approximately 5 mol/kg

The present invention relates to the use of compounds of the formula I

< / BR>
in which R1and R5at the same time or independently of one another denote hydrogen, halogen, hydroxyl, (NISS. )alkyl, halogen(NISS. )alkyl, (NISS. )alkoxy, halogen (ness.)alkoxy, carboxyl, carbarnoyl, N-(NISS. )allylcarbamate, N,N-di(ness.)allylcarbamate or nitrile,

R2and R4at the same time or independently of one another denote hydrogen, unsubstituted or substituted (ness.)alkanoyl or aroyl or a radical that can be removed in Phi is carboxy(NISS. )alkyl, (ness.)alkoxycarbonyl-(ness.)alkyl, R6R7N-C(O)-(ness.)alkyl, unsubstituted or substituted aryl or aryl(ness.)alkyl or unsubstituted or substituted heteroaryl or heteroalkyl,

R6and R7at the same time or independently of one another denote hydrogen, (NISS. )alkyl, hydroxy(NISS. )alkyl, alkoxy(NISS. )alkyl, hydroxyalkoxy(ness.)alkyl, amino(ness.)alkyl, N-(ness.)alkylamino-(ness.)alkyl, N,N-di(NISS. )alkylamino-(ness.)alkyl, N-(hydroxy(ness.)alkyl)amino-(ness.)alkyl, N, N-di(hydroxy(ness.)alkyl)amino-(ness.)alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring,

and their salts for the treatment of diseases which cause an excess of metal in a human or animal, or which is due to them, preferably in the form of pharmaceutically acceptable preparations, in particular by using method intended for therapeutic treatment of the human body, and to a method of treatment of this type.

Halogen, for example, denotes chlorine, bromine or fluorine, but also can represent iodine.

Console "(ness.)" denotes a radical having not more than 7, in particular not more than 4 carbon atoms.

Al is from other groups, as, for example, (ness.)alkoxygroup, (ness.)the alkylamine, (ness.)alkanoyl, (NISS. )alkylaminocarbonyl may be unsubstituted or substituted, for example, halogen, hydroxyl, (NISS. )alkoxygroup, trifluoromethyl, cyclo(ness.)the alkyl, salicicola or phenyl, preferably it is unsubstituted or substituted by hydroxyl.

(NISS. )alkyl denotes, for example, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably methyl, ethyl and n-propyl. Halogen (ness.)alkyl denotes (NISS. )alkyl, substituted with halogen, preferably chlorine or fluorine, in particular having as substituents up to three chlorine atoms or fluorine.

(Ness.)alkoxy denotes, for example, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-amyloxy, isoamylase, preferably methoxy, ethoxy. Halogen(ness.)alkoxy denotes (NISS. )alkoxygroup, substituted with halogen, preferably chlorine or fluorine, in particular, having as substituents up to three chlorine atoms or fluorine.

Carbarnoyl denotes the radical of H2N-C(O)-, N-(ness.)allylcarbamate means (ness.)alkyl-N-C(O)- and N,N-di(ness.)allylcarbamate obamer, acetyl, propanol, butanol or pivaloyl.

(Ness.)alkoxycarbonyl denotes a radical (ness.)alkyl-O-C(O)- and refers to, for example, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, n-aryloxyalkyl, isoamylalcohol, preferably methoxycarbonyl and etoxycarbonyl.

Aryl as such or as part of other groups, refers to, for example, aryl(ness.)alkyl or aroyl, for example phenyl or naphthyl which can be substituted or unsubstituted. Aryl preferably denotes phenyl which may be unsubstituted or replaced by one or more substituents, in particular one or two substituents, for example (NISS. )alkyl, (ness.)alkoxygroup, hydroxyl, nitro, amino, halogen, trifluoromethyl, carboxyla, (ness.)alkoxycarbonyl, amino, N-(NISS. )alkylamino-, N, N-di(NISS. )alkylaminocarbonyl, aminocarbonyl, (NISS. )alkylaminocarbonyl, di(NISS. )alkylaminocarbonyl, heterocyclization, heteroaryl or cyano. Preferably the aryl represents unsubstituted phenyl or naphthyl or phenyl, substituted (ness.)the alkyl, (NISS. )alkoxygroup, hydroxyl, halo is P CLASS="ptx2">

Aroyl represents the radical aryl-C(O)- and refers to, for example, benzoyl, toluoyl, naphtol or para-methoxybenzoyl.

Aryl(NISS. )alkyl denotes, for example, benzyl, para-of chlorbenzyl, ortho-tormentil, phenylethyl, para-trimethyl, para-dimethylaminobenzoyl, para-diethylaminomethyl, para-tenbensel, para-pyrrolidinones.

Heteroseksualci denotes cycloalkyl radical that contains 3 to 8, in particular from 5 to not more than 7 ring atoms and in which at least one of them predstavlyaet a heteroatom, preferably oxygen, nitrogen and sulfur. Salicyclic represents a saturated cycloalkyl radical with 3-8, in particular with 5-7 ring atoms, at least one of which is a nitrogen atom. Salicyclic may also contain additional ring heteroatoms, for example oxygen, nitrogen or sulfur, and denotes, for example, piperidinyl, piperazinil, morpholinyl or pyrrolidinyl. Salicylidene radicals can be unsubstituted or substituted with halogen or (NISS. )alkyl. Salicylidene radicals linked via a ring nitrogen atom and which is preferred, as is well known, indicate piperidine, piperazine derivatives, morpholine, pyrrolidine and so heteroaryl(ness.)the alkyl, denotes an aromatic radical containing from 3 to not more than 7, in particular from 5 to not more than 7 ring atoms, at least one of which is a heteroatom. As examples pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, furanyl, thiophenyl, pyridyl, pyrazinyl, oxazinyl, triazinyl, pyranyl or pyrimidinyl. Heteroaryl can be replaced or unsubstituted. Preferred heteroaryl, which is unsubstituted or which is substituted by one or more, in particular one or two substituents, for example (ness.)by alkyl, halogen, trifluoromethyl, carboxyla or (ness.)alkoxycarbonyl.

Heteroaryl(ness.)alkyl denotes (ness.)the alkyl radical in which at least one of the hydrogen atoms, preferably C-terminal atom, a substituted heteroaryl group, if the alkyl chain contains two or more carbon atoms.

N-(NISS. )alkylamino means, for example, n-propylamino, n-butylamino, isopropylamino, isobutylamino, hydroxyethylamino, preferably methylamino, ethylamino. In N,N-di(ness.)alkylamino alkyl substituents may be the same or different. Thus, N,N-di(ness.)alkylamino means, on the Mino, N-methyl-N-benzylamino.

Salts of compounds of formula I represent, in particular, pharmaceutically acceptable salts, especially salts formed with bases, such as acceptable salts of alkali metals or alkaline-earth metals, for example salts of sodium, potassium or magnesium salts, pharmaceutically acceptable salts of transition metals, such as zinc salts, or salts formed with organic amines, such as cyclic amines, for example mono-, di -, or three(NISS. )bonds alkylamines, such as hydroxy(ness.)the bonds alkylamines, for example mono-, di - or trihydroxy(NISS. )bonds alkylamines, hydroxy(NISS. )alkyl-(NISS. )bonds alkylamines or polyhydroxy(NISS. )alkylamines followed. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine. Acceptable mono(NISS. )bonds alkylamines are, for example, ethyl - and tert-butylamine, di(ness.)the bonds alkylamines are, for example, diethyl - and Diisopropylamine, and three(NISS. )bonds alkylamines are, for example, trimethyl - and triethylamine. Acceptable hydroxy(ness.)the bonds alkylamines are, for example, mono-, di - and triethanolamine, hydroxy(ness.)alkyl-(ness.)the bonds alkylamines are, for example, N,N-dimethylamino and N,N-Diethylaminoethanol suitable p the Finance acid additive salts, for example, with strong inorganic acids such as mineral acids, for example sulfuric acid, phosphoric acid or galoidvodorodnykh acid, with strong organic carboxylic acids such as (NISS. )alcancarao acid, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example malonic, maleic or fumaric acid, or such as hydroxycarbonate acid, for example tartaric or citric acid, or with sulfonic acids, such as (NISS. )alkanesulphonic acid or substituted or unsubstituted benzosulfimide acid, for example methane - or para-toluensulfonate acid. The compounds of formula I having an acidic group, such as carboxyl, and a basic group such as amino, may also be present in the form of internal salts, i.e. amphoteric form, or parts of molecules may be present as internal salts, and the other part in the form of a normal salt.

In particular, the invention relates to the use of compounds of formula I for the treatment of diseases that are caused by an excess of iron in the human or animal, or which is due to them, preferably in the form of a pharmaceutically priemel the ZMA person, and to a method of treatment of this type.

In addition, the invention relates to new drugs, including at least one compound of the formula I, in which R1and R5at the same time or independently of one another denote hydrogen, halogen, hydroxyl, (ness.)alkyl, halogen (NISS. )alkyl, (ness.)alkoxy, halogen(ness.)alkoxy, carboxyl, carbarnoyl, N-(ness.)allylcarbamate, N,N-di(ness.)allylcarbamate or nitrile, R2and R4at the same time or independently of one another denote hydrogen, unsubstituted or substituted (ness.)alkanoyl or aroyl or a radical that can be removed in a physiological environment, R3denotes hydrogen, (NISS. )alkyl, hydroxy(NISS. )alkyl, halogen (ness.)alkyl, carboxy(ness.)alkyl, (NISS. )alkoxycarbonyl-(NISS. )alkyl, R6R7N-C(O)-(ness.)alkyl, unsubstituted or substituted aryl, aryl(ness.)alkyl, substituted N-(ness.)alkylamino-, N, N-di-(ness.)alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroalkyl, R6and R7at the same time or independently of one another denote hydrogen, (ness.)alkyl, hydroxy(ness.)alkyl, alkoxy(NISS. )alkyl, hydroxyalkoxy(NISS. )alkyl, amino(ness.)alkyl, N-(NISS. )alkylamino-(NISS. )alkyl, N, sh. )alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring, or their salts, and at least one pharmaceutically acceptable carrier, and to methods of producing these compounds.

These pharmaceutical drugs are drugs intended for enteral, especially oral, and rectal administration, and drugs intended for parenteral administration warm-blooded animal, especially man, the pharmacologically active ingredient included in the composition of the drug only in pure form or in combination with other conventional pharmaceutical auxiliary means. The pharmaceutical preparations contain, for example, from about 0.001 to 100 wt.%, preferably from about 0.1 to about 100 wt.%, the active substance.

Pharmaceutical preparations for enteral or parenteral administration are, for example, drugs in the form of standard dosage forms, such as a covered sugar pills, tablets, dispersible tablets, "effervescent tablets, capsules, suspendiruemye powders, suspensions or suppositories or ampoules. Get them a well-known method, and lyophilization. Pharmaceutical preparations for oral administration, thus, can be obtained by combining the active ingredient with solid carriers, optionally pelletizing the resulting mixture and processing the mixture or granulate, if necessary, or necessarily after adding suitable auxiliaries to obtain tablets or cores covered with sugar pills.

Suitable carriers are in particular fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, preparations based on cellulose and/or calcium phosphates, for example, secondary calcium phosphate or secondary of calcium hydrogen phosphate, and also binders, such as starch pastes based on, for example, corn, wheat, rice or potato starch, gelatin, tragakant, methylcellulose and/or polyvinylpyrrolidone, and, if necessary, leavening agents, such as the above-mentioned starches, and also carboxymethylate starch, Poperechnaya polivinilpirolidon, agar or alginic acid or its salt, such as sodium alginate. Excipients are primarily substances that regulate the fluidity, and the oil, for example, salicylic, Koloa tablets sugar coated cover suitable if necessary intersolubility coatings, using, inter alia, concentrated sugar solutions, which optionally contain gum Arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or in mixtures of solvents or for cooking intersolubility coatings, solutions of suitable preparations based on cellulose, such as cellulose acetate phthalate or phthalate of hydroxypropylmethylcellulose. In tablets or coatings covered sugar tablets can be added dyes or pigments, for example, for identification or marking of different doses of active ingredient.

Dispersible tablets are tablets which rapidly disintegrate in a relatively small quantities of liquid, such as water, and which optionally contain corrigentov or compounds, masking the taste of the active substance. They mainly can be used for oral administration of large single doses, in which the amount of the active substance is so large that its introduction in the form of tablets, which should be swallowed whole with or without grinding, AMI for oral administration are capsules with solid, and with soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Gelatin capsules with a hard coating may contain the active substance in the form of granules, for example, in a mixture with fillers, such as lactose, binders, such as starches, and/or oiling agents, such as talc or magnesium stearate, and, if necessary, with stabilizers. Capsules, soft coated active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, it is also possible the addition of stabilizers.

In addition, as forms for oral administration suitable suspendiruemye powders, for example, which are called "powder in vial, abbreviated PIB, or ready to drink suspension. For the manufacture of this form of the active substance is mixed with, for example, pharmaceutically acceptable surfactants, for example, lauryl sulfate or Polysorbate, with suspendresume auxiliary substances, for example with hydroxypropylcellulose, hypromellose or other substances known from the prototype, described earlier, for example,ninety in USP buffer, and optionally with fillers such as lactose, and other auxiliary substances, and poured into suitable containers, mainly in the bubbles with a single dose or capsules. Immediately before use add a certain amount of water and by shaking receive a suspension. In another embodiment, water may be added before filling in the bubbles.

Input rectal pharmaceutical preparations are, for example, suppositories which contain the active substance in combination with the base of the suppository. Suitable basis for suppositories are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Can also be used gelatine rectal capsules which contain the active substance in combination with a substance base. As a matter of bases can be used, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

For parenteral administration are primarily preferred aqueous solutions of the active ingredient in water-soluble form, for example in the form of soluble salts. In addition, you can apply the suspension of daltoniana or carriers, such as fatty oils, for example sesame oil, or synthetic esters of fatty acids, for example etiloleat or triglycerides, or aqueous injection suspensions that contain substances that increase the viscosity, for example sodium carboxymethyl cellulose, sorbitol and/or dextran, and optionally also stabilizers.

The dose of active ingredient may depend on various factors, such as activity and duration of action of the active substance, the severity of the disease to be treated, or its symptoms, the route of administration, the species of warm-blooded animals, sex, age, weight, and/or individual condition of the warm-blooded animal. Daily dose used in the case of oral administration ranges from approximately 10 to approximately 120 mg/kg, in particular from 20 to about 80 mg/kg, and for warm-blooded animal, the body weight of approximately 40 kg, and preferably ranges from approximately 400 to approximately 4800 mg, in particular from approximately 800 to 3200 mg, and is useful to divide the 2-12 separate doses.

Preferably the invention relates to new drugs, containing at least one compound of the formula I, in which R1and R5odnl, (ness.)alkoxy or halogen(ness.)alkoxy, R2and R4at the same time or independently of one another denote hydrogen or a radical that can be removed in a physiological environment, R3means (NISS. )alkyl, hydroxy(ness.)alkyl, carboxy(ness.)alkyl, (NISS. )alkoxycarbonyl-(NISS. )alkyl, R6R7N-C(O)-(NISS. )alkyl, substituted aryl, aryl(NISS. )alkyl, substituted N-(ness.)alkylamino-, N,N-di(ness.)alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroalkyl, R6and R7at the same time or independently of one another denote hydrogen, (ness.)alkyl, hydroxy(ness.)alkyl, alkoxy(ness.)alkyl, hydroxyalkoxy(NISS. )alkyl, amino(ness.)alkyl, N-(ness.)alkylamino-(ness.)alkyl, N, N-di(NISS. )alkylamino-(NISS. )alkyl, N-(hydroxy(ness.)alkyl)amino-(NISS. )alkyl, N, N-di(hydroxy(ness.)alkyl)amino-(ness.)alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring, or salts thereof and at least one pharmaceutically acceptable carrier, and to methods for their preparation. These pharmaceutical drugs are drugs intended for enteral, especially oral, and rectal administration, and drugs, pregnang ingredient, part of the drug either in pure form or in combination with other conventional pharmaceutical auxiliary means. The pharmaceutical preparations contain, for example, from about 0.001 to 100 wt.%, preferably from about 0.1 to about 50 wt.%, the active substance.

The present invention also provides new compounds of General formula II

< / BR>
in which R1and R5at the same time or independently of one another denote hydrogen, halogen, (ness.)alkyl, halogen(ness.)alkyl, (ness.)alkoxy, halogen (NISS. )alkoxy, carboxyl, carbarnoyl, N-(ness.)allylcarbamate, N,N-di(NISS. )allylcarbamate or nitrile,

R2and R4at the same time or independently of one another denote hydrogen, unsubstituted or substituted (ness.)alkanoyl or aroyl or a radical that can be removed in a physiological environment,

R3denotes the R6R7N-C(O)-(ness.)alkyl, unsubstituted or substituted aryl, aryl(NISS. )alkyl, substituted N-(ness.)alkylamino-, N,N-di(ness.)alkylamino or pyrrolidino, or unsubstituted or substituted heteroaryl or heteroalkyl provided that R3not denotes phenyl or phenyl substituted by halogen, NITR is carbonyl, if R2and R4represent hydrogen and R1and R5denote hydrogen, halogen, (ness.)alkyl, halogen(ness.)alkyl, (ness.)alkoxy or nitrile,

R6and R7at the same time or independently of one another denote hydrogen, (NISS. )alkyl, hydroxy(NISS. )alkyl, alkoxy(NISS. )alkyl, hydroxyalkoxy(ness.)alkyl, amino(ness.)alkyl, N-(ness.)alkylamino-(ness.)alkyl, N,N-di(NISS. )alkylamino-(ness.)alkyl, N-(hydroxy(ness.)alkyl)amino-(ness.)alkyl, N, N-di(hydroxy(ness.)alkyl)amino-(ness.)alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring,

and their salts.

Primarily the invention relates to compounds of formula II in which R1and R5at the same time or independently of one another denote hydrogen, halogen, (NISS. )alkyl, halogen(NISS. )alkyl, (ness.)alkoxy or halogen(NISS. )alkoxy, R2and R4at the same time or independently of one another denote hydrogen or a radical that can be removed in a physiological environment, R3denotes the R6R7N-C(O)-(ness.)alkyl, substituted aryl, aryl(ness.)alkyl, substituted N-(ness.)alkylamino-, N,N-di(ness.)alkylamino or pyrrolidino, or unsubstituted or substituted heteroalkyl, the sh. )alkyl, halogen(NISS. )alkyl, (NISS. )alkoxygroup or (NISS. )alkoxycarbonyl, if R2and R4represent hydrogen and R1and R5denote hydrogen, halogen, (ness.)alkyl, halogen(ness.)alkyl or (ness.)alkoxy, R6and R7at the same time or independently of one another denote hydrogen, (NISS. )alkyl, hydroxy(NISS. )alkyl, alkoxy(NISS. )alkyl, hydroxyalkoxy(NISS. )alkyl, amino(NISS. )alkyl, N-(ness.)alkylamino-(ness.)alkyl, N,N-di(NISS. )alkylamino-(NISS. )alkyl, N-(hydroxy(NISS. )alkyl) amino-(ness.)alkyl, N, N-di(hydroxy(NISS. )alkyl)amino-(NISS. )alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring, and their salts.

In particular, the invention relates to compounds of formula II in which R1and R5at the same time or independently of one another denote hydrogen, halogen or (NISS. )alkyl, R2and R4denote hydrogen, R3denotes the R6R7N-C(O)-(NISS. )alkyl, substituted aryl, substituted carboxyla or R8R9N-C(O)-, aryl(NISS. )alkyl, substituted N-(ness.)alkylamino-, N,N-di(ness.)alkylamino or pyrrolidino, or unsubstituted or substituted heteroalkyl, R6and R7at the same time or independently is hydroxy(NISS. )alkyl, amino(NISS. )alkyl, N-(ness.)alkylamino-(ness.)alkyl, N,N-di(NISS. )alkylamino-(NISS. )alkyl, N-(hydroxy(ness.)alkyl)amino-(ness.)alkyl, N,N-di(hydroxy(NISS. )alkyl)amino-(NISS. )alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring, R8and R9at the same time or independently of one another denote hydrogen or (ness.)alkyl or together with the nitrogen atom to which they are attached, form analiticheskoi ring, and their pharmaceutically acceptable salts.

The invention primarily relates to certain compounds of formula II and their salts, in particular their pharmaceutically acceptable salts, which are described in the examples.

Connections can be obtained by a well known method, for example

(a) the interaction of the compounds of formula III

< / BR>
in which R1, R2, R4and R5have the above meanings, and X-denotes an anion,

with the compound of the formula IV

R3-NH-NH2(IV)

in which R3has the above values,

or its salt or

b) the interaction of the compounds of formula V

< / BR>
in which R1, R4and R5have the above values,

or Sodeistvie the compounds of formula VI

< / BR>
in which R1, R2, R4and R5have the above values,

with the compound of the formula IV in which R3has the above significance, or its salt, and the subsequent conversion of this compound optionally in the compound of formula II by the removal of the protective groups and optionally converting it into another compound of formula II, and/or, if necessary, the transformation of the salt obtained into the free compound or into another salt, and/or if necessary transformation in Sol obtained free of compounds of formula II, which has the ability to form a salt.

Below method is described in more detail, the characters R1-R5have the meanings given for formula II, III, IV, V and VI, unless otherwise indicated.

Method (a). The reaction according to variant (a) corresponds to a rearrangement reaction ring 1,2,4-citiesalive in 1,2,4-triazole using hydrazines, which is well-known (G. Wagner and others, Pharmazie, 35, 48049 (1980)). X-can designate any desired ion, preferably the anion of halogen, in particular bromine anion. The reaction can be carried out using a solvent or without, preferably it is carried out in polar restorationa as MES, in particular in the form of a hydrate. The reaction is carried out under cooling, at ambient temperature or at elevated temperature up to the temperature of reflux distilled reaction mixture. Preferably the reaction is carried out at ambient temperature or at elevated temperature.

Method (b). The reaction according to variant (b) corresponds to the reaction benzoxazinones with hydrazines, which is well-known (G. Wagner and others, Z. hm. 21, 261 (1981), and Ryabukhin Y. and others, Khim. Geterotsiklicheskikh Soed. , 1983 (3), 406-410). The reaction is carried out in a polar solvent or solvent mixture, preferably in (ness.)alkanol, in particular methanol or ethanol, optionally with addition of a base such as tertiary amine, in particular three(ness.)alkylamino, if the compound III and/or IV is present in the form of a salt, for example in the form of halogenation. The reaction is carried out under cooling, at ambient temperature or at elevated temperature up to the temperature of reflux distilled reaction mixture. In a particularly preferred embodiment, the reaction is carried out at a temperature of reflux distilled ethanol.

The initial compounds of formula V can be obtained, for example, the interaction accordingly Brunetti N. and others, CH 388252, and Brunetti N. and C., Helv. Chim. Acta, 55, 1566 (1972)). In addition, the source compounds of formula V can be obtained by heating a mixture of appropriately substituted salicylanilide and appropriately substituted salicylamide.

Method (b). The reaction according to variant (b) corresponds to the reaction of diarylamino with hydrazines, which is well-known (A. Einhorn and others, Liebigs Ann. Chem., 343, 229 (1905), Brunner K., Ber. dtsch. chem. Ges. 47, 2671 (1914), and Mh. Chem., 36, 509 (1915)). The reaction is carried out in a polar, proton solvent using as a catalyst a weak acid, preferably in an aqueous solution of acetic acid at elevated temperature.

The compounds of formula II can also be obtained by using additional methods that are well known, for example by the methods described in Temple S. in The Chemistry of Heterocyclic Compouds, volume 37, John Wiley & Sons, New York, 1981.

Protective groups, their introduction and removal are described, for example, in J. F. W. McOmie, "Ptotective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, and in "Methods der organischen Chemie" [Methods of organic chemistry], Houben-Weyl, 4th ed., so 1571, Georg-Thieme-Verlag, Stuttgart, 1974, and in Theodora W. Greene, "Ptotective Groups in Organic Chemistry", John Wiley & Sons, New York, 1981. Feature protective groups is that they can be easily removed, so another option under physiological conditions.

Hydroxyl groups may be present, for example, in the form of easily degradable group complex or simple ester, preferably alkanoyloxy or arachnology group of ester or cyclogeraniol, aranceles or alkoxyalkyl group of simple ether, but also salelologa ether or silyl ester group, in particular in the form of acetylator or benzilovogo of ester or in the form of tetrahydropyranyl, benzyl or methoxymethyl simple ether.

The initial products of the compounds of formulas III, IV, V and VI are in some cases new and also fall under the scope of the present invention. If necessary, can be acceptable protective group or may be an additional derivatization according to known methods.

Protective groups that are not constituents of the desired end product of formula II, remove the well-known manner, for example by means of solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or through recovery, not necessarily sequential or simultaneous.

The compounds of formula II can also be converted into other compounds of formula II or of formula I.

So the ether arylcarbamoyl acid, obtaining the appropriate arylcarbamoyl acid, receiving the connection formula II in which R3denotes a residue of carboxylic acid. The reaction is carried out, for example, in a mixture of polar solvents of cyclic simple ether and alkanol with the addition of the hydroxide of an alkali metal.

When the starting compound of the formula I or any of the intermediate products contain interacting reactive group such as carboxyl, hydroxyl or amino groups, they can be temporarily protected by easily removable protective groups.

For the final processing of the compounds of formula II, which can be obtained, or their salts and, if necessary, intermediate products used conventional methods, for example, solvolysis of excess quantities of reagents, recrystallization, chromatography, such as distribution, ion or gel chromatography, the distribution between the inorganic and the organic phase solvents, single or multiple extraction, in particular, after acidification or increasing the basicity or increasing the salt content, drying over hygroscopic salts or at an elevated temperature by passing if necessary struti in vacuum or high vacuum), distillation, precipitation, centrifugation, crystallization, for example, compounds obtained in the form of oil or in the form of the mother liquor, it is also possible to obtain the final product with the help of the seed crystal, lyophilization, or a combination of two or more specified final stages of processing, which can also be reused, and so on

The source and intermediate products can be used in pure form, for example, after final processing, as indicated in the previous paragraph, in a partially purified form or in the form of a crude product.

The compounds, including their salts, can also be obtained in the form of a hydrate or solvate, or their crystals can include for example the solvent used for crystallization.

Solvents and diluents are, for example, water, alcohols, for example (ness.)the alkanols, such as methanol, ethanol, propanol, butanol or onomatology ether of ethylene glycol (methylcellosolve), diols such as ethylene glycol, tri - or polyols, such as glycerol or diethylene glycol, or akrilovye alcohols, such as phenol or benzyl alcohol, acid amides, such as carboxamide, such as N,N-the e esters, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or dimethyl ether of ethylene glycol, halogenated hydrocarbons, such as halogen(NISS. )alkanes, for example methylene chloride or chloroform, ketones, such as acetone, NITRILES, such as acetonitrile, esters such as ethyl acetate, balkanologie, such as dimethyl sulfoxide, nitrogen-containing heterocycles, such as N-organic or pyridine, hydrocarbons, for example (NISS. )alkanes, such as hexane or heptane, or aromatic hydrocarbons, such as benzene, toluene or xylene(s), or mixtures of these solvents, in each case for the above reactions and the final stages of processing can be selected from suitable solvents.

In the method according to the present invention is preferably in each case to use such source compounds or intermediates, in free form or in salt form, which allow to obtain the compounds of formula II or their salts mentioned in the beginning of the description as particularly valuable. New source materials and intermediates, in each case in free form or in salt form, prednaska scope of the invention.

The invention also relates to such variants of the method, in which a connection is received on any of the relevant stages of the process as an intermediate product, is used as the source of the product and spend the missing stage of the process, or in which the original substance get in the reaction conditions or is used in the form of a derivative, for example in the form of its salts.

Salts of compounds of formula II can be obtained by a well-known manner. Thus, the acid additive salts, for example, compounds of formula II are obtained by treatment of a suitable acid or a suitable ion exchange reagent, and salts accession grounds receive treatment suitable base or a suitable ion exchange reagent. Salts of compounds of formula II can be converted into the free compounds of formula II conventional method, the acid additive salts can be converted, for example, treatment with a suitable alkaline agent or a suitable ion exchange reagent, and salts joining bases can be converted, for example, treatment with a suitable acid or a suitable ion exchange reagent.

Salts of compounds of formula II can be converted into other salts of compounds to acid additive salt, for example, treatment with a salt of an inorganic acid such as hydrochloride, suitable metal salt, such as sodium, barium or silver salt of another acid, for example with silver acetate, in a suitable solvent in which the resulting inorganic salt, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.

Depending on the process or reaction conditions, the compounds of formula II with salt-forming properties can be obtained in free form or in the form of salts.

Due to the large similarities between the compound of formula II in free form and in the form of its salts, as described previously noted below, the free compound of the formula II or its salt should be regarded as similar and, if necessary, under these concepts, it is advisable to include also the corresponding salts or the free compound of the formula II.

The compounds of formula II, including salt compounds which can form salts, can also be obtained in the form of their hydrates and/or may include other solvents, for example, if necessary, the solvent used for the crystallization of compounds present in solid form.

Soedinenii in the form of one of the possible isomers, for example in the form of stereoisomers or tautomers or mixtures thereof. In this context, the obtained pure isomers are, for example, pure enantiomers, pure diastereoisomers or net tautomers. Accordingly, a mixture of isomers that may be present are, for example, racemates or diastereoisomeric mixture. Mixtures of isomers of compounds of formula II in free form or in salt form, obtained by the method according to the invention or in other ways, can be divided into components in the conventional manner, for example on the basis of the physicochemical differences of the constituents, known method fractionated crystallization, distillation and/or chromatography. It is preferable to select the most active isomer.

Below the invention is illustrated by way of examples, which, however, do not limit its scope. (Above and below used the following abbreviations: unless otherwise stated, h means hour(s), tPLdenotes melting point, DMSO-d6denotes hexacyanometallate.)

Example 1: 3,5-bis(2-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-[1,2,4]triazole.

12.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is suspended in 100 ml of methanol and treated with 7.6 g 2-g is rectally, deposited during this stage, filtered and washed with methanol/water. After drying remains listed in the title compound as colourless crystals, tPL145-147oC.

The initial connection can be obtained, for example, as follows.

a) 2-(2-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one

to 106.0 g salicylanilide and 93.0 g of salicylamide mixed and incubated at 170oC for 30 min to complete the termination of allocation of hydrogen chloride. The mixture is cooled and the residue crystallized from ethanol. After drying receive 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-one as yellowish crystals, tPL206-208oC.

Example 2: ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate.

51,5 g 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it, 30,5 ml of triethylamine and 33.4 g of the hydrochloride of acylhydrazines refluxed for 0.5 h in 450 ml of ethanol. When cooled, the precipitated product in crystalline form. It is filtered off and washed with ethanol. After drying remains ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate as colorless crystals, tPL172-174oC.

Example 3: 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-triptorelin)-1H-[1,2,4]T5 h with 1.6 ml of 2,2,2-cryptgetuserkey in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-triptorelin)-1H-[1,2,4]triazole as colorless crystals, tPL154-156oC.

Example 4: 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4]triazole.

1.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-she, 0.5 ml of triethylamine and 0.7 g of the hydrochloride of nitrophenylhydrazine refluxed for 1 h in 10 ml of ethanol. When cooled, the precipitated product in crystalline form. It is filtered off and washed with ethanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(4-nitrophenyl)-1H-[1,2,4] triazole as colorless crystals, tPL180-183oC.

Example 5: 4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]Betina acid.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-she and 3.5 g of 4-hydrazinobenzene acid is refluxed for 2 h in 75 ml of ethanol. The crystals precipitated upon cooling, is washed with ethanol. After drying remains 4-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] Betina acid in the form of bescot the folin-4-ylmethanol.

3.0 g of 4-[3,5-bis(2-hydroxyphenyl)[1,2,4]-triazole-1-yl]betinol acid (example 5) and 1.25 ml of 1-chloro-N,N,2-trimethyl-1-propen-1-amine [CAS-registration 26189-59-3] stirred for 2 h in 50 ml of tetrahydrofuran. Add 2.2 ml of triethylamine and 0.8 ml of the research and the mixture is stirred at room temperature for 18 hours It was poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains {4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]phenyl} morpholine-4-ylmethanol in the form of colorless crystals, tPL157-160oC.

Example 7: [4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]phenyl}(4-methylpiperazin-1-yl)methanon.

3 g of 4- [3,5-bis(2-hydroxyphenyl)[1,2,4]-triazole-1-yl]betinol acid (example 5) and 1.25 ml of 1-chloro-N,N,2-trimethyl-1-propen-1-amine is stirred for 2 h in 50 ml of tetrahydrofuran. Add 2.2 ml of triethylamine and 1 ml of N-methylpiperazine and the mixture is stirred at room temperature for 48 hours the mixture was poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopro the de colorless crystals, tPL226-229oC.

Example 8: 3,5-bis(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-[1,2,4]triazole.

5 g of 2-(2-hydroxyphenyl)benzo[e] [1,3] oxazin-4-it, 3.7 g of the hydrochloride of 4-methoxyphenylhydrazine and 3 ml of triethylamine is refluxed for 2 h in 75 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-[1,2,4]triazole as colorless crystals, tPL179-181oC.

Example 9: 3,5-bis(2-hydroxyphenyl)-1-(2,4-differenl)-1H-[1,2,4]triazole.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it, of 3.9 g of the hydrochloride of 2,4-dipohenhydramine and 3 ml of triethylamine is refluxed for 2 h in 25 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(2,4-differenl)-1H-[1,2,4]triazole as colorless crystals, tPL144-146oC.

P is refluxed for 4 h with 3.4 g of the hydrochloride of benzylpiperazine and 5.9 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-benzyl-1H-[1,2,4]triazole as colorless crystals, tPL166-168oC.

Example 11: 4-[3,5-bis(2-hydroxyphenyl[1,2,4]triazole-1-ylmethyl]benzonitrile.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it, of 3.9 g of the hydrochloride of 4-lebensunwerten and 6 ml of triethylamine is refluxed for 3 h with 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethanol/water. After drying remains 4-[3,5-bis(2-hydroxyphenyl[1,2,4]triazole-1-ylmethyl]benzonitrile in the form of colorless crystals, tPL147-149oC.

Example 12: 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminophenyl)-1H-[1,2,4] triazole.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is refluxed for 18 h from 5.4 g of the hydrochloride of 4-diethylaminobenzylidene and 6.7 ml of triethylamine in 50 ml of ethanol. The mixture is poured NAT on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminophenyl)-1H-[1,2,4]triazole as colorless crystals, tPL125-127oC.

Example 13: 3,5-bis(2-hydroxyphenyl)-1-(4-pyrrolidin-1-ylbenzyl)-1H-[1,2,4]triazole.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is refluxed for 18 h with 5.2 g of hydrochloride (4-pyrrolidin-1-ylbenzyl)of hydrazine and 6.7 ml of triethylamine in 50 ml of ethanol. The mixture was poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethyl acetate/hexane. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(4-pyrrolidin-1-ylbenzyl)-1H-[1,2,4] triazole as colorless crystals, tPL153 to 155oC.

The original product can be obtained, for example, as follows.

a) Hydrochloride (4-pyrrolidin-1-ylbenzyl)of hydrazine

7.0 g of 4-pyrrolidinecarboxamido and 5.3 g of tert-BUTYLCARBAMATE refluxed for 5 h in 50 ml of ethanol. The mixture is cooled, diluted with ethanol, 250 ml, add 1.0 g of palladium on coal (10%) and the mixture hydronaut to the absorption of 1 mole of hydrogen per 1 mol of the original products the t in 90 ml of a mixture of 4 M hydrogen chloride/dioxane and allowed to stand at room temperature for 20 hours After freeze-drying receive hydrochloride (4-pyrrolidin-1-ylbenzyl)of hydrazine in the form of a solid yellow color. MS: 192 (M++H).

Example 14: 3,5-bis(2-hydroxyphenyl)-1-(pyridine-4-ylmethyl)-1H-[1,2,4] triazole.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is refluxed for 4 h with 5.9 g of the hydrochloride of 4-hydrazinopyridazine [reg. CAS number 89598-56-1] and 10 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 3,5-bis(2-hydroxyphenyl)-1-(pyridine-4-ylmethyl)-1H-[1,2,4] triazole as colorless crystals, tPL197-199oC.

Example 15: 3,5-bis(2-hydroxyphenyl)-1-(pyridine-3-ylmethyl)-1H-[1,2,4] triazole.

5.0 g of 2-(2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is refluxed for 5 h with 6.2 g of the hydrochloride of 3-hydrazinopyridazine (57616-01-0) and 13 ml of triethylamine in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The remainder Krista colorless crystals, tPL174-176oC.

Example 16: 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-[1,2,4] triazole.

15.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benzo[e] [1,3]oxazin-4-it is refluxed for 2 h with 4 ml of hydroxyethylhydrazine in 50 ml of ethanol. The crystals precipitated upon cooling, crystallized from a mixture of ethanol/water. After drying remains 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(2-hydroxyethyl)-1H-[1,2,4]triazole as colorless crystals, tPL166-170oC.

The original product can be obtained, for example, as follows.

a) 6-Chloro-2-(5-chloro-2-hydroxyphenyl)benzo[e][1,3]oxazin-4-one

40,0 g 5-chlorosalicylic and of 54.0 g of 5-chlorosalicylic acid after adding 2.5 ml of pyridine is refluxed in 400 ml of xylene. Within 2 h add 38 ml of thionyl chloride, the mixture is stirred for 1 h and then the solvent is distilled off under reduced pressure. The residue is suspended in 200 ml of ethanol, filtered and washed with ethanol. After drying receive 6-chloro-2-(5-chloro-2-hydroxyphenyl)benzo[e] [1,3] oxazin-4-one as yellowish crystals, tPL246-248oC.

Example 17: 4-[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoic acid.

PL275-278oC.

Example 18: 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridine-2-ylmethyl)-1H-[1,2,4]triazole.

3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benzo[e][1,3]oxazin-4-it is refluxed for 5 h with 1.7 g of the hydrochloride of 2-hydrazinopyridazine and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitated upon cooling, crystallized from ethanol. After drying remains 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridine-2-ylmethyl)-1H-[1,2,4] triazole as colorless crystals, tPL227-229oC.

Example 19: 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzoyl)-1H-[1,2,4]triazole.

3.0 g of 6-chloro-2-(5-chloro-2-hydroxyphenyl)benzo[e][1,3]oxazin-4-it is refluxed for 4 h with 2.2 g of the hydrochloride of 4-dimethylaminopyridine and 3 ml of triethylamine in 50 ml of ethanol. The crystals precipitated upon cooling, is washed with ethanol. After drying remains 3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzoyl)-1H-[1,2,4] triazole as colorless crystals, tPL205-207oC.

The use of the Nile)benzo[e][1,3]oxazin-4-she and 1.6 g of 4-hydrazinobenzene acid is refluxed for 3 h in 25 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethyl acetate/hexane. After drying remains 4-[3,5-bis(5-fluoro-2-hydroxyphenyl)[1,2,4] triazole-1-yl]benzoic acid as colourless crystals, tPL252-255oC.

The original product can be obtained, for example, as follows.

a) 6-fluoro-2-(5-fluoro-2-hydroxyphenyl)benzo[e][1,3]oxazin-4-one

4.3 g of 5-fortaleciendo and 4.7 g of 5-floralicious acid after adding 0.3 ml of pyridine is refluxed in 50 ml of xylene. Within 2 hours added to 4.4 ml of thionyl chloride, the mixture is stirred for 1 h and then the solvent is distilled off under reduced pressure. The residue is suspended in 30 ml of ethanol, filtered and washed with ethanol. After drying receive 6-fluoro-2-(5-fluoro-2-hydroxyphenyl)benzo[e] [1,3] oxazin-4-one as yellowish crystals, tPL250-252oC.

Example 21: 4-[3,5-bis(2-hydroxy-5-were)[1,2,4]triazole-1-yl]benzoic acid.

of 1.15 g of 2-(6-hydroxy-meta-tolyl)-6-methyl-4H-[1,3] benzoxazin-4-[CAS registration number 24789-62-7] and 0.6 g of 4-hydrazinobenzene sour allsouth from isopropanol. After drying remains 4-[3,5-bis(2-hydroxy-5-were)[1,2,4]triazole-1 - yl]benzoic acid as colourless crystals, tPL268-269oC.

Example 22: [3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]acetic acid.

0.6 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) was dissolved in 20 ml of methanol with 0.4 g of sodium hydroxide and the mixture is stirred at room temperature for 2 hours It is acidified with 0.1 G. of hydrochloric acid and saducees the crystals are filtered. After washing with water and drying remains [3,5-bis(2-hydroxyphenyl) [1,2,4]triazole-1-yl]acetic acid as colorless crystals, tPL231-233oC.

Example 23: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-methylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]acetate (example 2) is dissolved in 15 ml of ethanol and treated with 0.8 ml of 8 M methylamine in ethanol. The mixture was stirred at 60oC for 3 h and then cooled. The crystals precipitated upon cooling, is filtered off and washed with ethanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-methylacetamide in the form of colorless crystals, tPL247-249oC.

Example 24: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-and oraut in 10 ml of ethanolamine and stirred at room temperature for 2 hours The mixture is concentrated to dryness in vacuo and the residue crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl] -N-(2-hydroxyethyl)ndimethylacetamide in the form of colorless crystals, tPL208-211oC.

Example 25: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2-methoxyethyl) ndimethylacetamide.

4.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) are dissolved in 30 ml of 2-methoxyethylamine and stirred at room temperature for 2 hours the Mixture is concentrated to dryness in vacuo and the residue crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-methoxyethyl)ndimethylacetamide in the form of colorless crystals, tPL184-186oC.

Example 26: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2,3-dihydroxypropyl)ndimethylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 2.4 g (the)-3-amino-1,2-propane diol incubated in 10 ml of ethanol at 60oC for 2 hours, the Crystals precipitated upon cooling, is filtered off and washed with ethanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-N-(2,3-dihydroxypropyl)ndimethylacetamide in the form of colorless crystals, tPL180-181oC.

Example 27: 2-[3,5-Bistrita-1-yl]acetate (example 2) and 2.9 ml of 4-(2-amino-ethyl)research refluxed for 18 h in 50 ml of tetrahydrofuran. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl] -N-(2-morpholine-4-retil)ndimethylacetamide in the form of colorless crystals, tPL180-182oC.

Example 28: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-N-(2-hydroxyethyl) -N-methylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 8 ml of N-methylethanolamine incubated at 60oC for 1 h the Mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-N-(2-hydroxyethyl)-N-methylacetamide in the form of colorless crystals, tPL101-104oC.

Example 29: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-N-[2-(2-hydroxyethoxy)ethyl]ndimethylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 10 ml of 2-(2-aminoethoxy)of ethanol was stirred at room temperature for 2 hours the Mixture drain irout on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-[2-(2-hydroxyethoxy)ethyl] ndimethylacetamide in the form of colorless crystals, tPL173-174oC.

Example 30: N-{2-[bis(2-hydroxyethyl)amino]ethyl}-2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]ndimethylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 1.0 g of N,N-bis(2-hydroxyethyl)Ethylenediamine refluxed for 24 h in 8 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The remainder chromatographic on silica gel. After concentration and drying remains N-{2-[bis(2-hydroxyethyl)amino] ethyl} -2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]ndimethylacetamide in the form of a colorless foam. The value of Rfof 0.35 (silica gel 60, methylene chloride/methanol in a ratio of 9/1).

1H-NMR (DMSO-d6): 2,5 (m, 6H), 3,1 (m, 2H), 3,4 (m, 4H), 4.2V (bs, 2H), 4,9 (s, 2H), 7,0 (m, 4H), to 7.4 (m, 3H), 7,95 (d, 1H), 8,1 (t, 1H), 11,0 hours /million (s, 1H).

Example 31: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2-hydroxy-1-hydroxymethylation)ndimethylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and the I when cooled, recrystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2-hydroxy-1-hydroxymethylation)ndimethylacetamide in the form of colorless crystals, tPL212-214oC.

Example 32: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]ndimethylacetamide.

3.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 2.5 g of 2-(4-methylpiperazin-1-yl)ethylamine refluxed for 20 h in 40 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The remainder chromatographic on silica gel. After concentration and drying receive 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-N-[2-(4-methylpiperazin-1-yl)ethyl]ndimethylacetamide in the form of a colorless foam. The value of Rfto 0.17 (silica gel 60, methylene chloride/methanol in a ratio of 9/1).

1H-NMR (DMSO-d6): 2,1 (s, 3H), 2,3 (m, 10H), 3.15 in (m, 2H), 4,9 (s, 2H), 7,0 (m, 4H), to 7.4 (m, 3H), 8,0 (m, 2H), 11,0 hours/million (s, 1H).

Example 33: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N,N-dimethylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) is dissolved in 15 ml ethanol solution Dima is kristallisoituu from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N,N-dimethylacetamide in the form of colorless crystals, tPL196-197oC.

Example 34: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]morpholine-4-ylatason.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 8 ml of the research is refluxed for 1 h the Mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethyl acetate/hexane. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] morpholine-4-ylatason in the form of colorless crystals, tPL149-151oC.

Example 35: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-1-(4-methylpiperazin-1-yl)Etalon.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 8 ml of 1-methylpiperazine stirred at 80oC for 3 hours the Mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from ethanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -1-(4-methyl which is(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-methylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 9 ml of N-methylbenzylamine stirred at 80oC for 16 hours the Mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethanol/water. After drying remains N-benzyl-2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-methylacetamide in the form of colorless crystals, tPL179-180oC.

Example 37: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N,N-bis(2-hydroxyethyl)ndimethylacetamide.

2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 6.5 g of diethanolamine refluxed for 2 h in 5 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The remainder chromatographic on silica gel. After concentration and drying receive 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N, N-bis(2-hydroxyethyl)ndimethylacetamide in the form of a colorless foam. The value of Rfof 0.28 (silica gel 60, methylene chloride/methanol in a ratio of 9/1).

1H-NMR (DMSO-d6): 3,2-3,6 (m, 8H), 4,4-5,1 (b, 2H), 5-1-yl]-N-(2-dimethylaminoethyl)-N-methylacetamide.

2.0 g of ethyl[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate (example 2) and 9 ml of N,N,N'-trimethylethylenediamine stirred at 80oC for 5 hours the Mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-dimethylaminoethyl)-N-methylacetamide in the form of colorless crystals, tPL172-174oC.

Example 39: 2-[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2-morpholine-4-retil)ndimethylacetamide.

4.0 g of ethyl[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4] triazole-1-yl]acetate (example 40) and 2.6 g of 4-(2-amino-ethyl)research refluxed for 18 h in 50 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from isopropanol. After drying remains 2-[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-morpholine-4-retil)ndimethylacetamide in the form of colorless crystals, tPL224-226oC.

Example 40 Ethyl[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4]triazole-1-yl]acetate.

PL195-200oC.

Example 41: 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoic acid.

4.8 g of 2-(2-hydroxyphenyl)benzo[e] [1,3] oxazin-4-she and 3.5 g of 2-hydrazinobenzene acid is refluxed for 4 h in 10 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from a mixture of ethyl acetate/hexane. After drying receive 2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoic acid as colourless crystals, tPL132-138oC.

Example 42 Ethyl-4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoate.

10 g of 4-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]benzoic acid (example 5) and 0.5 ml of sulfuric acid is refluxed for 20 h in 200 ml of ethanol. The crystals precipitated upon cooling, crystallized from a mixture of isopropanol/water. After drying receive ethyl-4-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] pharmaceutical compositions.

Below the term "active ingredient" refers to the compound of formula I in free form or in the form of a pharmaceutically priemlemoj salts, in particular the connection of the type described in the quality of the product in the above examples.

Example A. Tablets, each containing 200 mg of active substance, can be obtained as follows.

Composition (10000 tablets), g:

Active substance - 2000,0

Lactose - 500,0

Potato starch - 352,0

Gelatin - 8,0

Talc - 60,0

Magnesium stearate - 10,0

Silicic acid (superfine) - 20,0

Ethanol - q.s.

The active substance is mixed with the lactose and 292 g of potato starch, the mixture is moistened ethanol solution of gelatin and granularit through a sieve. After drying, mix the remainder of the potato starch, magnesium stearate, talc and silicic acid and the mixture tabletirujut, getting pills weight 295,0 g each, containing 200 mg of active ingredient and, if necessary, may be provided with notches for breaking with the purpose of more accurate dose adjustment.

Example b coated Tablets, each containing 400 mg of the active substance, can be obtained following the initial starch - 70,0

Talc - 8,5

Calcium stearate and 1.5

The hypromellose - 2,36

Shellac - 0,64

Water - q.s.

Dichloromethane - q.s.

The active substance is mixed with the lactose and 40 g of corn starch to moisturize and granularit with the paste obtained from 15 g of corn starch and water (with heating). The granules are dried and add the remainder of the corn starch, the talc and calcium stearate and mixed with the granules. The mixture tabletirujut getting tablets that are coated with hypromellose and shellac in dichloromethane. The final weight of the coated tablets is 583,

Example Cent. Gelatine capsules with a hard coating containing 500 mg of the active substance, can be obtained, for example, as follows.

Composition (1000 capsules), g:

Active substance - 500,0

Lactose - 250,0

Microcrystalline cellulose - 30,0

Sodium dodecyl sulfate - 2,0

Magnesium stearate - 8,0

Sodium lauryl sulfate sieved by liofilizirovannoe active substance through a sieve with a mesh size of 0.2 mm Both components are mixed until homogeneous. Then first sieved lactose through a sieve with a width of 0.6 mm, and then microcrystallinecellulose state within 10 minutes In conclusion, the stearate is sifted through a sieve with a mesh size of 0.8 mm After 3 minutes of additional mixing 790 mg of the obtained composition is filled gelatin capsules of appropriate size with a hard surface.

Example, Suspendiruemye powder for oral administration, containing 300 mg of the active substance may be obtained, for example, as follows.

The composition (1 introduction):

The active ingredient, g - 300,0

Hydroxypropylcellulose (Klucel HF), mg - 50

Tartaric acid, mg - 100

Sodium lauryl sulfate, mg - 100

Sodium lauryl sulfate sieved by liofilizirovannoe active substance through a sieve with a mesh size of 0.2 mm Both components are mixed until homogeneous. Then the microcrystalline cellulose is sifted through a sieve with a mesh size of 0.9 mm After that the ingredients mix again until smooth within 10 minutes At the end tartaric acid sieved through a sieve with a mesh size of 0.8 mm After 3 minutes of additional mixing a mixture fill the container with a capacity of at least 10 ml For use, the mixture is diluted with water to 10 ml and strongly shaken.

1. Pharmaceutical composition for treatment of owley them, containing at least one compound of the formula I

< / BR>
in which R1and R5at the same time or independently of one another denote hydrogen, halogen, hydroxyl, C1-C4alkyl, Gialos1-C4alkyl, C1-C4alkoxy, Gialos1-C4alkoxy, carboxyl, carbarnoyl, N-C1-C4allylcarbamate, N, N-di-C1-C4allylcarbamate or nitrile;

R2and R4at the same time or independently of one another denote hydrogen, C1-C4alkanoyl, benzoyl, toluoyl, naphtol or para-methoxybenzoyl, or a radical that can be removed in a physiological environment;

R3denotes hydrogen, C1-C4alkyl, hydroxys1-C4alkyl, Gialos1-C4alkyl, carboxy1-C4alkyl, C1-C4alkoxycarbonyl1-C4alkyl, R6R7N-C(O)-C1-C4alkyl, phenyl, unsubstituted or substituted by carboxyla, nitrogroup, halogen, C1-C4alkoxygroup,1-C4alkoxycarbonyl or group R8R9N-C(O)-, panels1-C4alkyl, a pair of chlorbenzyl, ortho-tormentil, para-trimethyl, a pair of p1-C4acylaminoalkyl, para-cyano what the Rupp; R6and R7at the same time or independently of one another denote hydrogen, C1-C4alkyl, hydroxys1-C4alkyl, alkoxyl1-C4alkyl, hydroxyalkoxy1-C4alkyl, amino1-C4alkyl, N-C1-C4alkylamino1-C4alkyl, N,N-dis1-C4alkylamino1-C4alkyl,

N-(hydraxis1-C4alkyl)amino1-C4alkyl, N,N-di(hydraxis1-C4alkyl)amino1-C4alkyl, benzyl, 4-morpholinylmethyl, (4-methyl-1-piperazinil)ethyl or together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine; R8and R9together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine,

or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.

2. Derivatives of 3,5-diphenyl-1,2,4-triazoles of the formula II

< / BR>
in which R1and R5at the same time or independently of one another denote hydrogen, halogen or1-C4alkyl;

R2and R4at the same time or independently of one another denote hydrogen or a radical that can be removed physiologists in the Silom or group R8R9N-C(O)-, para-dis1-C4acylaminoalkyl, para-pyrrolidines or pyridyl, unsubstituted or linked via C1-C4alkylenes group; R6and R7at the same time or independently of one another denote hydrogen, C1-C4alkyl, hydroxys1-C4alkyl, alkoxyl1-C4alkyl, hydroxyalkoxy1-C4alkyl, N,N-dis1-C4alkylamino1-C4alkyl, N, N-di(hydraxis1-C4alkyl)amino1-C4alkyl, benzyl, 4-morpholinylmethyl, (4-methyl-1-piperazinil)ethyl or together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine; R8and R9together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine,

and its salts.

3. The compound of formula II under item 2, in which R1and R5at the same time or independently of one another denote hydrogen, halogen or1-C4alkyl; R2and R4denote hydrogen; R3denotes the R6R7N-C(O)-C1-C4alkyl, phenyl, substituted carboxyla or R8R9N-C(O)-, para-dimethylaminobenzoyl, para-diethylaminomethyl, para-pyrrolidines or perigee independently of one another denote hydrogen, WITH1-C4alkyl, hydroxys1-C4alkyl, alkoxyl1-C4alkyl, hydroxyalkoxy1-C4alkyl, N,N-dis1-C4alkylamino1-C4alkyl, N,N-di(hydraxis1-C4alkyl)amino1-C4alkyl, benzyl, 4-morpholinylmethyl, (4-methyl-1-piperazinil)ethyl or together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine; R8and R9together with the nitrogen atom to which they are attached, form morpholino - or 4-methylpiperazine,

and its pharmaceutically acceptable salts.

4. A compound selected from the group including

{ 4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]phenyl}(4-methylpiperazin-1-yl)methanon,

{ 4-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]phenyl}morpholine-4-ylmethanone,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]-1-(4-methylpiperazin-1-yl)Etalon,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-1-morpholine-4-ylatason,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N, N-bis(2-hydroxyethyl)acetamide", she

2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N,N-dimethylacetamide,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2,3-dihydroxypropyl)ndimethylacetamide,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-dimethylene the ID,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-hydroxyethyl)acetamide", she

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-hydroxyethyl)-N-methylacetamide,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-(2-methoxyethyl)ndimethylacetamide,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-morpholine-4-retil)ndimethylacetamide,

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-[2-(2-hydroxyethoxy)ethyl]acetamide", she

2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-[2-(4-methylpiperazin-1-yl)ethyl]acetamide", she

2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]-N-methylacetamide,

2-[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-(2-morpholine-4-retil)ndimethylacetamide,

3,5-bis(2-hydroxyphenyl)-1-(4-diethylaminophenyl)-1H-[1,2,4]triazole,

3,5-bis(2-hydroxyphenyl)-1-(4-pyrrolidin-1-ylbenzyl)-1H-[1,2,4]triazole,

3,5-bis(2-hydroxyphenyl)-1-(pyridine-3-ylmethyl)-1H-[1,2,4]triazole,

3,5-bis(2-hydroxyphenyl)-1-(pyridine-4-ylmethyl)-1H-[1,2,4]triazole,

3,5-bis(5-chloro-2-hydroxyphenyl)-1-(4-dimethylaminobenzoyl)-1H-[1,2,4] triazole,

3,5-bis(5-chloro-2-hydroxyphenyl)-1-(pyridine-2-ylmethyl)-1H-[1,2,4]triazole,

4-[3,5-bis(2-hydroxy-5-were)[1,2,4] triazole-1-yl] benzoic acid

2-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoic acid

4-[3,5-bis(5-chloro-2-hydroxyphenyl)[1,2,4]triazole-1-yl]beetel)amino] ethyl}-2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl]acetamide", she

N-benzyl-2-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] -N-methylacetamide,

4-[3,5-bis(2-hydroxyphenyl)[1,2,4]triazole-1-yl]benzoic acid

and their pharmaceutically acceptable salts.

5. The compound of formula II under item 2, a 4-[3,5-bis(2-hydroxyphenyl)[1,2,4] triazole-1-yl] benzoic acid or its pharmaceutically acceptable salt.

6. Pharmaceutical composition for the treatment of diseases which cause an excess of iron in the human or animal, or which is due to them containing at least one compound according to any one of paragraphs. 2-5 or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.

7. The compound according to any one of paragraphs.2-5, intended for the treatment of diseases which cause an excess of iron in the human or animal, or which is due to them.

 

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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 new carboxyterminal cyclic carboxamide derivative of formula 1

< / BR>
where G1- CH2; G2- C(O); m = 2 or 3, n is 0 or 1; R1is 1-3 substituent, independently selected from H, G, C1-C6alkoxy; R2is 1-3 substituent, independently selected from H, C1-C6alkoxy; R3means N or

< / BR>
< / BR>
< / BR>
R4- H; Ar1means

< / BR>
< / BR>
R8means 1-3 substituent, independently selected from H, G; R9means N;

And means

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3, or 4; X is-O-, -CH2-; R10-H, C1-C6alkyl or

< / BR>
">< / BR>
< / BR>
< / BR>
where q = 2 or 3; R5- C1-C4alkyl, (CH2)2HE; R6- C1-C4alkyl, -(CH2)2HE, (CH2)2N(CH3)2; R5', R6' - C1-C4alkyl; R7- C1-C6alkyl, and the stereoisomers and pharmaceutically acceptable salts

The invention relates to new derivatives of pyrrolidine or piperidine F.-ly (I), their enantiomers and pharmaceutically acceptable salts

< / BR>
where R10- H or C(O)N(R1)YZ, R1- N, Y - (CH2)p, (CH2)qCH(R3) or CH(R3)(CH2)q, R3- aryl, aralkyl or heteroaryl, q = 1-3, p = 2 or 3, Z - CO2H, CO2-alkyl or 5-tetrazol, X-S(O) M-(CH2)nor piperidine-1-yl, m = 2, n = 2, R5Mr. And selected from piperidine-2-yl, piperidine-3-yl, piperidine-4-yl or N-substituted piperidine

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to pharmaceutical compositions containing two or more compounds having anti-HIV activity

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

The invention relates to aryl - and getelemen carboalkoxylation acids of formula 1

< / BR>
where R1selected from the group of arrow or getarrow, R2selected from the group of Akilov

The invention relates to medicine, specifically to pharmaceutical technology, namely the method of production of drugs having antifungal activity of fluconazole

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The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen
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